faculty of medicine university of ottawa epi 7999: thesis title · 2017-01-31 · faculty of...

FacultyofMedicineUniversityofOttawa

EPI7999:Thesis

Title:

ThePharmacologicProphylaxisofPediatricMigraine:ASystematicReview,SurveyandDesignofaRandomizedControlledTrial

(AthesissubmittedinpartialfulfillmentoftherequirementsforthedegreeofMScEpidemiology)

By:

SerenaOrr,MD,MScCandidate

ThesisAdvisoryCommittee:DarDowlatshahi,MD,PhD,FRCPC(ThesisSupervisor)

TimothyRamsay,PhD(ThesisCo-Supervisor)SuzanneN.Christie,MD,FRCPC(ContentExpert)

Preparedfor:TheGraduateStudiesCommittee

DegreeSought:MScEpidemiology

©SerenaOrr,Ottawa,Canada,2016

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TableofContents

TABLEOFCONTENTS....................................................................................................................IILISTOFTABLES.............................................................................................................................VILISTOFFIGURES...........................................................................................................................VILEGEND.............................................................................................................................................VIENGLISHTHESISABSTRACT...................................................................................................VIIIFRENCHTHESISABSTRACT.......................................................................................................IXACKNOWLEDGEMENTS.................................................................................................................XTHESISPARTI:SYSTEMATICREVIEW.....................................................................................11. BACKGROUND............................................................................................................................................11.1. Theprevalenceandimpactofpediatricmigraine.............................................................11.2. Thepathophysiologyofmigraine..............................................................................................11.3. Generalapproachtothetreatmentofpediatricmigraine.............................................31.4. Educationandlifestylechangesforthemanagementofpediatricmigraine........31.5. Psychologicalinterventionsforpediatricmigraine..........................................................41.6. Complimentaryandalternativemedicineforpediatricmigraine..............................51.7. Nutraceuticalsforpediatricmigraine.....................................................................................71.7.1. Butterbur....................................................................................................................................................................71.7.2. Riboflavin...................................................................................................................................................................71.7.3. Magnesium................................................................................................................................................................81.7.4. CoenzymeQ10...........................................................................................................................................................81.7.5. FishOils.......................................................................................................................................................................81.7.6. L-5-Hydroxytryptophan......................................................................................................................................81.7.7. CombinationTherapies........................................................................................................................................8

1.8. PharmaceuticalsforPediatricMigraine................................................................................91.8.1. AntiepilepticMedications...................................................................................................................................91.8.2. Calcium-ChannelBlockersandBeta-Blockers.........................................................................................111.8.3. Antidepressants....................................................................................................................................................121.8.4. Antiemetics..............................................................................................................................................................131.8.5. Others........................................................................................................................................................................13

1.9. Conclusions.......................................................................................................................................142. METHODS.............................................................................................................................................152.1. Objectives..........................................................................................................................................152.2. StudyDesign.....................................................................................................................................152.3. CriteriaforConsideringStudiesforthisReview..............................................................162.3.1 TypesofStudies.....................................................................................................................................................162.3.2 TypesofParticipants...........................................................................................................................................162.3.3. TypesofInterventions.......................................................................................................................................172.3.4 TypesofComparisons.........................................................................................................................................182.3.5 TypesofOutcomes................................................................................................................................................182.3.6 LanguageofStudies..............................................................................................................................................18

2.4. SearchMethodsforIdentificationofStudies.....................................................................192.5. ScreeningProcess..........................................................................................................................202.5.1 FirstScreenMethodology..................................................................................................................................202.5.2 SecondScreenMethodology.............................................................................................................................21

2.6. DataExtraction..............................................................................................................................222.7. Meta-Analyses.................................................................................................................................23

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3. RESULTS...............................................................................................................................................253.1. CharacteristicsofIncludedStudies........................................................................................253.2. NutraceuticalInterventions......................................................................................................343.2.1 Butterbur(Petasiteshybridus).......................................................................................................................343.2.2 Riboflavin(VitaminB2).......................................................................................................................................36

3.3. Pharmaceuticals............................................................................................................................383.3.1 Topiramate...............................................................................................................................................................383.3.2 ValproicAcid............................................................................................................................................................433.3.3. Flunarizine...............................................................................................................................................................443.3.4 Timolol.......................................................................................................................................................................473.3.5 Clonidine....................................................................................................................................................................483.3.6 Trazodone.................................................................................................................................................................503.3.7 Nimodipine...............................................................................................................................................................513.3.8 Cinnarizine...............................................................................................................................................................523.3.9 Dimethothiazine.....................................................................................................................................................533.3.10 Papaverine.............................................................................................................................................................54

3.4. UnpublishedTrials........................................................................................................................553.5. Meta-Analyses.................................................................................................................................553.5.1 Riboflavinvs.Placebo..........................................................................................................................................553.5.2 Topiramatevs.Placebo.......................................................................................................................................563.5.3 Flunarizinevs.Placebo........................................................................................................................................583.5.4 OtherInterventions..............................................................................................................................................58

4. DISCUSSION.........................................................................................................................................58THESISPARTII:SURVEYONNON-INFERIORITYMARGINSFORMIGRAINETRIALS:

DETERMININGANON-INFERIORITYMARGINFORMIGRAINETRIALS:THENON-INFERIORITYMARGINSINMIGRAINERESEARCH(NIMM)SURVEY...................................61

1. BACKGROUND.........................................................................................................................................612. OBJECTIVES.............................................................................................................................................652.1. Primaryobjectives.........................................................................................................................652.2. Secondaryobjectives....................................................................................................................65

3. METHODS................................................................................................................................................663.1. StudyDesign&Protocol.............................................................................................................663.2. Inclusion&ExclusionCriteria..................................................................................................683.2.1 InclusionCriteria...................................................................................................................................................683.2.2 ExclusionCriteria..................................................................................................................................................68

3.3. Statistics.............................................................................................................................................684. HUMANPROTECTION............................................................................................................................684.1. TimeCommitment.........................................................................................................................684.2. RisksInvolvedinParticipatingintheStudy......................................................................684.3. BenefitsAssociatedwithParticipatingintheStudy......................................................69

5. RESULTS..................................................................................................................................................696. DISCUSSION.............................................................................................................................................74

THESISPARTIII:DESIGNOFARANDOMIZEDCONTROLLEDTRIAL...........................771. BACKGROUND....................................................................................................................................772. METHODS.............................................................................................................................................812.1. StudyObjectives..............................................................................................................................812.1.1. PrimaryObjective.................................................................................................................................................812.1.2 SecondaryObjectives...........................................................................................................................................81

2.2. StudyDesign.....................................................................................................................................822.3. EligibilityCriteria..........................................................................................................................832.3.1 InclusionCriteria...................................................................................................................................................832.3.2 ExclusionCriteria..................................................................................................................................................84

2.4. Interventions....................................................................................................................................86

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2.5. Outcomes...........................................................................................................................................882.6. Randomization................................................................................................................................912.7. StudyVisits........................................................................................................................................92

3. PROTECTINGAGAINSTSOURCESOFBIAS.........................................................................................933.1. SelectionBias...................................................................................................................................933.2. PerformanceBias...........................................................................................................................933.3. AttritionBias...................................................................................................................................933.4. DetectionBias.................................................................................................................................94

4. STATISTICS..........................................................................................................................................944.1. SampleSizeCalculations............................................................................................................944.2. PlannedStatisticalAnalyses.....................................................................................................964.2.1 PrimaryHypotheses.............................................................................................................................................964.2.2 PrimaryOutcomeAnalysisPlan......................................................................................................................974.2.3 SecondaryOutcomeAnalysisPlan.................................................................................................................974.2.4 DealingwithMissingDataandApproachtoDataAnalysis.................................................................984.2.5 InterimDataAnalyses.........................................................................................................................................98

5. TRIALMANAGEMENTISSUES.....................................................................................................995.1. RecruitmentProcess.....................................................................................................................995.1.1 RecruitmentTargets............................................................................................................................................995.1.2 StrategiestoMaximizeRecruitmentandFollow-Up..........................................................................100

6. PERSONNELANDROLES.............................................................................................................1016.1. StudyPersonnel...........................................................................................................................1016.1.1 SiteResearchCoordinators............................................................................................................................1016.1.2 SiteInvestigators................................................................................................................................................1026.1.3 SiteResearchPharmacists..............................................................................................................................1036.1.4 LeadSiteResearchCoordinator...................................................................................................................1036.1.5 LeadSitePrincipalInvestigator...................................................................................................................1036.1.6 LeadSiteResearchPharmacists...................................................................................................................1046.1.7 LeadSiteBiostatistician...................................................................................................................................104

6.2. DataandSafetyMonitoringBoard.....................................................................................1046.3. TrialSteeringCommittee........................................................................................................105

7. ETHICALCONSIDERATIONS......................................................................................................1057.1. ClinicalEquipoiseRegardingLevetiracetamforPediatricMigraineProphylaxis

1057.2. InformedConsent........................................................................................................................1067.3. SpecialConsiderationsinthePediatricPopulation....................................................1077.4. PrivacyandConfidentiality....................................................................................................107

REFERENCES................................................................................................................................109THESISAPPENDIX......................................................................................................................1208. APPENDIXA.ELECTRONICSEARCHSTRATEGIESFORIDENTIFICATIONOFSTUDIES...............1209. APPENDIXB.SYSTEMATICREVIEWINCLUDEDSTUDIESELIGIBILITYFORMS.........................12310. APPENDIXC.SYSTEMATICREVIEWINCLUDEDSTUDIES‘CHARACTERISTICSOFSTUDIES’

TABLES 14211. APPENDIXD.SYSTEMATICREVIEWINCLUDEDSTUDIES‘RISKOFBIASASSESSMENT’TABLES

16412. APPENDIXE.EMAILINVITATIONTOPOTENTIALPARTICIPANTS............................................18613. APPENDIXG.NON-INFERIORITYMARGINSINMIGRAINERESEARCH(NIMM)SURVEY....18814. APPENDIXH.NIMMRESPONSESIN“OTHER”CATEGORY.......................................................19315. APPENDIXI.RCTELIGIBILITYCRITERIARATIONALE...............................................................19616. APPENDIXJ.RCTHEADACHEDIARYTEMPLATE.......................................................................19817. APPENDIXK.PEDMIDASQUESTIONNAIRE................................................................................200

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18. APPENDIXL.TRIALINFORMEDCONSENTFORMFORPARENTSANDPARTICIPANTSAGED16ANDOVER........................................................................................................................................................201

19. APPENDIXM.TRIALASSENTFORMFORPARTICIPANTSAGEDLESS16YEARS..................20720. APPENDIXN.BROCHURETOEXPLAINSTUDYPROCEDURESTOPARTICIPANTS..................21021. APPENDIXO.PASSREPORT1–SUPERIORITYHYPOTHESISSAMPLESIZECALCULATION

21222. APPENDIXP.PASSREPORT2–NON-INFERIORITYHYPOTHESISSAMPLESIZE

CALCULATION........................................................................................................................................................214

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LISTOFTABLES

1. Table1.Eligibilitycriteriaforstudies…………………………………………………………………..........27-282. Table2.Summaryofincludedstudies………………………………………………………………………..34-403. Table3.CharacteristicsofNIMMrespondents…………………………………………………………...77-784. Table4.Non-inferioritymarginresponsesforprophylacticmigrainetrials…………………78-795. Table5.Non-inferioritymarginresponsesforacutemigrainetrials……………………………79-806. Table6.Expertopiniononappropriatenon-inferioritymarginsforcommonlyused

migraineoutcomes…………………………………………………………………………………………………...80-817. Table7.ICHDcriteriaforpediatricmigrainewithoutaura………………………………………………918. Table8.ICHDcriteriaforpediatricmigrainewithaura………………………………………………91-92

LISTOFFIGURES1. Figure1.PRISMADiagram……………………………………………………………………………………………..342. Figure2.Riskofbiasgraph:reviewauthors'judgementsabouteachriskofbiasitem

presentedaspercentagesacrossallincludedstudies………………………………………………………403. Figure3.Riskofbiassummary:reviewauthors'judgmentsabouteachriskofbiasitemfor

eachincludedstudy…………………………………………………………………………………………………….…414. Figure4.Topiramatevs.placebo:pooledanalysisofthepercentage(%)reductionin

migrainefrequencycomparingbaselinetothetreatmentperiod……………………………………..655. Figure5.Illustrationofthedifferencebetweenasuperiorityandnon-inferiority

hypothesis……………………………………………………………………………………………………………………..716. Figure6.Studytimelines………………………………………………………………………………………………..89

LEGENDχ2:ChisquareAHS:AmericanHeadacheSocietyANOVA:AnalysisofvarianceCAM:ComplimentaryandalternativemedicineCANTAB:CambridgeNeuropsychologicalTestAutomatedBatteryCBT:CognitivebehaviortherapyCHS:CanadianHeadacheSocietyCI:ConfidenceintervalDSMB:DataandSafetyMonitoringBoardFDA:FoodandDrugAdministrationICHD:InternationalClassificationofHeadacheDisordersIHS:InternationalHeadacheSocietyKg:KilogramsMCID:MinimalclinicallyimportantdifferenceMedDRA:MedicalDictionaryforRegulatoryActivityMcg:Micrograms

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Mg:MilligramsN:NumberNIH:NationalInstitutesofHealthNIMM:Non-InferiorityMarginsinMigraineResearchOHSN-REB:OttawaHealthScienceNetworkResearchEthicsBoardOR:OddsratioPDF:PortableDocumentFormatPedMIDAS:PediatricMigraineDisabilityAssessmentScalePRN:Prorenata(asneeded)qAM:Quaquedieantemeridiem(everydaybeforenoon)qHS:Quaquehorasomne(everynightatbedtime)REDCap:ResearchElectronicDataCaptureRevMan:ReviewManagerRCT:RandomizedcontrolledtrialSAS:StatisticalAnalysisSystemSD:StandarddeviationWHO:WorldHealthOrganization

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ENGLISHTHESISABSTRACT

Objectives:1)Todescribethestateoftheevidenceforinterventionsinpediatricmigraine,2)to

surveyexpertsregardingnon-inferioritymarginsinmigraineresearchand3)todesignaclinical

trialinthisareaofresearch.

Methods:Asystematicreviewwascarriedouttoidentifyrandomized,placebo-controlledtrialsof

pharmaceuticalandnutraceuticalinterventionsusedtopreventmigraineinchildrenand

adolescents,usingCochranemethods.Secondly,neurologistswithexpertiseinHeadacheMedicine

wereinvitedtoparticipateinasurveyregardingtheiropinionsonnon-inferioritymarginsfor

outcomesusedinclinicaltrialsofmigraineinterventions.Thirdly,aprotocolwaswrittenfora

three-arm,parallel-group,randomizedtrialcomparingtheefficacyandsafetyoftopiramate,

levetiracetamandplacebofortheprophylaxisofpediatricmigraine.

Results:Thesystematicreviewidentified19articlesof12interventionsforpediatricmigraine.The

qualityoftheevidencewaspoorandfewconclusionscouldbemade.Ninety-nineeligible

respondentscompletedthesurveyandnon-inferioritymarginsforsixoutcomesweredetermined.

Arandomizedcontrolledtrialprotocolwasdevelopedtodetermineiftopiramateandlevetiracetam

aresuperiortoplacebo,andiflevetiracetamisnon-inferiortotopiramateforthepreventionof

migrainesinchildrenandadolescents.

Conclusions:Itishopedthattheresultsofthisthesiscanbeappliedtofurthertheevidenceinthis

areaofclinicalresearch.

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FRENCHTHESISABSTRACT

Objectifs:1)Décrirel’étatdelarecherchesurlamigrainechezlesenfants,2)faireunsondage

parmilesexpertsparrapportauxseuilsdenon-inférioritépourlesessaiscliniquessurlamigraine

and3)fairelaconceptiond’unessaicliniquesurdesinterventionspréventifspourlamigrainechez

lesenfants.

Méthodes:Unerevuesystématiqueaétéexecutéeafind’identifierdesessaiscliniquessurlesujet

d’interventionspharmaceutiquesetnutraceutiquespourprévenirlamigrainechezlesenfants,en

utilisantlesméthodesCochrane.Desneurologuesavecexpertiseparrapportauxmauxdetêtesont

étéinvitésàparticiperdansunsondagesurlesujetdesseuilsdenon-inférioritéutiliséspourla

recherchesurlamigraine.Unprotocolaétédeveloppépourdécrireunessaicliniquequi

compareral’efficacitéetlatolérabilitédetopiramate,levetiracetametd’unplacebopourla

préventiondesmigraineschezlesenfants.

Résultats:Larevuesystématiqueaidentifiée19articlessurlesujetde12interventionspourla

migrainechezlesenfants.Laqualitédelarechercheétaitfaibleetpeudeconclusionsétaient

possibles.Quatre-vingt-dix-neufrépondentsontcompletéslesondageetsixseuilsdenon-

inférioritéontétéspecifiés.Unessaicliniqueaétédéveloppéafindedeterminersitopiramateet

levetiracetamsontsupérieursauplacebo,etsilevetiracetamestnon-inférieuràtopiramatepourla

préventiondesmigraineschezlesenfants.

Conclusions:Lesrésultatsdecettethèsepeuventêtreappliquéspouraméliorerlaqualitédela

recherchedanscedomaine.

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ACKNOWLEDGEMENTSIwouldliketoacknowledgetheCanadianInstitutesofHealthResearchfortheirroleinfundingthis

workthroughtheCanadianGraduateScholarshipandtheOntarioGovernment,fortheirrolein

fundingthisworkthroughtheOntarioGraduateScholarship.

IwouldalsoliketothanktheOttawaHealthScienceNetworkResearchEthicsBoardforreviewing

theprotocolfortheNon-InferiorityMarginsinMigraineResearch(NIMM)survey(protocol

#20150651-01H).

Forthesystematicreview:IwouldliketothankMargaretSampson,MLIS,PhD,AHIPforherrolein

designingtheelectronicsearchstrategiesforthesystematicreviewandJanetJoyce,MLIS,forher

roleinpeerreviewingtheelectronicsearchstrategies.IwouldalsoliketothankDr.SuzanneN.

Christie,MD,FRCPCforherroleinscreeningtheresultsofthesystematicreviewasasecond

screener,andDr.ErickSell,MD,FRCPC,forhisroleintranslatingPortugueseandSpanisharticles.I

wouldliketothankDrs.Ramsay,ChristieandDowlatshahifortheirrolesinassistingmewith

questionsaboutsystematicreviewdesignandimplementation.

Forthesurvey:IwouldliketothanktheAmericanHeadacheSocietyandtheCanadianHeadache

SocietyfordistributingtheNon-InferiorityMarginsinMigraineResearch(NIMM)surveytotheir

members.Thisprojectwasacollaborationbetweenmyself,SerenaOrr,MDandDrs.Dariush

Dowlatshahi,MD,PhD,FRCPC,SuzanneN.Christie,MD,FRCPC,TimothyRamsay,PhD,Jonathan

Gladstone,MD,FRCPCandDavidDodick,MD,FRCPC,FACP,FAHS.Theroleofeachauthoris

outlinedbelow:

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• SerenaOrr:Conceptualizedthesurvey,designedthesurvey,wrotetheprotocol,submitted

theprotocoltotheOHSN-REB,carriedouttheanalysesandwrotethemanuscript.

• DariushDowlatshahi:HelpedDr.Orrindesigningthesurvey,planningsurveydistribution

andreviewedtheprotocolandmanuscript.

• SuzanneN.Christie:HelpedDr.Orrindesigningthesurvey,planningsurveydistribution

andreviewedtheprotocolandmanuscript.

• TimothyRamsay:HelpedDr.Orrindesigningthesurvey,planningsurveydistributionand

reviewedtheprotocolandmanuscript.

• JonathanGladstone:HelpedDr.Orrinplanningsurveydistribution,distributedthesurvey

tomembersoftheCanadianHeadacheSociety,reviewedtheprotocolandmanuscript.

• DavidDodick:HelpedDr.Orrinplanningsurveydistributionandreviewedtheprotocoland

manuscript.

Fortherandomizedtrialprotocol:IwouldliketothankDr.TimothyRamsayforhisassistancein

samplesizecalculationsandplanningstatisticalanalysesforthetrial.IwouldliketothankDrs.

DowlatshahiandChristiefortheirrolesinassistingmewithquestionsabouttrialdesign.

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THESISPARTI:SYSTEMATICREVIEW

1. Background

1.1. Theprevalenceandimpactofpediatricmigraine

Migraineisoneofthemostcommondiagnosesencounteredbythepediatricneurologist.Ithas

beenestimatedthattheworldwideprevalenceofmigraineis7.7%inthepediatricagegroup,with

considerablevariationwithage,wherebytheprevalenceincreasessignificantlyinadolescence1.

Notonlyismigrainecommon,butitalsohasanimportantimpactontheindividualandsocietyin

termsofdisability.Inthe2010GlobalBurdenofDiseases,InjuriesandRiskFactorsStudy,migraine

wastheeighthmostcommoncauseofglobalyearsoflifelivedwithdisabilityamongstthemost

commonlyreporteddiseasesandinjuries2.Amultitudeofstudieshavefoundthatchildrenand

adolescentswithmigrainesufferfromimpairedhealth-relatedqualityoflife3–5.Furthermore,

childrenandadolescentswithmigraineexperienceasignificantamountofdisabilityrelatedtotheir

headaches6–8,whichengendersimportantfunctionalconsequencesontheirday-to-daylives.For

example,childrenandadolescentswithmigrainehaveinferioracademicperformanceascompared

totheirpeers9,10.Therefore,migraineisnotonlycommoninthepediatricagegroupbuthas

importantconsequencesforday-to-dayfunctioningandqualityoflife.

1.2. Thepathophysiologyofmigraine

Migraineismostoftenconceptualizedasaneurovasculardisorder,althoughits

pathophysiologyisnotcompletelyunderstood.Thepainarisingfrommigraineoriginatesinthe

trigeminovascularsystem:nociceptorsresidinginmeningealbloodvessels,cranialsinusesand

proximalcerebralbloodvesselsbecomeactivatedandsendafferentpainsignalstothespinal

trigeminalnucleusinthebrainstemandtotheuppercervicalspinalcord11.Itisunclearhowthese

nociceptorsbecomeactivatedattheonsetofmigraine,althoughaleadingtheoryimplicates

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peripheralsensitizationprovokedbysterilemeningealinflammation.Itisthoughtthatapro-

inflammatorystateexistsinthemeningesduringmigraineandthatthisstatecausesalower

thresholdfornociceptoractivationorperhapsevensustainedactivationofthenociceptors12.

Fromthespinaltrigeminalnucleus,secondorderneuronsprojecttoamultitudeofbrainareas,

includingtheparabrachialnucleus,andseveralthalamicandhypothalamicnuclei.Thesecond

orderneuronslocatedintheuppercervicalspinalcordalsoprojecttoseveraltargetsinthe

thalamusandhypothalamusaswellastargetsinbrainstemincludingtheperiaquedualgrayinthe

midbrain,thereticularformationandthesuperiorsalivatorynucleus12.Theseprojectionsfrom

secondorderspinaltrigeminalanduppercervicalneuronsarethoughttoplayaroleingenerating

someofthesymptomsassociatedwithmigraine(eg.nausea,anorexiaandfatigue)11.

Asisdescribedabove,manyofthesecondorderneuronsfromthespinaltrigeminalnucleusand

uppercervicalspinalcordprojecttothalamicnuclei.Inturn,thirdorderneuronsinthethalamus

sendprojectionstovariouscorticalareas,withindividualnucleiprojectingtospecificcortical

regions(eg.dura-sensitiveneuronsintheventroposteromedialnucleusofthethalamusprojectto

theprimarysomatosensoryandinsularcortices).Thesethirdorderthalamicneuronsarethought

tomodulatecorticalactivityintheirrespectivetargetregions,andsomeofthehigherorder

symptomsassociatedwithmigraine,suchasallodyniaanddifficultyconcentrating,maybe

explainedbyactivationofthesepathways11.

Inadditiontotheseascendingpathways,therearealsonumerousdescendingpathwaysthatact

tomodulatetheexperienceofpainandthatmayplayaroleincentralsensitization.Variouscortical

andbrainstemregionshaveadescendinginfluenceonthetrigeminovascularsystem,andrecent

evidencesuggeststhatthehypothalamusalsohasamodulatoryeffectontrigeminalnociception11.

Migraineursarethoughttohavealteredexcitabilityatthelevelofthecortexandperhapsalso

dysfunctionofmodulatorybrainstemregionssuchastheperiaqueducalgrayareaofthe

midbrain11.

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Becauseofthecomplexityofmigrainepathophysiology,migraineinterventionsarenumerous,

varied,andhavediversetheoreticalmechanismsofaction.

1.3. Generalapproachtothetreatmentofpediatricmigraine

Giventheimpacttheyhavenotonlyonpatients’lives,butonsocietyasawhole,theoptimal

treatmentofmigrainesisvital.Treatmentrequiresamultiprongedapproach.Therearetwobroad

classesofinterventionsformigraines:pharmacologicalandnon-pharmacological.Thereisalsoa

seriesofinterventionsthatfallundertheumbrellaofcomplimentaryandalternativemedicines

(CAM).Avarietyofnon-pharmacologicalinterventionshavebeenstudiedformigraine.

1.4. Educationandlifestylechangesforthemanagementofpediatricmigraine

Firstly,patienteducationisnecessary.Manyfactorsunderthepatient’scontrolcaninfluence

thefrequencyofmigraines.Lifestylefactorsappeartohaveanimportantimpactonprimary

headaches.Adolescentswithlowphysicalactivityaremorelikelytoreportrecurrent

headaches13,14,andamongstthosewithmigraine,lowphysicalactivityisassociatedwithhigher

levelsofmigraine-relateddisability15.Otherlifestylefactorsincludingdiet14,16andsleep-related

problems17–22havebeenshowntohaveanimportantrelationshipwithmigraineinthepediatric

agegroup.Inaddition,studiesamongstadultmigraineurshaveshownthatdysfunctionalcoping

withstressisprevalentinthispopulation23–25.Onestudyamongstchildrenwithprimary

headaches,includingmigraine,foundthatpoorcopingskillswereassociatedwithlowerqualityof

lifescores26.

Inadditiontoresearchdocumentingtheassociationsabove,afewstudieshaveexploredthe

efficacyoflifestyleinterventionsforpediatricmigraineprevention.Arandomizedtrialcarriedout

amongstpediatricmigrainepatientswithknownsleephygieneproblemsdemonstratedthat

educationaboutsleephygieneguidelinessignificantlyimprovedtheirmigrainesinregardsto

severalparametersascomparedtothecontrolcondition27.Acoupleofstudieshavealsotriedto

assesstheeffectofremovingdietarymigrainetriggersonmigraineparametersinthepediatric

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population.Onerandomizedtrialcomparedahighfiberdiettoahighfiberdietpluseliminationof

foodshighinvasoactiveaminesinasampleofchildrenwithmigrainesandfoundnodifference

betweeninterventionarms28.However,anon-randomized,uncontrolledstudyfoundthat

eliminationofavarietyofcommontriggerfoodsfromthedietsofchildrenwithmigrainesresulted

in93%ofparticipantsreportingsignificantimprovementintheirmigraines29.Therefore,in

addressingthetreatmentofmigraines,itiscrucialtocounselthepatientonlifestylefactorsthat

canimpacttheirheadaches,priortoanydiscussionsofactiveinterventionsforthemigraines.

1.5. Psychologicalinterventionsforpediatricmigraine

Thereareseveralotherclassesofnon-pharmacologicinterventionstoconsiderinthispatient

population,whichfallundertheumbrellaofpsychologicalinterventions.Giventhefactthat

childrenandadolescentswithmigrainearethoughttohaveissueswithstresscoping,relaxation

therapyhasbeenstudiedasaprophylactictherapyformigraine.Asystematicreviewpublishedin

2006identifiedthreestudiesonrelaxationtherapyforthisindication.Theresultsofthestudies

wereinconsistent,andthereviewersconcludedthatrelaxationtherapymightbesuperiortoawait

listcondition30.Sincepublicationofthisreview,twostudieshaveexploredrelaxationtherapy

techniquesinthispopulationandhaveshownpromisingpreliminaryresultsinregardstothe

potentialofrelaxationtherapyforpediatricmigraineprophylaxis31,32.Thesame2006systematic

reviewalsopooledtheevidenceforbiofeedback,andfoundthatitdidnotdiffersignificantlyfrom

placeboforthepreventionofmigrainesinchildrenandadolescents30.Onesmallstudypublished

sincethenfoundthatbiofeedbackwaseffectiveinyieldingareductioninmigrainefrequencyand

severityinagroupofchildrenwithmigrainewithoutaura33.Despitethescarceevidence,

biofeedbackisusedfrequentlyincertainpediatricheadachepracticesandhasbeenrecommended

forselectpatientsinpediatricmigrainemanagementguidelines34.Cognitivebehaviortherapy

(CBT)hasalsobeenassessedforpreventionofmigrainesinchildrenandadolescents.Priorto

2006,twostudieshadassessedCBTinthispopulationandfoundnosignificantdifferencesinits

5

efficacyascomparedtoplacebo,additionalpainbehavioralmanagementoraprogressive

relaxationtechnique30.In2013,arandomizedcontrolledtrialcomparingamitriptylineplus

headacheeducationtoamitriptylineplusCBTinagroupofchildrenandadolescentswithchronic

migraineshowedthatthearmreceivingCBThadsignificantlygreaterimprovementinthe

frequencyoftheirmigrainesandintheirmigraine-relateddisabilityscores35.A2009Cochrane

reviewcarriedoutapooledanalysisofallpsychologicaltreatmentsforpediatricheadache,which

includedstudiesonrelaxationtherapy,biofeedbackandCBTandalsoincludedchildrenwithnon-

migrainousprimaryheadaches.Intotal,15studiesassessedtheefficacyofpsychological

interventionsforpediatricheadacheimmediatelyaftertreatment,andfoundastrongeffecton

immediatepainreduction(OR=5.51,95%CI:3.28-9.24).Sixofthestudiesassessedpainatfollow-

up,andresultswerealsoverypromisinginregardstotheefficacyofpsychologicalinterventionsin

reducingheadache-relatedpain(OR=9.91,95%CI:3.73-26.33)36.A2006meta-analysisof

psychologicalinterventionsforrecurrentheadachesinchildrenandadolescentscametosimilar

conclusionsabouttheefficacyoftheseinterventionsasthe2009Cochranereview37.Thus,thereare

severalnon-pharmacologicinterventionswithvaryingdegreesofevidenceforefficacyinthe

treatmentofpediatricmigraine.

1.6. Complimentaryandalternativemedicineforpediatricmigraine

Thenextcategoryofinterventionsforpediatricmigrainepertainstocomplimentaryand

alternativetherapies(CAM).TheNationalInstitutesofHealthhasdefinedCAMasa:“groupof

diversemedicalandhealthcaresystems,practices,andproductsthatarenotpresentlyconsidered

tobepartofconventionalmedicine”38.TheuseofCAMisincreasing39,anditiscurrentlya

multibillion-dollarperyearindustryintheUS40.Inthepediatricworld,headacheisthemost

commonreasonforCAMuse,alongwithpain41.Acoupleofstudieshavehighlightedtheprevalence

ofCAMuseamongstpediatricheadachepatients.AstudycarriedoutinanItalianheadacheclinic

foundthat76%ofthechildrenwithheadaches,mostofwhomhadmigraines,reportedusingCAM,

6

withthemostcommonmodalitiesbeingherbalremediesorvitaminandmineralsupplements42.

ThisstudymayhaveoverestimatedtheuseofCAMgiventhehighlyselectedpopulation,butastudy

amongstapopulation-basedsampleofUSchildrenfoundthat30%ofthechildrenreporting

headacheswerealsousingCAM43.Therefore,itindeedappearsthatCAMuseforheadachesis

commoninchildrenandadolescents,thoughanaccurateestimateoftheprevalenceisnotcurrently

available.AvarietyofCAMmodalitieshavebeenstudiedforpediatricheadache:acupuncture,

homeopathy,nutritionalsupplements,vitamins,herbalpreparationsandmanualtherapies

includingosteopathyandchiropractictechniques44.Twostudieshavefoundacupuncturetobe

effectiveinpediatricmigraineprophylaxis.Inonestudy,asmallgroupofchildrenwithmigraine

wererandomizedtoacupunctureorshamacupuncture.Theacupuncturegrouphadsignificantly

greaterreductionsinthefrequencyandintensityoftheirmigraines45.Thesecondstudywasamore

recentrandomizedtrialcomparinglaseracupuncturetoshamlaseracupunctureinagroupof

childrenandadolescentswithprimaryheadaches.Thoserandomizedtolaseracupuncturehad

significantlygreaterdecreasesinmigrainefrequencyandintensityascomparedtothesham

group46.Homeopathyhasonlybeenstudiedforthisindicationinoneinstance.Amulticenter,open-

label,non-randomized,prospectivestudyassessedavarietyofindividualizedhomeopathic

remediesforthepreventionofmigrainesinchildrenaged5to15years47.Although209

participantswererecruited,only168wereincludedintheanalysesandnointention-to-treat

analyseswereattempted.Duringthefirstthreemonthsoftreatment,alloutcomeschanged

favorably.Migrainefrequency,intensityanddurationdecreasedsignificantlyovertimeandthe

percentageofchildrenwithabsenteeismfromschoolwassignificantlyreduced.However,thelack

ofacontrolgroupandthediversityoftreatmentsusedmakesitdifficulttodrawconclusionsabout

theefficacyofhomeopathyforthisindicationfromthisstudy.Althoughosteopathyhasbeen

assessedforcervicogenicheadacheinchildren,nostudieshaveexamineditspotentialefficacyfor

pediatricmigraine44.Thus,someevidenceexistsinrelationtotheefficacyofacupunctureand

7

homeopathyforpediatricmigraineprophylaxis,butotherCAMmodalitiessuchasosteopathyand

energymedicinehavenotyetbeenexploredforthisindication.

1.7. Nutraceuticalsforpediatricmigraine

Nutraceuticals,definedas“anysubstancethatmaybeconsideredafoodorpartofafoodand

providesmedicalorhealthbenefits,includingthepreventionandtreatmentofdisease”48,comprise

nutritionalsupplements,vitaminsandherbalpreparations.Avarietyofnutraceuticalshavebeen

assessedfortheprophylaxisofpediatricmigraine.Inthissystematicreview,evidencederivedfrom

eligiblerandomizedcontrolledtrialsontheefficacyofnutraceuticalsforthisindicationwillbe

reviewed.However,themagnitudeofevidencefromnon-randomizedstudiesisnotnegligible.The

mainnutraceuticalsthathavebeenstudiedforpediatricmigraineprophylaxisare:butterbur,

riboflavin,magnesium,coenzymeQ10,fishoilsandcombinationtherapies49.

1.7.1. Butterbur

Oneopen-labelstudyamongstasampleofchildrenandadolescentswithmigrainefound

Petadolex®,aformulationofbutterbur,tobeeffectiveformigraineprevention,withresults

showingthatafter4monthsoftreatmentthefrequencyofmigraineswassignificantlyreduced,

withnomajoradverseeventsreported50.

1.7.2. Riboflavin

Twonon-randomizedstudieshaveexploredthepotentialforriboflavinasaninterventionin

pediatricmigraineprevention.Inaretrospectivechartreviewinvolvingasmallseriesofchildren

withavarietyofheadachedisorders,themajorityofwhomhadmigraine,riboflavinwasfoundto

significantlydecreasemigrainefrequencyinthefirst4monthsoftreatment,butnotbeyondthat

initialtreatmentperiod51.Riboflavinwasalsostudiedretrospectivelyinagroupofadolescentswith

chronicheadaches,mostofwhomhadchronicmigraine,andwasfoundtoyieldimprovementin

73%ofthesubsetofparticipantswithchronicmigraine52.Thus,basedonnon-randomized

8

evidence,itappearsthatriboflavinisapromisingprophylactictherapyformigraineinchildrenand

adolescents.

1.7.3. Magnesium

Onlyonenon-randomizedstudyhasevaluatedmagnesiumfortheprophylaxisofpediatric

migraine.Thissmallopen-labelstudyassessedmagnesiuminavarietyofchildhoodperiodic

syndromesincludingmigraine.Overall,77.5%oftheparticipants,ofwhommosthadmigraine,had

agoodclinicalresponsewherebytheirattackswereeliminatedorreducedtolessthanonethirdof

thebaselinefrequency53.Thesizeofthestudyandheterogeneityoftheparticipantsrendersitlow

qualityevidenceforthequestionofinterest.

1.7.4. CoenzymeQ10

Onenon-randomizedstudyevaluatedtheuseofcoenzymeQ10formigraineprophylaxisina

relativelylargesampleofchildrenandadolescentswhowerefoundtobedeficientincoenzymeQ10.

Aftervariabletreatmentperiods,participantsbenefitedfromastatisticallysignificantreductionin

migrainefrequencyandmigrainedisabilityscores54.Thisstudythereforeshowspromisefor

coenzymeQ10asatargetedinterventioninpediatricmigraineprevention.

1.7.5. FishOils

Inchildrenandadolescents,onlyonestudyassessedtheefficacyoffishoilsinmigraine

preventionanditwasrandomizedbydesign55.Therefore,itwillnotbesummarizedhere.

1.7.6. L-5-Hydroxytryptophan

L-5-hydroxytryptophanisanaturallyoccurringaminoacidwithantidepressantpropertiesthat

hasalsobeenstudiedformigraine,butthereisonlyonestudythatwascarriedoutinthepediatric

populationanditwasrandomized56.Therefore,itwillnotbereviewedhere.

1.7.7. CombinationTherapies

9

Therearethreenon-randomizedstudiesontheefficacyofcombinationnutraceuticaltherapies

formigraineinthepediatricpopulation.Eachofthesestudiesassessedtheefficacyofthesame

combinationofginkgolideB,coenzymeQ10,magnesiumandriboflavinovertime57–59,withonlyone

ofthestudieshavingacomparisonintervention59:acombinationofL-tryptophan,5-

hydroxytryptophan,vitaminPPandvitaminB6.Allthreestudiesdemonstratedthatthe

combinationtherapyyieldedstatisticallysignificantdecreasesinmigrainefrequencyovertime,and

thestudywithacomparisongroupdemonstratedthattheginkgolide-containingcombination

therapywassuperiortothealternatetherapy.Therefore,thiscombinationofginkgolideB,

coenzymeQ10,magnesiumandriboflavinmaybeeffectiveforthepreventionofmigrainesin

childrenandadolescentsbasedonnon-randomizedpreliminaryfindings.

1.8. PharmaceuticalsforPediatricMigraine

Ahostofpharmaceuticalmedicationshavebeenstudiedforpediatricmigraineprophylaxis.In

thissystematicreview,wewillsummarizetheevidencefromeligiblerandomizedcontrolledtrials

forpharmaceuticalagentsinpediatricmigraineprophylaxis.However,manynon-randomized

studiesalsoexist.Here,abriefoverviewofthenon-randomizedliteratureinthisareawillbe

provided.

1.8.1. AntiepilepticMedications

Topiramateisoneofthebest-studiedmedicationsformigraineprophylaxisinbothadultsand

children.Theefficacyandsafetyoftopiramateforthepreventionofmigrainesinchildrenand

adolescentshasbeenassessedinfournon-randomizedstudies.Threeretrospectivechartreviews

havebeencarriedout.Twoofthechartreviewsdidnothaveacomparisongroup,andfoundthat

overtime,topiramateyieldedsignificantreductionsinmigrainefrequencyandotherheadache

parameters60,61.Theotherretrospectivestudycomparedtopiramateprophylaxistoflunarizine

prophylaxisinarelativelylargegroupofpediatricpatients,andfoundthatbothinterventions

10

resultedinreductionsinmigrainefrequency,withnosignificantgroupdifferencesnoted62.One

prospectiveopen-labelstudyevaluatedtheefficacyoftopiramateinthepreventionofmigrainesfor

childrenwithmigrainesrefractorytoothertreatments.Thissmallstudy,whichincludedonly24

participants,didnotyieldanysignificantdifferencesinmigrainefrequencyovertime,though

migraineseverityandassociatedsymptomsdidsignificantlyabatewithtopiramate63.Adverse

eventsratesvariedbetween10%and33%inthesefourstudies,withthemostcommonsideeffects

reportedbeingweightchanges,anorexia,cognitivesideeffects,paresthesiasanddrowsiness60–63.

Evidencefromnon-randomizedstudiesthereforesupportstheefficacyandtolerabilityof

topiramatefortheprophylaxisofpediatricmigraine.

Valproicacidhasalsobeenfrequentlystudiedasapotentialinterventionforthepreventionof

migrainesinthisagegroup.Thenon-randomizedliteratureonvalproicacidasaprophylacticagent

forpediatricmigraineiscomprisedoffivestudies.Twoofthesestudieswereretrospectivechart

reviews,encompassingatotalofonly67patients64,65.Bothofthesestudieshintedatafavorable

responsetodivalproex,whichistheenteric-coatedcounterpartofvalproicacid.Theotherthree

non-randomizedvalproicacidstudieshadopen-labelprospectivedesigns,withamuchlarger

numberofparticipants:intotal,368childrenandadolescentswithmigrainewereincludedinthese

studies66–68.Oneofthestudiesdidnotassessefficacy,butonlysafetyandtolerabilityofdivalproex

forthisindication67.Thetwostudiesthatreportedonefficacyfoundthatdivalproexandsodium

valproatebothsignificantlydecreasedmigrainefrequencyovertimeandleadtoimprovementin

otherclinicaloutcomes66,68.Thesafetystudyuncoveredahighrateofsideeffects:88%ofthe

participantsreportedatleastonesideeffect,withthemostcommonbeingweightgain,nausea,

somnolenceandupperrespiratorytractinfections.Fiveseriousadverseeventswerereported,of

whichonlyone,hyperammonemia,wasdeemedrelatedtodivalproexsodiumextended-release.

Theinvestigatorsalsofoundthat,overall,ammonialevelsincreasedduringtreatment66.Theother

studiesreportedsimilarsideeffectprofilesandoverallratesofsideeffectsbetween48and84%64–

11

66,68.Basedonthisnon-randomizeddata,itisevidentthatvalproicacidmightbeeffectivefor

pediatricmigraineprophylaxis,butthatitisassociatedwithasignificantrateofsideeffects,notto

mentionitsquestionableuseinteenagedfemalesgivenitsknownteratogeniceffects,whichhas

leadtorecommendationstoavoiditsuseinwomenofchildbearingpotentialwheneverpossible69.

Althoughtraditionally,theonlytwoantiepilepticmedicationsthathavebeencommonlyused

clinicallyandstudiedforpediatricmigraineprophylaxisaretopiramateandvalproicacid,interest

inthepotentialuseoflevetiracetamforthisindicationisemerging.Twoverysmallstudies

prospectivelyassessedtheefficacyandsafetyoflevetiracetamforpediatricmigraine70,71.Migraine

frequencydecreasedsignificantlyovertimeinbothstudiesandtolerabilitywasfavorable.Ineach

study,approximately10%ofthepatientsexperiencedbehavioralorpsychiatricadverseevents,

whichhavebeenwelldocumentedwiththismedication.Moreevidenceisrequiredpriorto

drawingconclusionsabouttheefficacyandsafetyoflevetiracetamforthepreventionofmigraines

inpediatrics,butthepreliminary,verylimiteddataispromising.

1.8.2. Calcium-ChannelBlockersandBeta-Blockers

Threemedicationsclassifiedascalcium-channelblockers,flunarizine,nimodipineand

cinnarizine,andtwomedicationsclassifiedasbeta-adrenergicblockers,propranololandtimolol,

havebeenstudiedinthispopulation.Infact,propranololwasthemostcommonlyprescribed

migraineprophylacticmedicationamongstagroupofUSpediatriciansbasedinMichiganina

surveyonpediatricmigrainemanagementpatterns72.

Threenon-randomizedstudieshavelookedatflunarizineasaprophylacticagentforpediatric

migraine.Oneofthestudieswasarelativelylargeretrospectivechartreview62,andtwoofthe

studiesweresmall,prospective-openlabelstudies73,74.Theretrospectivestudycomparedthe

efficacyofflunarizinetothatoftopiramatein261childrenandadolescentswithmigraineand

foundnodifferenceinresponderratescomparingthetwomedications;bothgroupshadfavorable

responses62.Bothoftheprospectivestudiesfoundpreliminaryevidencefortheefficacyof

12

flunarizineinpediatricmigraineprophylaxis:inonestudy,66%ofthepatientsimproved74,andin

theotherstudy,allpatientshadsomeresponsetoflunarizine73.Intwoofthestudies,noadverse

eventswerereported73,74.Intheretrospectivestudy,6%oftheparticipantstakingflunarizine

reportedadverseevents,withweightgain,drowsinessanddizzinessbeingthemostcommon.Thus,

flunarizinedoesappeartohavesomepotentialforpediatricmigraineprophylaxisbasedonnon-

randomizedevidence.Nimodipineandcinnarizehavenotbeenassessedinanynon-randomized

studiesinthispopulation.

Theliteratureisdevoidofevidencefromnon-randomizedstudiesfortheuseoftimololin

pediatricmigraineprophylaxis.Onenon-randomizedstudy,witharetrospectivechartreview

design,assessedtheefficacyofpropranololforthepreventionofmigrainesinasampleofchildren

andadolescents.Inthisstudy,bothpropranololandamitriptylineyieldedsignificantresponder

rates,withnodifferencesbetweenthegroupsexceptforhigherratesofsideeffectsreportedinthe

amitriptylinegroup75.Thisonestudythereforesupportstheuseofpropranololinthispopulation.

1.8.3. Antidepressants

Amitriptylineandtrazadonearethetwoantidepressantsthathavebeencommonlyusedand

studiedforthepreventionofmigrainesinthepediatricagegroup.Infact,inmanycenters,

practitionersuseamitriptylineasafirstlinepharmacologicprophylacticagentforthisindication76.

Tworetrospectivechartreviews75,76andoneprospective,open-labelstudy77haveexploredthe

efficacyandsafetyofamitriptylineforpreventionofmigrainesinchildrenandadolescents.Both

retrospectivestudiesfoundfavorableefficacyresultsforamitriptyline:oneofthestudies

demonstratedthat89%ofparticipantshadapositiveresponsetoamitriptylinewithasignificant

decreaseinmigrainefrequency76andtheotherfoundthatbothamitriptylineandpropranolol

yieldedsignificantdecreasesinmigrainefrequencyovertime75.Migrainefrequencydecreased

significantlyand84.2%ofchildrendemonstratedimprovementintheirheadacheswith

amitriptylineprophylaxisintheprospectivestudy77.Althoughtwoofthesestudiesdidnotreport

13

onsideeffects,oneofthestudiesfoundthatamitriptylineresultedinhigheradverseeventrates

thanpropranolol,withweightgain,fainting,drowsinessandtremorbeingthemostcommonly

reportedsideeffects75.Evidencefromnon-randomizedtrialssupportsthecurrentwidespreaduse

ofamitriptylinetopreventmigrainesinchildrenandadolescents.Therearenonon-randomized

studiesthathaveexploredtheefficacyoftrazadoneforthisindication.

1.8.4. Antiemetics

Severalantiemeticsmightbeusefulinpediatricmigraineprophylaxis:domperidone,

metoclopramideandcyproheptadine.Domperidoneandmetoclopramidehavenotbeenassessedin

anynon-randomizedstudies.Theefficacyofcyproheptadineforpediatricmigraineprophylaxishas

onlybeentestedinonenon-randomizedstudy.Aretrospectivechartreviewshowedthat

cyproheptadinesignificantlyreducedmigrainefrequencyandwasassociatedwithan83%

responserateinasmallsampleofpediatricmigraineurs76.Cyproheptadinewasassociatedwith

sedationandincreasedappetite,thoughtheproportionofpatientswithsideeffectswasnot

specified.Thus,thereislittleevidencefromnon-randomizedstudiestoassesstheuseof

antiemeticsinpediatricmigraineprophylaxis.

1.8.5. Others

Thereareseveralotherpharmacologicagentsusedinthiscontextbeyondthosedescribedin

theclassesabove:Botox,clonidine,papaverineandpizotifen.Twochartreviewsretrospectively

evaluatedtheefficacyandsafetyofOnabotulinumtoxinA(Botox)forthepreventionofchronic

headaches,includingchronicmigraine.Onesmallretrospectivecaseseriesof6adolescentswith

chronicheadachesfoundthatallpatientsrespondedtoBotoxinjectionsgivenevery3months,with

threepatientsreportingtransientsideeffects:ptosis,neckinjectionsitehematomaandburningat

injectionsites78.ThesecondretrospectivestudyassessedtheefficacyofBotoxin45childrenand

adolescentswithchronicheadaches.Therewasastatisticallysignificantdecreaseinmigraine

14

frequencywiththeinjections.Sevenpatientshadadverseevents,includingpainattheinjection

sites,eyelidinflammation,eyelidpainandneckandshouldermyalgias79.Inadditiontothese

studies,thereisarandomizedcontrolledtrialcurrentlyunderwaythataimstoassesstheefficacy

andsafetyofBotoxformigrainepreventioninadolescentswithchronicmigraine(clinicaltrials.gov

identifier:NCT01662492)80.Basedonthislimitedretrospectiveevidence,thereispromisefor

Botoxinpediatricchronicmigrainepreventionandresultsfromtherandomizedstudywillaidin

assessingitsefficacymoredefinitively.

Clonidinehasbeenusedformigraineprophylaxisinthepast,buthasfallenoutoffavorbothin

theclinicalandresearchcommunitiesinthelastcoupleofdecades.Ithasonlybeenassessedinone

non-randomizedstudyinthepediatricpopulation.Aprospectiveopen-labelpilotstudyamongst

childrenwithmigrainerevealedthat50%ofparticipantshadmeaningfulreductionsintheir

migrainefrequencies,with40%benefitingfromcompleteandlastingremissionfromtheir

headaches81.Inthisgroupof50children,sixdevelopedsideeffects:threerasheswerereported,

twochildrenhaddrowsinessandonechildhadcontinuousheadaches.Thereislittleevidenceto

supporttheuseofclonidineforpediatricmigraineprophylaxis,thoughthisonestudydoessuggest

somepotential.

Papaverineandpizotifenhavenotbeenassessedinnon-randomizedstudiesthisindication.

1.9. Conclusions

Asisevidencedfromtheoverviewabove,thereisawiderangeoftherapeuticoptionsfor

pediatricmigraine,noneofwhichhavebeenparticularlyrigorouslyorwellstudied.Mostofthe

evidenceforpediatricmigraineinterventionsisderivedfromlowquality,non-randomizedstudies.

Pharmaceuticalsremainthemainstayofallopathicmedicaltreatmentsofferedbypractitioners

lookingafterchildrenandadolescentswithmigraine.However,nutraceuticalsareanimportant

partofthegrowingCAMmovement,whichcurrentlyrepresentsamultibilliondollarperyear

industryintheUS40.InoneItalianstudy,76%ofchildrenandadolescentsinatertiarycare

15

headacheclinicwereusingherbaltherapiesand40%wereusingvitaminandmineralsupplements

fortheirheadaches42.IntheUS,30%ofchildrenwithheadachesreportedusingCAMtherapies,

includingnutraceuticals,intoanationallyrepresentativesurvey82.Thus,nutraceuticalsare

increasinglypopular,andthisiscompellingpractitionersofallopathicmedicinetoeducate

themselvesaboutnutraceuticaloptions.

Inthissystematicreview,wewillaimtosummarizetheevidencefromthehighestquality

randomizedstudiesfortheefficacyandsafetyofpharmaceuticalandnutraceuticaloptionsinthe

prophylaxisofpediatricmigraine.

2. METHODS

2.1. Objectives

Theprimaryobjectiveofthissystematicreviewistosummarize,evaluateandquantifythe

evidencefortheefficacyofnutraceuticalandpharmaceuticalinterventionsintheprophylaxisof

pediatricmigraine.

Thesecondaryobjectiveofthissystematicreviewistosummarize,evaluateandquantifythe

evidenceforthesafetyandtolerabilityofnutraceuticalandpharmaceuticalinterventionsinthe

prophylaxisofpediatricmigraine.

2.2. StudyDesign

Themethodologyfollowedinthissystematicreviewadherestotheguidelinessetoutinthe

CochraneCollaboration’sHandbookforSystematicReviewsofInterventions83.Thismethodological

approachiscomplimentedbyconsiderationoftheGuidelinesforControlledTrialsofDrugsin

Migraine,whichweredevelopedin2012bytheInternationalHeadacheSociety,theleading

authorityonprimaryheadaches84.Stipulationsintheseguidelineswereusedtorefinetheeligibility

criteriaforstudiesinthissystematicreview.Thegoalofusingtheguidelinestoestablisheligibility

16

criteriawastoensurethatonlythemostmethodologicallyrigorousrandomizedstudieswouldbe

includedinthisreview,soastomaintainasummaryofthehighestqualityofevidence.

Inadditiontothesystematicreview,meta-analyseswerecarriedoutonbodiesofevidencethat

wereamenabletopooling.Again,themethodologylaidoutintheCochraneHandbookisadheredto

forthepurposesofthemeta-analyses.

2.3. CriteriaforConsideringStudiesforthisReview

2.3.1 TypesofStudies

Theaimofthissystematicreviewistosummarizethehighestqualityevidencefortheefficacy

andsafetyofprophylacticnutraceuticalandpharmaceuticalpediatricmigraineinterventions.In

ordertolimitincludedstudiestothoseofhighmethodologicalquality,onlyrandomized,placebo-

controlledtrialswereconsidered.Parallel-groupandcross-overdesignswereeligible.Inorderto

complywiththerecommendationssetforthintheInternationalHeadacheSocietyGuidelinesfor

ControlledTrialsofDrugsinMigraine84,cross-overstudieswererequiredtohaveaminimum

washoutperiodof4weeksbetweenstudyinterventions.Thepurposeofsettingaminimum

washoutperiodwastoavoidtheinclusionofstudieswithbiasedresultsduetocarry-overeffects.

Theunitofrandomizationwasrequiredtobetheindividualandcluster-randomizedtrialswere

excluded.Limitingeligiblestudiestothoserandomizedbyindividualreducesthechanceof

selectionbias,whichisoftenasignificantproblemwithclusterrandomizedtrials85.

Inordertominimizeperformancebias,includedstudieswererequiredtoblindparticipants,

suchthateithersingle-blindordouble-blindtrialswereeligible.Unblindedstudieswereexcluded.

2.3.2 TypesofParticipants

Onlystudieslimitedtopediatricpatients,aged18yearsandunder,wereincluded.Studiesthat

includedadultswereconsideredonlyifresultsofasubgroupanalysisonpatientsundertheageof

18yearswereavailable.Participantswererequiredtohavemigraineorasubtypeofmigraine(eg.

17

migrainewithaura,chronicmigraine,probablemigraine)asperasetofvalidatedcriteria.The

threemostcommonlyusedmigrainecriteriainthepediatricliteraturearetheInternational

ClassificationofHeadacheDisorders(ICHD)criteria,nowintheirthirditeration86,theAdHoc

criteria87andtheVahlquistcriteria88;thelattertwosetsofcriteriaweremostlyusedpriortothe

firstiterationoftheICHDcriteriain1988.Currently,theICHDcriteriaareconsideredthegold

standardforthediagnosisofmigraine.TheICHDandVahlquistcriteriahavebothbeenshowntobe

valid89andthetwosetsofcriteriaareconsistentwithanoverallkappaof0.57reportedinone

pediatricstudy90.TheAdHoccriteriawerecreatedin1962andareconsideredtobethe

predecessoroftheICHDcriteria87.AlthoughtheyaremorevaguethantheICHDcriteria,oneadult

studyshowedthattheAdHoccriteriaagreedwiththeICHDcriteria91.7%ofthetime91,indicating

highconsistencybetweenthetwoclassificationsystems,andsupportingthevalidityofusingtheAd

HoccriteriaagainstthegoldstandardoftheICHDcriteria.Therehasalsobeenapediatricstudy

publishedthatfoundremarkableconsistencyinmigraineprevalenceratesregardlessofwhether

theICHD,AdHocorVahlquistcriteriawereusedfordiagnosis,especiallyinthecaseofmigraine

withoutaura92.Therefore,studiesusingICHD,VahlquistorAdHoccriteriawereeligible,andother

criteriahadtobevalidatedinordertobeconsideredforinclusion.

2.3.3. TypesofInterventions

Asisdescribedindetailintheintroduction,thereisawidevarietyofinterventionsaimedat

preventingmigrainesinchildrenandadolescents.Inordertolimitthescopeofthisreview,only

pharmacologicandnutraceuticalinterventionswereincluded.Pharmacologicinterventionsfor

pediatricmigraineprophylaxisaremedicationsusedinallopathicmedicinethatfallintoavarietyof

categories,listedabove(ie.antiepilepticmedications,antidepressants,etc).Asdescribedabove,

nutraceuticalsarefoodderivativesthatareusedformedicalpurposesandhavebeendefinedas:

“anysubstancethatmaybeconsideredafoodorpartofafoodandprovidesmedicalorhealth

benefits,includingthepreventionandtreatmentofdisease”48.Interventionsfallingoutofthescope

18

ofpharmaceuticalsornutraceuticals,suchaslifestyleinterventionsandpsychologicaltreatments,

wereexcluded.

2.3.4 TypesofComparisons

Allincludedstudieswererequiredtohaveatleastonestudyarmcomprisingaplacebocontrol.

Theplacebocontrolisnecessarygiventhatnoneoftheseinterventionshavebeenadequately

studiedandthereforeassaysensitivitymustbeestablished.Inaddition,theInternationalHeadache

SocietyGuidelinesforControlledTrialsofDrugsinMigraine84statethatprophylactictrialsfor

migraineshouldincludeaplacebocontrolandtheyspecifythatevenstudieswithactive

comparatorsshouldincludeaplaceboarm.

Norestrictionswereplacedonactivecomparators:anytypeofactivecomparatorwaseligible

aslongastherewasalsoaplacebocomparatorarm.

2.3.5 TypesofOutcomes

Studieswerenotexcludedbasedonoutcomes.TheCochraneCollaborationrecommendsthat

priorityoutcomesbeestablishedbutstates:“reportingofoutcomesshouldrarelydetermine

eligibilityofstudies”83.Forthepurposesofthisreview,anytrialwithanoutcomepertainingto

migraineprophylaxiswaseligibleforinclusion.Theprimaryoutcomeofinterestrelatestomigraine

frequency.TheInternationalHeadacheSocietyGuidelinesforControlledTrialsofDrugsin

Migraine84stipulatethattheprimaryoutcomeinmigraineprophylaxistrialsshouldbethe

differencebetweenmigrainefrequencyattheendoftreatmentorthroughouttreatmentand

migrainefrequencyatbaseline.Thus,whenavailable,thisoutcomewashighlightedandusedfor

poolingtheresultsinmeta-analyses.

2.3.6 LanguageofStudies

19

Eligibilityofthestudieswasnotrestrictedbylanguageofpublication.Articlesdeemed

potentiallyeligibleandwritteninlanguagesotherthanEnglishorFrenchweretranslatedto

Englishandincludediftheymetalleligibilitycriteria.

Table1.Eligibilitycriteriaforstudies

ComponentofStudy InclusionCriteria ExclusionCriteriaStudytype • Randomizedat

individuallevel• Parallel-groupdesign• Crossoverdesignwith

minimumwashoutperiodof4weeks

• Singleblind• Doubleblind

• Non-randomized• Clusterrandomized• Crossoverdesignwith

washoutperiodlessthan4weeks

• Unblinded

Participants • Aged18yearsorless• Migraineormigraine

subtypeasperICHDcriteria,Vahlquistcriteriaorothervalidatedcriteria

• Studieswithparticipantsover18yearswithnosubgroupanalysisonthoseunder18years

• Non-migraineheadaches

• Migrainediagnosedwithunvalidatedcriteria

Interventions • Pharmaceuticalinterventions

• Nutraceuticalsinterventions

• Lifestyleinterventions• Psychological

interventions• CAMinterventions

otherthannutraceuticals(eg.acupuncture)

Comparisons • Placebo• Activecomparatorif

placeboarmincluded

• Activecomparatorifnoplaceboarm

Outcomes • Oneoutcomemustpertaintomigraineprophylaxis

• Primaryoutcomeofinterestischangeinmigrainefrequencyovertreatmentperiod

• Nooutcomesrelatingtomigraineprophylaxis

2.4. SearchMethodsforIdentificationofStudies

20

Thefollowingdatabasesweresearched:MEDLINEincludingIn-Process&OtherNon-Indexed

Citations(1946-May19,2015),Embase(1947toWeek20,2015)andCochraneCentralRegisterof

ControlledTrials(CENTRAL,April2015).AllweresearchedusingtheOvidinterface.TheMEDLINE

searchstrategywasdevelopedbyalibrarianexperiencedinsystematicreviewsearching(Margaret

Sampson),andpeerreviewedbyanotherlibrarian(JanetJoyce),usingthePRESSstandard93.The

MEDLINEsearchwasthenadaptedfortheotherdatabases.Nolanguagelimitswereappliedbutthe

searchwaslimitedtorandomizedcontrolledtrialsandthepediatricagegroupusingvalidated

filters.Includedreferencelistswerescreenedforadditionalreferences.Thedetailedelectronic

searchstrategiesarepresentedinAppendixA.

Aswell,theInternationalClinicalTrialsRegistryPlatformSearchPortalandClinicalTrials.gov

weresearchedonJuly2nd2015forongoingorrecentlycompletedtrials.Authorsofpotentially

eligibleunpublishedtrialswerecontactedinordertoinquireabouttimingofmanuscript

publicationandaccesstotheunpublisheddata.

2.5. ScreeningProcess

2.5.1 FirstScreenMethodology

Twoscreeners(SerenaOrrandSuzanneNadineChristie)completedthefirsteligibilityscreen.

ThesearchresultswereuploadedintotheAbstrackrsoftware,whichwasusedtofacilitatethefirst

screenofstudies.Abstrackrisanopen-sourcedweb-basedapplicationavailabletousersatno

charge94.Itisdesignedtoassistresearchersintheprocessofscreeningreferencesforasystematic

review.ReferencesareuploadedtoAbstrackrandmultiplescreenerscanthenusetheapplication

torapidlyandefficientlyscreenthetitlesandabstractsresultingfromthesearch.Thistoolallows

userstokeeptrackofeligibilitydecisionsmadeduringthefirstscreen.Eachreferencecanbe

assignedadescriptivetagthatsummarizeswhyaparticulareligibilitydecisionwasmadeaboutthe

givenstudy(eg.excludedbecausenotrandomized).Abstrackrstoresalleligibilitydecisionsand

21

tags,andtheresultsofthescreencanbeexportedoncecomplete.Inaddition,theapplicationwill

automaticallyidentifyconflictsbetweenscreenersinregardstoeligibilitydecisionsandallows

userstoenteradecisionreconciliationmodewhereconflictscanberesolved.Anotherfeaturethat

allowsAbstrackrtomaximizescreeningefficiencyisitsabilitytohighlightkeywordsinabstracts

andtitles.Userscandefinekeywordsthatindicateeitherweakorstrongpotentialforinclusionor

exclusion.Abstrackrwillsearcheachsubsequentreference’stitleandabstractforthesekeywords,

highlightingwordsassociatedwithinclusioningreenandwordsassociatedwithexclusioninred.

2.5.2 SecondScreenMethodology

AfterthefirstscreenwascompleteinAbstrackr,twoscreeners(SerenaOrrandSuzanne

NadineChristie)undertookthesecondeligibilityscreen.Mendeleywasusedtomanagethesecond

eligibilityscreen.Mendeley(www.mendeley.com)isafreereferencemanagerthatallowstheuser

touploadreferenceswithPortableDocumentFormat(PDF)filesintotheapplication,organizethe

referencesintofolders,highlightandannotatethePDFfilesandcreategroupswherereferences

canbesharedbetweenusers.

Forthepurposesofthisreview,oncethefirsteligibilityscreenwascompleteinAbstrackr,the

referenceswereuploadedtoMendeley.ResultsoftheAbstrackrscreenwereexportedintoanExcel

file.EligibilitydecisionsandtagsintheExcelfilewerereviewedandusedtoorganizethe

referencesintofoldersinMendeley.Allreferencesthatpassedthefirsteligibilityscreenwere

includedinthesecondscreenandtheirassociatedPDFfileswereuploadedintoMendeley.ThePDF

fileswerereadduringthesecondscreeninordertomakefinaleligibilitydecisions.Eligibility

decisionswererecordedbyorganizingthefilesintofolders(eg.“includedaftersecondscreen”,

“excludedaftersecondscreenbecausemigrainecriterianotvalidated”,etc).Conflictsbetweenthe

twoscreenerswereresolvedinaconsensustelephonemeeting,heldonJanuary4th2016,onceboth

screenershadcompletedthesecondscreen.

22

2.6. DataExtraction

Foreachincludedstudy,aneligibilityscreeningformwascompletedinordertoensurethatthe

studyindeedmetallinclusioncriteriaandnoneoftheexclusioncriteria(seeAppendixB).

Datafromincludedstudieswereextractedusingastandardizedformcalledthe“Characteristics

ofStudiesTable”(seeAppendixC),whichwasmodeledbasedontherecommendedformatinthe

CochraneHandbook83.The“CharacteristicsofStudiesTables”areorganizedintofivesections

designedtocomprisetheentiretyofthemostpertinentdatafromeachstudy:methods,

participants,interventions,outcomesandnotes.Inthe“Methods”section,thedesignofthetrial

wasdescribed,includingwhetherthestudywasparallel-grouporcrossover,howmanystudyarms

wereincluded,theblindingstatusofthestudyanddetailsonrecruitmentandstudyduration.The

“Participants”sectionprovideddetailsaboutthenumberofparticipantsandthemostimportant

definingcharacteristicsoftheparticipantpopulation,thatistheageoftheparticipants,the

migrainedefinitionusedinthestudy,thedurationandfrequencyofthemigrainesatbaselineand

whetherornotimportantgroupdifferencesexistedintermsofbaselinecharacteristicsinthe

interventiongroups.Theactiveintervention(s)andplaceboarmweredescribedindetailinthe

“Interventions”sectionofthetable,wherebythenumberofparticipantsassignedtoeachgroup

wasgiven,inadditiontothename,route,dose,frequency,andifavailable,theappearanceand

smellofeachintervention.Theprimaryandsecondaryoutcomes,aswellastheadverseevents,

weredescribedindetailinthe“Outcomes”section,withpointestimates,varianceestimates,and

testsofsignificancereportedfortheprimaryoutcomewhenavailable.The“Notes”sectionwas

usedtodocumentparticularitiesaboutthestudyinquestionthatmayimpactinterpretationofits

results,thequalityratingofthestudyandanyothersalientdetails.

Qualityratingswerecompletedoneachstudy.The“CochraneRiskofBiasTool”isatoolthat

wasdevelopedbytheCochranecollaborationtomakeadeterminationontheinternalvalidityofa

particularstudy83.Inthissystematicreview,the“CochraneRiskofBiasTool”wasusedtomake

23

determinationsabouttheriskofbiasinsixdifferentdomains(seeAppendixD):selectionbias

(randomsequencegenerationandallocationconcealment),performancebias(blindingof

participantsandpersonnel),detectionbias(blindingofoutcomeassessmentforself-reportedand

objectiveoutcomes),attritionbias(incompleteoutcomedata),reportingbias(selectivereporting)

andotherbias.Eachdomainwasgivenariskofbiasratingbasedontheinformationinthe

manuscript:1)“highriskofbias”whenthemethodusedclearlycouldhaveledtobiasedresults,2)

“unclearriskofbias”whenthemethodusedwasinadequatelydescribedtomakeajudgmentonthe

qualityrating,3)“lowriskofbias”whenthemethodusedwasadequateandtheriskofbiasforthat

domainwasconsideredtobenegligible.InaccordancewiththeCochraneguidelines83,astudywas

givenanoverall“highriskofbias”ifatleastonedomainwasratedashavinga“highriskofbias”,

whereasthequalityratingwas“unclearriskofbias”ifatleastonedomainwasratedashavingan

“unclearriskofbias”andtherewerenodomainswith“highriskofbias”,andastudyhadtohave

“lowriskofbias”throughoutalldomainsinordertobegivenanoverallratingof“lowriskofbias”.

2.7. Meta-Analyses

Whenseveralstudieswereavailableforoneintervention,theoutcomesineachstudywere

reviewedindetail.Wheregroupsofstudieshadoverlapinoutcomeswithsufficientdataavailable

forpoolingtheresults,ameta-analysiswasconsidered.Meta-analyseswerecarriedoutif:1)

outcomesoverlappedasabove,2)theinterventionswerethesame,2)thecomparatorswerethe

same(ie.placebo),3)thestudieswerenotexcessivelyclinicallyheterogeneous.Ifastudywithin

oneinterventioncategorywaslackingtheoutcomeusedtopoolthedataorlackingcomponentsof

thedatanecessaryforthemeta-analysis,theauthorswerecontactedinordertorequestthe

missingdata.Uptothreeattemptsweremadetocontactauthorstoobtainsupplementaldata.Ifthe

authorsdidnotrespondorwereunwillingtosharethedata,thenthestudyinquestionwas

excludedfromthemeta-analysis.

24

Allmeta-analyseswerecarriedoutusingtheCochraneCollaborations’ReviewManager5.3.5

software(RevMan:http://tech.cochrane.org/revman).RevManisasoftwarepackageendorsedby

theCochraneCollaborationthathastheabilitytoconvertrawdatafromagroupofstudiesinto

pooledestimatesofeffectsusingavarietyofstatisticaltechniquesformeta-analysis.Therawdata

forthemeta-analyseswereentereddirectlyintoRevManandappropriateanalysisoptionswere

selecteddependingontheoutcomeinquestionandthecharacteristicsofthestudiesbeingpooled.

Alloutcomesamenabletopoolingwerecontinuousandthuspointestimates,standard

deviationsandsamplesizeswereenteredforeachstudy’sinterventionandcomparator.Ifthescale

usedtomeasurethecontinuousoutcomewasidenticalacrossstudies,thenanestimateofthemean

differencewith95%confidenceintervals(CI)wasgenerated.Ifthescaleusedtomeasurethe

continuousoutcomewasdifferentacrossstudies,thenanestimateofthestandardizedmean

differencewith95%CIwasgenerated.Arandomeffectsinverse-variancemethodwasusedasthe

defaultmodeltogenerateestimatesofthemeandifferenceorstandardizedmeandifference.In

decidingbetweenusingafixedorarandomeffectsmodel,statisticalandclinicalheterogeneityof

thestudieswereconsidered,withclinicalheterogeneitybeinggivengreaterweightinthedecision.

Statisticalheterogeneitywasassessedusingtwostatistics:1)thechisquaretestofheterogeneity,

wherethebodyofevidencewasdeemedstatisticallyheterogeneousifthepvaluewaslowerthan

0.1and,2)theI2statistic,wherestatisticalheterogeneitywasdefinedasanI2inexcessof30%.

Eachofthesedefinitionsofstatisticalheterogeneitywaschosenbasedonrecommendationsinthe

CochraneHandbookforSystematicReviewsofInterventions83:1)thep=0.1cutoffisrecommended

forthechisquaretestofheterogeneitygiventhelackofpowerofthetesttodetectstatistical

homogeneitywiththetypicalsmallsamplesizesseeninmeta-analyses,2)the30%cut-offfortheI2

statisticwaschosenbasedonthecut-offformoderateheterogeneitylistedintheHandbook.Inno

casewerethedatafrompooledstudiesconsideredclinicallyhomogeneousenoughtojustifyusinga

fixedeffectsmodel.

25

3. RESULTS

3.1. CharacteristicsofIncludedStudies

ThePRISMAdiagraminFigure1illustratestheresultsofthesystematicreviewthrougheach

stageofscreening.Intotal19articleswereeligibleforinclusion,comprising27studies.Detailson

eachstudyaresummarizedinTable2.Twelveinterventionswerereviewedinthesestudies:

butterbur,riboflavin,topiramate,valproicacid,flunarizine,timolol,clonidine,trazadone,

nimodipine,cinnarizine,dimethothiazineandpapaverine.Allofthestudieshadaplacebo

comparator,andthreeofthestudieshadanotherarminvolvinganactivecomparator.Fiveofthe

studieshadacrossoverdesign,andtheremainingarticlesreportedonparallel-grouptrials.Twoof

thearticlescomprisedpooledanalysesfromgroupsoftrials.TwelveofthearticlesusedICHD

criteria,fiveusedVahlquistcriteriaandtwousedAdHoccriteriatodiagnosemigraine.Outcomes

variedsignificantlybetweenstudies,renderingitachallengetopooldataintometa-analyses.

Sevenofthestudiesweregivenahighriskofbias,eightofthestudieshadanunclearriskofbias

andfourstudieshadalowriskofbias.Theoverallriskofbiasforthisbodyofliteratureis

summarizedinFigure2andtheriskofbiasresultsforeachindividualstudyaredisplayedinFigure

3.

26

Figure1.PRISMADiagram

Table2.Summaryofincludedstudies

Intervention Study Design Participants Interventions Efficacy Safety RiskofBias

Butterbur Oelkers-Ax2008

Randomized,partlydouble-blind,3-arm,parallel-grouptrialwith12weektreatmentphaseand8weekfollow-upphase

39childrenaged8-12yearswithmigraineasperICHDcriteria

20randomizedtoPetadolex®50mg/dayif8-9yoor50mgbidif10-12yo(doseincreasedto75mg/dayor75mgbidrespectivelyPRNat8weeks)vs.19randomizedto

Allthreegroupshadasignificantreductioninheadachefrequencywithmusicsuperiortoplaceboatpost-treatment(p=0.042)andbothmusicandPetadolex®superiortoplaceboat6mthfollow-up

Petadolex®groupreportedGIsymptoms,allergicsymptomsanddermalsymptoms;nosignificantdifferences

High

27

placebovs.24randomizedtomusictherapy

comparingthegroups

Riboflavin Bruijn2010

Randomized,double-blind,crossoverstudywith4weekbaseline,12weektreatment,4weekwashoutandsecond12weektreatmentperiod


20randomizedtoriboflavin50mgdailyforthefirstperiodvs.22randomizedtomatchedplaceboforthefirstperiod

Nogroupdifferencesintermsofthechangeinmigrainefrequency(p=0.44)

Noadverseeventsineithergroup

Unclear

MacLennan2008

Randomized,double-blind,2-arm,parallel-grouptrialwith4weekbaselineperiodand12weektreatmentperiod


27randomizedtoriboflavin200mgdailyvs.21randomizedtoplacebo

Nodifferenceintheproportionofparticipantsachievinga50%+reductioninmigrainefrequency:thetrialwasstoppedearlyduetolowlikelihoodofdetectingadifference

Oneparticipantonriboflavinhadanincreaseinthenumberoftensionheadaches,4childrentakingriboflavinhadachangeintheirurinecolor

Low

Topiramate Ford2014 Pooledanalysisofpediatricdatafrom5differentrandomized,double-blind,placebo-controlled,parallel-grouptrialswithtreatmentperiodsrangingfrom16-26weeks


Thenumberofpatientsrandomizedtoeachgroupisnotgiven:somewererandomizedtotopiramate2-3mg/kg/day,50mgdaily,100mgdailyor200mgdaily,somewererandomizedtoplaceboandonestudyhadanactivecomparatorarminvolvingpropranolol160mgdaily

Intermsofthe%reductioninmigraines:inTOPMAT-MIG3006thetopiramate100mgdailywassuperiortoplacebo(p=0.0164);inCAPS-122thetopiramateandplacebogroupsdidnotdiffer;inTOPMAT-MIGR-001/002/003therewasatrendtowardstopiramate100mgdailybeingsuperiortoplacebo

Somepatientsinthetopiramategroupsreportedinfluenza-likesymptoms,languageproblemsandparesthesias

Unclear

Lakshmi2007

Randomized,double-blind,placebo-controlled,2-arm,parallelgroupstudy


22randomizedtotopiramate25mgdailywithweeklyincreasesof25mgtoamax

Thetopiramategrouphadagreaterdecreaseinmigrainefrequencyfrombaselinetotheendofthestudy

Moreadverseeventswithtopiramatewithmost

Low

28

with4weektitrationperiodand12weekmaintenanceperiod

of50mgbidvs.22randomizedtoplacebo

(from16.14+9.35to4.27+1.95vs.from13.38+7.48to7.48+5.94,p=0.025)

commonbeing:weightloss,lossofappetite,paresthesiasandlackofconcentrationinschoolbeingthemostcommon

Lewis2009

Randomized,double-blind,placebo-controlled,3-arm,parallel-grouptrialwith9weekbaseline,16weektreatmentand6weektaperandexitphase

103adolescentsaged12-17yearswithmigraineasperICHDcriteria

35randomizedtolowdosetopiramate(25mg/dayuptoamaximumof25mgbid)vs.35randomizedtohighdosetopiramate(25mg/dayuptoamaximumof50mgbid)vs.33randomizedtoplacebo

Highdosetopiramategrouphadalargerdecreaseinmigrainefrequencyascomparedtoplacebo(72.2%vs.44.4%,p=0.016),butnosignificantdifferencecomparinglowdosetopiramatetoplacebo(p=0.798)

Moreadverseeventswithtopiramate(74%vs.48%)withmostcommon:upperrespiratorytractinfections,paresthesiasanddecreasedappetite

Low

Pandina2010

Randomized,double-blind,placebo-controlled,3-arm,parallel-grouptrialwith9weekbaseline,16weektreatmentand6weektaperandexitphase(analysisofsubsetofdatafromLewis2009)


35randomizedtolowdosetopiramate(25mg/dayuptoamaximumof25mgbid)vs.35randomizedtohighdosetopiramate(25mg/dayuptoamaximumof50mgbid)vs.33randomizedtoplacebo

N/A–analysisofsubsetofthedatarelatedtocognitiveadverseevents

Oncognitivetesting,highdosetopiramateassociatedwithsmallincreasesinpsychomotorreactiontimesanddecreaseinthenumberofuniquewordstheycouldgenerate

Low

Winner2005

Randomized,double-blind,placebo-controlled,parallel-grouptrialwith2:1assignmenttotheinterventiongroupand4


112randomizedtotopiramate15mgdailytitrateduptomaxof2-3mg/kgdailyor200mgdailyvs.50randomizedtoplacebo

Greaterreductioninmigrainefrequencyinthetopiramategroupinper-protocolanalysisandtrendinintention-to-treatanalysis(2.8+2.4vs.2.2+2.1,p=0.033forPPand2.6+2.6

Nodifferenceinsideeffectsoverall;4seriousadverseeventswithtopiramate

Unclear

29

weekbaselineperiod,8weektitrationperiodand12weekmaintenanceperiod

daysvs.2.0+3.1days,p=0.061forITT)

Winner2006

Pooledanalysisofpediatricdatafromthreerandomized,double-blind,placebo-controlled,parallel-grouptrialswith2weekwashout,4weekbaseline,8weektitrationand18weekmaintenanceperiods

49adolescentsaged12-18withmigraineasperICHDcriteria

11randomizedtolowdosetopiramate(50mgdaily)vs.13randomizedtomediumdosetopiramate(100mgdaily)vs.13randomizedtohighdosetopiramate(200mgdaily)vs.12randomizedtoplacebo

Greaterreductionsinmigrainefrequencyinthemediumandhighdosetopiramategroupsascomparedtoplacebo(63%and65%comparedto13%reductions,p<0.04)

Nooveralldifferenceinadverseevents;moreweightlossandcognitivesideeffectswithtopiramate;mostcommonadverseeventswithtopiramate:upperrespiratorytractinfections,paresthesiasandweightloss

Unclear

Valproicacid Apostol2008

Randomized,double-blind,placebo-controlled,4-armparallelgrouptrialwith2weekwashoutperiod,4weekbaselineperiod,2weektitrationperiodand10weektreatmentperiod


83randomizedtolowdosedivalproex(250mgdaily)vs.74randomizedtomediumdosedivalproex(startedat250mgdailyandincreasedto500mgdaily)vs.75randomizedtohighdosedivalproex(startedat500mgdailyandincreasedto1000mgdaily)

Nodifferencebetweenanydoseofdivalproexandplacebointermsofdecreaseinmigrainefrequency

Nooveralldifferencesinadverseevents;mostcommonwithdivalproex:upperrespiratorytractinfections,somnolenceandfatigue

Unclear

Flunarizine MachínAltueña1987

Randomized,double-blind,placebo-controlled,3-arm,parallel-groupstudywith16weektreatmentperiod

45childrenaged5-13yearswithmigraineasperAdHoccriteria

15randomizedtoflunarizine0.15mg/kgdailyvs.15randomizedtodimethothiazine1mg/kgdailyvs.15randomizedto

Nodifferencesinratesofclinicalimprovementbetweenthegroups(93.3%fordimethothiazinevs.86.7%forflunarizinevs.80%forplacebo,

23.1%offlunarizinepatientsgainedweight

High

30

placebo p>0.05)Sorge1985 Randomized,

double-blind,placebo-controlled,2-arm,parallel-grouptrialwith12weektreatmentperiod

48childrenunderage18yearswithmigraineasperVahlquistcriteria

24randomizedtoflunarizine5mgdailyvs.24randomizedtoplacbeo

Lowerheadachefrequencyattrialcompletionintheflunarizinegroup(p<0.001)

Lackingdetailsonadverseevents;3patientswithdrewfromtheflunarizinegroupduetosideeffects(GIsymptoms,drowsinessandfatigue)

High

Sorge1988 Randomized,double-blind,placebo-controlled,crossovertrialwith4weekbaseline,12weektreatment,4weekwashoutandsecond12weektreatmentperiod

70childrenaged5-11yearswithmigraineasperVahlquistcriteria

35randomizedtoflunarizine5mgdailyforfirsttreatmentperiodvs.35randomizedtoplaceboforfirsttreatmentperiod

Greaterreductioninmigrainefrequencyduringflunarizinetreatmentperiodascomparedtoplacebotreatmentperiod(p<0.001)

Mostcommonlyweightgainanddrowsinessbutgroupcomparisonsnotmade

High

Timolol Noronha1985

Randomized,double-blind,placebo-controlled,crossoverstudywith4weekbaseline,8weektreatment,4weekwashoutand8weeksecondtreatmentphase

17patientsaged5-16yearswithmigraineasperVahlquistcriteria

9randomizedtotimolol5mgdailyforfirsttreatmentperiodand8randomizedtoplaceboforfirsttreatmentperiod

Therewerenogroupdifferencesinanyoftheoutcomes,includingmigrainefrequency

Lackingdetailonadverseevents;twopatientswithdrewfromtimololduetoheadacheandvomiting

High

Clonidine Sillanpää1977

Randomized,double-blind,placebo-controlled,2-armparallelgroupstudywith8weektreatmentperiod

57children15yearsandunderwithmigraineorvascularheadacheasperVahlquistcriteria

28randomizedtoclonidine25micrograms(mcg)dailyifunder40kgorand25mcgbidifover40kgvs.29randomizedtoplacebo

Lackofdetailwithreportingofresults(mosthypothesistestsnotgiven):1/3oftheparticipantswereheadache-freeduringtreatmentineachgroup,57%ofclonidineparticipantsand42%ofplaceboparticipantshad

Adverseeventsin11clonidineparticipantsvs.6placebo;mostcommonwithclonidinewasfatigueand

High

31

only1or2headachesduringtheentirestudy

nausea

Trazodone Battistella1993

Randomized,double-blind,placebo-controlled,crossoverstudywith12weektreatment,4weekwashoutandsecond12weektreatmentperiod


20randomizedtotrazadone1mg/kgdailyforfirsttreatmentperiodvs.20randomizedtoplaceboforfirsttreatmentperiod

Nogroupdifferencesinthefirsttreatmentphase;inthesecondphasethetrazodonegrouphadagreaterdecreaseinmigrainefrequency(trazadonereducedfrom2.1+0.2attacks/monthto1.8+0.2vs.placeboincreasedfrom1.8+0.1to2.1+0.2,p<0.005)

Lackingdetailsonadverseevents;noseriousadverseeventsoccurred

Unclear

Nimodipine Battistella1990

Randomized,double-blind,placebo-controlled,crossoverstudywith4weekbaseline,12weektreatment,4weekwashoutandsecond12weektreatmentperiod

37patientsaged7-18yearswithmigraineasperAdHoccriteria

18patientsrandomizedtonimodipine10-20mgtidforfirsttreatmentperiodvs.19randomizedtomatchedplaceboforfirsttreatmentperiod

Nogroupdifferencesinthefirsttreatmentphase;inthesecondphasethenimodipinegrouphadagreaterdecreaseinmigrainefrequencythantheplacebogroup(from2.7+0.8attacks/monthto1.9+1.7vs.from2.6+0.8to2.8+0.6,p<0.01)

Lackingdetailsonadverseevents

Unclear

Cinnarizine Ashrafi2014

Randomized,double-blind,placebo-controlled,2-armparallelgroupstudywith4weekbaselineand12weektreatmentperiod

62children5-17yearswithmigraineasperICHDcriteria

30randomizedtocinnarizine1.5mg/kgdailyifweightlessthan30kgand50mgdailyif30kgormorevs.32randomizedtoplacebo

Cinnarizineyieldedahigherproportionachieving50%orgreaterreductioninmigraines(60%vs.31.3%,p=0.023);nodifferencesingroupsforchangeinmigrainefrequency

3cinnarizineparticipantsvs1placeboparticipanthaddrowsiness;1incinnarizinegrouphadsignificantweightgain

Unclear

Dimetho-thiazine

MachínAltueña1987

Randomized,double-blind,placebo-controlled,3-arm,parallel-groupstudywith16weektreatmentperiod

45childrenaged5-13yearswithmigraineasperAdHoccriteria

15randomizedtodimethothiazine1mg/kgdailyvs.15randomizedtoflunarizine0.15mg/kgdailyvs.15randomizedtoplacebo

Nodifferencesinratesofclinicalimprovementbetweenthegroups(93.3%fordimethothiazinevs.86.7%forflunarizinevs.80%forplacebo,p>0.05)

23.1%offlunarizinepatientsgainedweight

High

Papaverine Sillanpää Randomized, 37children 19randomized Morepatientsin Adverse High

32

1978 double-blind,placebo-controlled,2-armparallel-groupwith

aged6-15yearswithmigraineasperVahlquistcriteria

topapaverine5-10mg/kgdaily(startedat5mg/kgdaily)vs.18randomizedtoplacebo

thepapaverinegroupwerepain-freeontreatment(6vs.0,p<0.001)andheadachefrequencywaslowerinthepapaverinegroup(p<0.001)

eventsnotreported

Figure2.Riskofbiasgraph:reviewauthors'judgementsabouteachriskofbiasitempresentedaspercentagesacrossallincludedstudies.

33

Figure3.Riskofbiassummary:reviewauthors'judgmentsabouteachriskofbiasitemforeachincludedstudy.

*NB.Redcirclesindicatehighriskofbias,greencirclesindicatelowriskofbiasandwhitesquaresindicateunknownriskofbias

34

3.2. NutraceuticalInterventions

3.2.1 Butterbur(Petasiteshybridus)

Butterbur(Petasiteshybridus)isaperennialshrubthatgrowsinseveraldifferentcontinents.Its

medicinalpotentialhasbeenrecognizedforcenturies95.Althoughithashadmanyusesthroughout

theyears,itiscurrentlytoutedasaremedyformigraines,asthma,rhinitisandchroniccough95,96.

Themechanismthroughwhichitmayexertaneffectonmigraineisunclear.Ithasbeenshownto

haveanti-inflammatorypropertiesthroughitsselectiveinhibitionoftheenzymecyclooxygenase-

297,andinthiswayitcouldrelievemigraineswithamechanismsimilartothatofthenon-steroidal

anti-inflammatorydrugs,whicharecommonlyusedinpediatricmigraine.Leukotrieneproduction

fromprimedgranulocytesalsoappearstobeinhibitedbyPetasites,furthercontributingtoitsanti-

inflammatoryactivity98.Petasiteshasanotherpropertythatcouldrenderitefficaciousinmigraine:

ithasbeenshowntoinhibitL-typevoltage-gatedcalciumchannels99,inamanneranalogousto

calciumchannelblockerslikeflunarizine,whichisrecommendedforpediatricmigraine

prophylaxis100.

Unfortunately,Petasitescontainspyrrolizidinealkaloids,whicharecompoundswithknown

hepatotoxicity.Arecentstudyfounddetectablelevelsofpyrrolizidinealkaloidsinalmosthalfofthe

samplesofPetasitescommercialproductsthatitassayed101.AformulationcalledPetadolex®,with

supposedlyundetectableamountsofpyrrolizidinealkaloids,hasbeendevelopedandwasoriginally

foundtobesafeforhumanuse102.However,post-marketingsurveillancehasidentifiedcasesof

hepatoxicitylinkedtoPetadolex®.Thishaspromptedregulatoryauthorities,includingtheGerman

FederalInstituteofMedicalDevicesandtheSwissAgencyforTherapeuticProducts,tobanitsuse

intheirrespectivecountries103.Therefore,althoughtheevidencefortheuseofPetadolex®from

placebo-controlledtrialswillbereviewedhere,itisnolongeraviableoptionforpediatricmigraine

prophylaxis.

35

Onlyonestudyassessingtheefficacyofbutterburforthisindicationmetinclusioncriteria.

Oelkers-Axetalcarriedoutapartlydouble-blind,randomized,3-armparallelgrouptrialinagroup

of63childrenwithmigraineaged8to12years104.Patientswererandomizedtoreceiveoneof

threetherapies:butterbur,placeboormusictherapy.ThebutterburgroupwasgivenPetadolex®,a

regulatedformulationofbutterbur,atastartingdoseof50mgdailyforchildrenaged8and9years,

or50mgtwicedailyforchildrenaged10-12years.Thestartingdosewasadministeredforthefirst

8weeks.Subsequently,childrenwithasuboptimalresponsehadtheirdoseincreasedby50%for

thenext4weeksoftreatment.Theplacebogroupwasgivenplacebopillsforthefirst8weeks,with

adoseadjustmentat8weeksifnecessary.Finally,themusictherapygroup,whocouldnotbe

blindedtotheirassignmentgiventhenatureofthetreatment,received12weeklysessionsofmusic

therapy,focusedonavarietyoftechniquesincludingmusic-aidedrelaxationtraining,body

awarenesstechniquesandconflicttraininginamusicalrole.Atthepost-treatmentassessment,

bothas-treatedandintention-to-treatanalysesshowedthatthegroupsallhadasignificant

decreaseintheirmigrainefrequencyascomparedtobaseline,whichwastheprimaryoutcome.At

thisstage,musictherapywassuperiortoplacebowithregardstotheprimaryoutcome,whereas

Petadolex®wasnot.However,atthe6monthfollow-upassessment,bothmusictherapyand

Petadolex®weresuperiortoplacebo.Furthermore,therewerenodifferencesinadverseevents

betweenthegroups.Thebutterburgroupprimarilyexperiencedgastrointestinal,cutaneousand

allergicsymptomsassideeffects.TwopatientsinthePetadolex®groupandandthreepatientsin

theplacebogrouphadtransientmildtransaminitis.Thisstudywasdeemedtohaveahighriskof

biasbasedonseveralkeyweaknesses.Namely,completeimplementationofadouble-blind

protocolwasnotpossiblegiventhatmusictherapycannotbeblindedtothepatients.Thisposeda

highriskforperformancebiasanddetectionbias.Inaddition,randomizationdidnotsucceedin

makingthegroupsbalancedonallbaselinecharacteristics:thePetadolex®grouphadalmost

doublethebaselinemigrainefrequencyascomparedtotheothergroups(9.8+7.6vs.5.5+4.4vs.

36

5.0+2.5,p=0.409),andthoughthisdidnotreachstatisticalsignificance,itisclinicallymeaningful.

Finally,therewasahighriskofattritionbiasgivenahigherrateofdrop-outsinthemusictherapy

andPetadolex®groupsascomparedtoplacebo(29%formusictherapyvs.25%inPetadolex®

groupvs.5%inplacebogroup,p=0.113).Thoughthedifferenceswerenotstatisticallysignificant,

theywereclinicallysignificantandthereforelikelycreatebiasintheresults.Thus,onlyonestudy

assessedtheefficacyofbutterburinchildrenandthisstudyisofinferiormethodologicalquality

givenseveralkeyareaswithahighriskofbias.This,coupledwithsafetyconcernsaboutbutterbur,

precludesrecommendationsforitsuseinpediatricmigraineprophylaxis.

Therefore,onlyonesmalltrialwithahighriskofbiaslendssomeevidenceinfavorof

Petadolex®.Giventhisandtheevidencesuggestingthatbutterburcompoundsmaybehepatotoxic,

itwouldbeunwisetorecommendtheuseofbutterburforpediatricmigraineprophylaxis.

3.2.2 Riboflavin(VitaminB2)

Unlikebutterbur,riboflavindoesnothavealonghistoryofmedicinaluse.Itwasonlyisolated

inthe1930sandsynthesizedshortlythereafter.Riboflavinisderivedfromamultitudeofdietary

sources.Itplaysavitalroleinmitochondrialenergymetabolismthroughitstwoactivecoenzymes:

riboflavin5’-phosphateandflavinadeninedinucleotide.Bothofthesecompoundsparticipateina

multitudeofmetabolicprocesses105.Itispreciselyitsroleinmitochondrialenergymetabolismthat

givesriboflavinsomecredibilityasapotentialtherapyformigraines.Thereisanaccumulating

bodyofevidencesuggestingthatmigraineursmaybeinastateofmitochondrialenergy

depletion106–113.Therefore,compoundslikeriboflavin,whichplayaroleinmitochondrialenergy

production,mayhelptopreventmigraines.

Twostudiesontheefficacyofriboflavinforpediatricmigraineprophylaxiswereincludedinthe

systematicreview.Thefirststudy,byMacLennonetal,randomized48childrenbetweentheagesof

5and15yearstoreceiveeither12weeksofriboflavin200mgdailyoramatchedplacebofortheir

migraines114.Effortsweremadetomaintainblindingamongstbothparticipantsandstudy

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personnel.After12monthsofrecruitmentandattainmentof86%oftheplannedsamplesize,the

trialwasstoppedgiventhataninterimdataanalysisshowedthattherewasaverylowprobability

offindingefficacyfortheriboflavinintervention.Theexactstoppingruleusedfortheinterim

analysisisnotclear.Therewerenogroupdifferencesintheprimaryoutcome,thatis,the

proportionofparticipantsachievinga50%orgreaterreductioninmonthlymigrainefrequency.

Also,noneofthesecondaryoutcomesfavoredriboflavin.Overall,however,riboflavinwaswell

tolerated:onechildhadanincreaseintheirtension-typeheadachesandfourchildrenreporteda

changeintheirurinecolorbutotherwisetherewerenoreportedadverseeventsforthetreatment

group.Thestudywaspoweredtodetecta40%differencebetweenplaceboandriboflavin,whichis

ambitiousandthereforethestudywaslikelyunderpowered.Thestudywasmethodologically

soundwithalowriskofbiasacrossallofthecoredomains.

ThesecondstudyonriboflavinwascarriedoutbyBruijnandcolleagues,andinvolved

randomizing42childrentoreceiveeitherriboflavin50mgdailyorplacebo,consistingof100mgof

carotene,inadouble-blind,cross-overdesign115.Eachtreatmentwasadministeredfor16weeks

andtherewasa4-weekwashoutperiodinbetweentheinterventions.Intheend,intention-to-treat

analysesdidnotuncoveranydifferencesbetweenthegroupsineithertheprimaryorsecondary

outcomes.Thestudywasonlypoweredtodetectadifferenceof0.6standarddeviationsbetween

thegroupsrelativetothechangeinmigrainefrequency.Thisminimalclinicallyimportant

differenceislikelytoolarge,andthestudywasthereforearguablyunderpowered.Also,thedoseof

riboflavinismuchlowerthanthatusedinotherstudiesandthanthetypicaldoseusedclinically.

Hence,itispossiblethatthelackofefficacywasduetounder-dosing.Anotherconcernrelatesto

theuseofcaroteneintheplacebo;althoughtherationaleforitsusewassound(riboflavincolors

theurineorangeandcarotenemimicsthissideeffect),itispossiblethatthecarotenecouldhavea

migraineprophylacticeffectrenderingitanactivecomparatorasopposedtoatrueplacebo.The

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studywasratedashavinganunclearriskofbiasgiventhattherewerenodetailsavailableonthe

methodofrandomization.Otherwise,thestudywasmethodologicallysound.

Therearethereforetwosmalltrialsthathavefoundnodifferencebetweenplaceboand

riboflavinforpediatricmigraineprophylaxis.Bothstudieswerelikelyunderpowered.TheBruijnet

alstudyhadseveralothermethodologicalshortcomingsaswell.Hence,itisdifficulttomake

conclusionsaboutriboflavin’sefficacybasedonthecurrentstateoftheevidence.Givenits

favorabletolerability,furtherhighqualitystudies,involvinglargergroupsofpatients,are

warranted.

3.3. Pharmaceuticals

3.3.1 Topiramate

Topiramateisacommonlyusedantiepilepticmedicationwithabroadanticonvulsantprofile

comprisingamultitudeofpotentialmechanismsofactionforseizureprophylaxis116.Itisunclear

howitmightoperateinmigraineprevention.Therationaleforitsuseinmigrainepertainstothe

beliefthatmigraineandepilepsymayoverlapintheirpathophysiologies,andthatmigraine,like

epilepsy,involvesastateofbrainhyperexcitability117.In2014,topiramatewasapprovedbythe

FoodandDrugAdministration(FDA)fortheprophylaxisofmigraineinadolescents.Itisthefirst

andonlydrugtoreceiveFDAapprovalforthisindicationinthepediatricagegroup118.Health

Canadacurrentlyhasnotapprovedanydrugsforpediatricmigraineprophylaxis,buttopiramateis

approvedformigraineprophylaxisinadults119.

Sixstudiesontheefficacyoftopiramateformigraineprophylaxisinchildrenandadolescents

wereincluded.Inadouble-blind,parallel-grouptrial,Winneretalrandomizedchildrenaged6to

15yearstoreceiveeithertopiramateintitratingdosesupto2-3mg/kg/dayortitratingdosesof

placeboina2:1ratio120.Afterthe4-weekbaselineperiod,an8-weektitrationperiodwasinitiated

foreachgroup,withthetopiramateparticipantsstartingatadoseof15mgdaily,followedbyaslow

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titrationuptoamaximumof200mgdailyor2-3mg/kg/dayasneeded,andtheplaceboparticipants

havinganartificialtitrationschedule.Afterthetitration,eachgroupentereda12-week

maintenancephase.During20weeksoftreatment,thetopiramategrouphadahighermean

reductionintheirheadachefrequencyintheper-protocolanalysis(2.6+2.6daysforthetopiramate

groupvs.2.0+3.1daysfortheplacebogroup,p=0.033),butthedifferencebetweentopiramateand

placeboonlyapproachedsignificanceintheintention-to-treatanalysis(2.8+2.4daysforthe

topiramategroupvs.2.2+2.1daysfortheplacebogroupp=0.061).Becausenosamplesize

calculationsarereported,itisunclearwhatminimalclinicallyimportantdifferencethetrialwas

poweredtodetect.Intention-to-treatanalysesforallsecondaryoutcomesfavoredtopiramateina

statisticallysignificantmannerexceptfortheanalysiscomparingtheproportionofpatientswitha

50%orgreaterreductioninmigrainefrequencyoverthetreatmentperiod:here,therewasno

differencewhencomparingplacebototopiramate(p=0.18).Topiramatewaswelltoleratedwithno

significantdifferenceintheincidenceofadverseeventsascomparedtoplacebo.Therewere4

seriousadverseeventsinthetopiramategroup.Thisstudywasratedashavingunclearriskofbias,

simplybecauseofalackofdescriptionastohowtherandomizationcodewasgenerated.Otherwise,

allotherdomainsofthestudyhadalowriskofbiasandoverallthemethodologicalqualityofthe

trialwasstrong.

Lakshmietalcarriedoutadouble-blind,placebo-controlled,parallel-grouprandomizedtrialin

44childrenaged8-14yearswithmigraine121.Theyrandomized22participantstotopiramate,

whichwasinitiatedatadoseof25mgdailyandtitratedupto50mgbidover4weeksfollowedby

maintenanceatthisdosefor12weeks,and22participantstomatchedplacebofor16weeks.

Topiramatewassignificantlybetterthanplaceboatreducingthefrequencyofmigraineswhen

comparingbaselinetotheendoftreatment(thetopiramategroupwentfromameanof16.14+9.35

migrainedays/monthto4.27+1.95days/monthvs.theplacebogroupthatwentfrom13.38+7.48

days/monthto7.48+5.94days/month,p=0.025).Topiramatewasalsosignificantlybetterthan

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placebointermsoftheproportionofpatientsachievinga50%orgreaterreductioninmigraine

frequency,inreducingdisabilityscoresonthePedMIDASandinreducingschoolabsenteeismas

comparedtoplacebo,butwasnodifferentfromplacebointermsofchangesinmigrainedurationor

intensity.Thereweremoreadverseeventswithtopiramate,withweightloss,reducedappetite,

paresthesiasanddecreasedconcentrationbeingthemostprevalent.Althoughthetrialwassmall,it

wasmethodologicallyrigorous,receivingajudgmentoflowriskofbiasforalloftheCochranerisk

ofbiasdomains.

Lewisetalrandomizedagroupof106adolescentsaged12to17yearswithmigrainetoeither

highdosetopiramate,lowdosetopiramateorplaceboinadouble-blind,3-arm,parallel-grouptrial

ina1:1:1fashion122.Thestudycompriseda9-weekbaselineperiod,duringwhichthefirstweek

wasdedicatedtoscreening,thenext4weeksinvolvedawash-outperiodforanyprophylactic

migrainemedicationsinuseandthelast4weeksconsistedofthebaselineperiod.Afterthese9

weeks,theparticipantsentereda16-weektreatmentperiod,whichwasfollowedbya6weektaper

andendofstudyperiod.Thetopiramategroupsbothstartedatadoseof25mgdaily,andthelow

dosegroupwasthentitratedupto25mgbidastolerated,whereasthehighdosegroupwastitrated

upto50mgbidastolerated.Theplacebogroupwasgivenmatchingplacebopills.Eachpatient

received4identical-appearingpillsperday,comprisedof25mgoftopiramateorplacebo,ora

combinationthereof.Theprimaryoutcome,thatis,thepercentreductioninmigrainefrequency

comparingthelast12weeksoftreatmenttobaseline,wasachievedinsignificantlymorepatients

takinghighdosetopiramateascomparedtoplacebo(72.2%vs.44.4%,p=0.016),whereasthere

wasnodifferencecomparinglowdosetopiramatetoplacebo(p=0.798).Mostofthesecondary

outcomesyieldedsimilarresultswithonlythehighdosetopiramatetreatmentbeingfavoredover

placebo.Thestudywaspoweredtodetectadifferenceof43%betweenthetopiramategroupsand

placebointermsoftheprimaryoutcome,thatisthepercentagereductioninmigrainefrequencyin

thelast12weeksoftreatmentcomparedtobaseline,atapowerof80%withaprobabilityoftypeI

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errorof5%usinga2-sidedMann-Whitneytest.Therefore,itispossiblethattherewasaclinically

meaningfuldifferencebetweenlowdosetopiramateandplacebothatwasnotdetectedgiventhe

relativelylowpowerofthestudy.Thisstudywasmethodologicallysoundwithalowriskofbias

acrossalldomainsofpotentialbias.

Inasubsequentpublication,Pandinaetal123reportedonneurocognitiveandmoodoutcomes

observedintheLewisetalstudy.ThesamepatientshadalsocompletedaCambridge

NeuropsychologicalTestAutomatedBattery(CANTAB)andaProfileofMoodStates.Thehighdose

topiramategrouphadsignificantincreasesintheirreactiontimesontheCANTABascomparedto

placebo,butlowdosetopiramateandplacebodidnotdifferintheirreactiontimes.Thelowdose

topiramategrouphadasignificantreductionintheirtotalnumberofuniquewordsascomparedto

placebo.However,changesseeninCANTABmemory,visualinformationprocessingandlearning

scoresdidnotdiffersignificantlybetweenthegroups,nordidtheProfileofMoodStateschanges

overtime.

Winneretalalsocarriedoutapooledanalysisontheefficacyandsafetyoftopiramatefor

adolescentmigraineprophylaxisusingdatafromthreeadultrandomizedcontrolledtrials124.

Fourty-nineadolescentswereincludedfromthethreetrials.Allthreetrialshadsimilar

methodologywhereparticipantswererandomizedinequalproportionstooneoffourtreatment

groups:topiramate50mgdailyorinonetrialpropranolol,topiramate100mgdaily,topiramate

200mgdailyorplacebo.Eachgroupunderwenta2-weekwashoutperiodandthena4-week

baselineperiod.Subsequently,thegroupsenteredan8-weektitrationphase,wherepatients

randomizedtotopiramatestartedadoseof25mgdaily,whichwassubsequentlyincreasedby

25mgweeklyuntilthetargetdosewasachieved.Followingthetitrationphase,participantsentered

an18-weekmaintenancephase.The100mgand200mgtopiramategroupsweresignificantly

betterthanplacebowithregardstotheprimaryoutcome:theyhadagreaterreductioninmigraine

frequencyduringtreatmentascomparedtobaseline(63%fortopiramate100mggroupand65%

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fortopiramate200mggroupcomparedto13%reductionforplacebogroup,p<0.04).However,the

treatmentgroupsdidnotdifferfromplacebointermsofthesecondaryoutcomes.Overall,

topiramatewaswelltoleratedwithnoseriousadverseeventsandnodifferencefromplaceboin

termsoftheincidenceofadverseevents.Cognitivesideeffectsweremorecommonwithtopiramate

thanwithplacebo.Themostcommonsideeffectsreportedwereupperrespiratorytractinfections,

weightlossandparesthesias.Thestudiesthatwereusedforthepooledanalysiswere

methodologicallystrong,butthisanalysiswasratedashavingunclearriskofbiasgiventhatitis

unclearwhetherallocationtotherandomsequencewasconcealedinanyofthestudies,evenafter

accessingtheoriginaladulttrials.

Finally,similarlytoWinneretal124,Fordetallookedatthesubsetofpediatricpatients

participatinginfivelarge,multicenterRCTs125.Thetrialswerealldouble-blind,placebo-controlled

parallel-groupdesignswithtreatmentperiodsrangingfrom16-26weeks.Dosingregimensfor

topiramatevariedfrom50mgdailyto200mgdailyandinonetrialthedosingwasflexibleat2-3

mg/kgdaily.Onestudyhadapropranolol160mgdailyactivecomparatorarminadditiontothe

placeboandtopiramatearms.Thisanalysisisonlypublishedinconferenceabstractformandthe

numbersrandomizedtoeacharmarenotgiven,butatotalof309pediatricparticipantswere

included.Twoefficacyoutcomeswereanalyzed:thepercentchangeinmonthlymigrainefrequency

andtheresponderrate,thatis,thepercentageofparticipantsachievinga50%orgreaterreduction

inmigrainefrequency.Withregardstothepercentreductioninmigrainefrequency,onlyonetrial

foundasignificantdifferencebetweentopiramateandplacebo:intheTOPMAT-MIG-3006trial,

topiramate100mgdailywassuperiortoplaceboforthisoutcome(p=0.0164).Similarly,onlythe

TOPMAT-MIG-3006trialyieldedasignificantdifferenceinresponderratescomparingtopiramate

withplacebo,withtopiramate100mgdailyoutperformingplaceboforthisoutcome(p=0.0048).

Sideeffectsarenotreportedonindetail,butthemostcommoneventswereflu-likesymptoms,

languageproblemsandparesthesias.Itisimportanttonotethatthreeoutofthefivetrials

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comprisedbothpediatricandadultpatientsandmaynothavebeenpoweredtodetectdifferences

intheoutcomesforthepediatricsubsetofparticipants.OnlytheTOPMAT-MIG-3006andCAPSS-

122trialsrecruitedexclusivelypediatricparticipantsandthusonlythosetrialsweredefinitely

adequatelypoweredfortheirprimaryoutcomes.Thisanalysiswasonlydescribedinconference

abstractformandtherewasunclearriskofbiasintermsofallocationconcealmentandattrition

bias.Thus,theanalysishadanunclearriskofbiasoverall.Theauthorsconcludedthattopiramate

100mgdailywasefficaciousinadolescents,giventhattheTOPMAT-MIG-3006study,which

supportedtheefficacyoftopiramateatthisdose,recruitedonlyadolescentsages12to17years.

Thereisconsistentevidencefromthesesixstudiesthattopiramateiseffectiveinpreventing

migrainesinchildrenandadolescents.Italsoappearedtobewelltoleratedamongstthesepatients,

thoughthepooledanalysisbyPandinaetal123confirmedwhatmanycliniciansobserveanecdotally

intheirpatients:thattopiramatehasadverseeffectsoncognition.Becauseofitssideeffects,

primarilythoserelatedtocognition,topiramatemustbeusedjudiciouslyinthispopulationgiven

thatcognitiveperformanceiskeyinthechildoradolescent’ssuccessinschoolandintheir

transitiontoemployment.

3.3.2 ValproicAcid

Valproicacid,liketopiramate,isabroad-spectrumantiepilepticdrugwithmultiplemechanisms

ofaction116thathasbeenusedoff-labelforpediatricmigraineprophylaxis.ValproicacidhasFDA

approvalforuseinmigraineprophylaxisinadults,whereasHealthCanadahasnotapproveditfor

thisindication.Again,therationaleforusingvalproicacidinmigrainepertainstothetheorythat

migraineandepilepsyhavesimilarunderlyingmechanisms126.

Theefficacyofvalproicacidforpediatricmigraineprophylaxishasonlybeenassessedinone

eligibletrial.InastudysponsoredbyAbbottPharmaceuticals,Apostoletalrandomized305

adolescentswithmigrainetoeitherdivalproex250mgdaily,divalproex500mgdaily,divalproex

1000mgdailyormatchedplaceboinadouble-blind,4-armparallel-grouptrial127.Participantsfirst

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hada2-weekwashoutperiod,followedbya4-weekbaselineperiod.Eligibleparticipantswerethen

randomizedtooneofthe4groupsanda2-weektitrationperiodstarted.Duringtitration,thosein

the250mgand500mgdivalproexgroupsstarteddivalproexatdoseof250mgdaily,whereasthose

inthe1000mgdivalproexgroupstarteddivalproexatadoseof500mgdaily.Followingthe2-week

titration,targetdoseswerestartedandmaintainedfor10weeks.Therewerenosignificant

differencesbetweenthegroupsintermsoftheprimaryoutcome,thatis,thechangeinmigraine

frequencycomparingbaselinetothe12-weektreatmentperiod.Inaddition,noneofthedivalproex

groupsweresignificantlydifferentfromplaceboinanyofthesecondaryoutcomes.Overall,there

wasnodifferenceinthefrequencyofadverseeventratesbetweenthegroups.Themostcommon

adverseeventswithdivalproexwereupperrespiratorytractinfection,somnolenceandfatigue.The

effectsizeusedtopowerthestudywasbasedonresultsofasimilartrialinadults.Theauthors

acknowledgethattheplaceboresponsewasmuchstrongerintheirtrialthanthatobservedinthe

adulttrial,whichisunsurprisinggiventhatpediatricstudiestendtoseehigherplaceboresponse

rates,especiallyinparallel-grouptrialsasopposedtocross-overtrials128.Therefore,itispossible

thatthetrialwasunderpoweredinthissetting.Thedescriptionofhowtherandomsequencewas

generatedlacksdetailanditisuncleariftheallocationwasconcealed.Hence,thisstudywasrated

ashavinganoverallunclearriskofbias,despiteotherdomainsofpotentialbiashavingalowriskof

bias.

Basedonthefactthatonlyonevalproatestudyhadenoughmethodologicalrigortobeincluded

inthisreviewandgiventheextensivesideeffectprofileofthismedication,valproatecertainlydoes

notappeartobeareasonablefirstlineagentforpediatricmigraineprophylaxis,althoughstrong

conclusionscannotbemadegiventhelimitedevidence.

3.3.3. Flunarizine

Flunarizinebelongstotheclassofmedicationsbythenameofcalcium-channelblockers.Its

mechanismofactioninmigraineisalsounknown.Onestudycarriedoutusingpatchclamp

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recordingsintrigeminalganglionneuronsshowedthatflunarizineinhibitedsodiumandcalcium

currents,resultinginhyperpolarizingneuronalmembranepotentials129.Thus,flunarizinelikely

inhibitsneuronaltransmissioninthetrigeminalganglion,whichplaysacrucialroleinmigraine

pathogenesis.Anotherstudyshowedthatflunarizinewasabletoreducethedegreeofcerebral

mitochondrialinjurythatoccursduringcorticalspreadingdepression130,whichisbelievedtobethe

underlyingpathophysiologicalcorrelateofmigraineaura131.Therefore,somepreliminaryevidence

suggeststhatflunarizinecouldhaveplausiblemechanismsofactioninpreventingmigraine.Inthe

mostcurrentAmericanAcademyofNeurology(AAN)practiceparameteronthetreatmentof

migraineinchildrenandadolescents,flunarizineistheonlymedicationthatreceiveda

recommendationtousebasedonevidencethatitis“probablyeffective”forthepreventionof

migrainesinthispopulation100.

Therewerethreeincludedstudiesthatassessedtheefficacyofflunarizinefortheprophylaxisof

migraineinchildrenandadolescents,twoofwhichwerebythesameauthorgroup.Adouble-blind,

placebo-controlled,2-arm,parallel-grouptrialwascarriedoutbySorgeetalinordertoassessthe

efficacyofflunarizineforthepreventionofpediatricmigraines132.Forty-eightchildrenwith

migrainewererandomizedtoreceivethreemonthsofeitherflunarizine5mgqHSorplacebo.

Duringthetreatmentperiod,theparticipantsonflunarizinehadasignificantlylowermean

migrainefrequencyascomparedtoplacebo(p<0.001)andhadasignificantlylowermeanmigraine

duration(p<0.05)aswell.However,thelattermayhavebeenanartifactofthefactthatthe

flunarizinegrouphadalowermigrainedurationatbaseline(p<0.05).Thereislittlementionofside

effectsinthemanuscript.Theauthorsdostatethatweightlossandsleepinesswerethemost

commonadverseevents,butdonotreportfrequenciesineachgroup.Also,threepatientswithdrew

fromtheflunarizinegroupduetosideeffects(gastrointestinalsymptoms,drowsinessandfatigue)

whereasthreepatientswithdrewfromtheplacebogroupduetolackofefficacy.Nointention-to-

treatanalyseswereused.Thetrialoverallhadahighriskofbiasduetothisattritionbias,withthe

46

twogroupshavingclearlydistinctreasonsfordrop-outs.Therewasalsounclearriskofbiasin

relationtothepossibilityofselectionbias,giventhatrandomizationandallocationconcealment

werenotdescribed.

Afewyearslater,Sorgeetalcarriedoutadouble-blind,placebo-controlled,crossovertrialina

groupof70childrenaged5to11yearswithmigraine133.Thetimelineofthetrialinvolveda4-week

baselineperiod,followedbya12-weektreatmentperiod,followedbya4-weekwashoutperiod,

andfinallyanother12-weektreatmentperiod.ParticipantsrandomizedtoGroupAreceived

flunarizine5mgdailyforthefirsttreatmentperiodandthenwerecrossedovertoplacebo,whereas

participantsinGroupBhadtheoppositetreatmentorder.Duringtheflunarizinetreatmentperiod,

bothgroupshadastatisticallysignificantdecreaseintheirmigrainefrequency(p<0.001inboth

cases).Inaddition,duringtheflunarizineperiod,bothgroupshadastatisticallysignificant

reductioninthedurationoftheirmigraines,startingatmonth3offlunarizineingroupAand

startingatmonth2offlunarizineingroupB(p<0.001inbothcases).Thereportingofsideeffectsis

vagueandonlymakesmentionoftheoverallfrequencyofthemostcommonsideeffects:22.2%of

participantsexperiencedweightgainand9.5%experienceddrowsiness.Itisunclearastowhether

therecouldhavebeenselectionbiasinthestudygiventhelackofdetailgivenwithregardsto

randomizationandallocationconcealment.Therewasahighriskofattritionbiasgiventhat2

patientswithdrewfromtheflunarizinegroupand5patientswithdrewfromplacebo,withno

intention-to-treatanalysesused.Therefore,thetrialwasgivenahighriskofbiasoverall.

AsmallstudycarriedoutbyMachínAltueñaetalrandomized45childrenaged5to13years

withmigrainetoeitherflunarizine,dimethothiazineorplaceboina4-monthdouble-blind,3-arm,

parallel-groupinterventionstudy134.Therewerenogroupdifferencesintermsoftheprimary

outcome:93.3%ofthedimethothiazinegrouphadclinicalimprovementvs.86.7%ofthe

flunarizinegroupvs.80%oftheplacebogroup(p>0.05).Inaddition,nogroupdifferenceswere

seeninanyofthesecondaryoutcomes.Weightgainoccurredin23.1%oftheflunarizinegroupbut

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noothersignificantsideeffectswerenotedinthemanuscript.Therewasahighriskofbiasinthis

studyinthatnosamplesizecalculationsweregivenandthestudywasverylikelyunderpoweredto

detectclinicallyimportantdifferencesintheefficacyoftheinterventions.Therewasalsounclear

riskofbiasrelatedtoallocationconcealment,thusintroducingthepotentialforselectionbias.This

studywasthereforeathighriskofbiasanditisdifficulttodrawanyconclusionsonflunarizine’s

efficacyfromtheseresults.

ThetwoSorgeetalstudies132,133,bothofwhichhadhighriskofbias,supporttheuseof

flunarizineinpediatricmigraineprophylaxisandtheMachínAltueñaisdifficulttointerpret134.

Becauseofthelowqualityofevidenceandthesmallnumberofparticipantsinthestudies,astrong

recommendationforitsuseshouldnotbemade.ThisislikelywhytheAANpracticeparameter

labeledflunarizineas“probablyeffective”forthisindication100,ratherthanmakingastronger

statementaboutitsuseinpediatricmigraineprophylaxis.

3.3.4 Timolol

Timololbelongstotheclassofmedicationscalledbeta-blockers,whichareantihypertensive

medicationsthatreducevasculartonebyinhibitingbeta-adrenergicreceptors.Howbeta-blockers

mightworktopreventmigrainesisunclear.Ithasbeenhypothesizedthattheircentralinhibitionof

beta-adrenergicreceptorsandtheirinteractionwithserotoninreceptorsmaymediatetheir

mechanismofactioninmigraine135,136.Timololisapprovedforuseinadultmigraineprophylaxisby

HealthCanadaandtheFDA.

Onestudyassessedtheefficacyoftimololforpediatricmigraineprophylaxis.Noronha

describedasmalldouble-blind,placebo-controlled,cross-overtrialthathecarriedout,whereby9

patientswererandomizedtoreceivedtimolol5mgdailyforthefirsttreatmentperiodthencrossed-

overtoplacebo,and8patientswererandomizedtoreceiveplaceboforthefirsttreatmentperiod

thencrossed-overtotimolol5mgdaily137.Therewasa4-weekbaselineperiodinthistrial,followed

by8weeksoftreatment,thena4-weekwashoutperiod,andthenfinallyanother8-weektreatment

48

period.Therearefewdetailsgivenabouttheresults.Theauthordoesreportthattherewereno

differencesbetweenthegroupsintermsofmigrainefrequency,severitynorduration.Theonly

mentionofadverseeventspertainstotheauthordescribinghowtwopatientswithdrewduetoside

effectsoftimolol,namelyheadacheandvomiting.Nosamplesizecalculationsaredescribedand

giventhattherewereonly17patientsinthetrial,itisverylikelythatthestudywasunderpowered.

Therewasahighriskofattritionbiasinthisstudygiventhat2patientswithdrewfordrug-specific

reasons(ie.duetotimololsideeffects).Therewasunclearriskofbiasrelatedtoselectionbiasgiven

aninadequatedescriptionofrandomizationandallocationconcealment.Therefore,thistrialwas

consideredtohaveahighriskofbias.

Basedontheavailableevidence,thereisnotenoughinformationtocommentontheefficacyof

timololforpediatricmigraineprophylaxis.Onlyonesmall,underpoweredtrialisavailable;future

studiesarethereforerequiredpriortodrawingconclusionsabouttimolol’suseforthisindication.

3.3.5 Clonidine

Clonidineisanalpha-2adrenergicagonistwithseveralpostulatedmechanismsofactioninpain

modulation.Alpha-2adrenergicagonistslikeclonidinemayhavearoleinalleviatingpainthrough

theiranti-inflammatorypropertiesandthroughtheirabilitytomodulatedescendingpainpathways

inthecentralnervoussystem:theycaninhibitnitricoxideandglutamatereleaseincentralpain

pathwaysandcanincreasedescendinginhibitionintherostralventromedialmedulla,whichplays

animportantroleindescendingpaininhibition138.Animalexperimentshaveleadtosome

interestinginsightsaboutthepotentialrolethatclonidineplaysinmodulatingpainassociatedwith

migraine.Itappearsthatclonidinemightinhibittrigeminalreferredpaininmigrainebyinhibiting

C1spinalneuronsthatreceiveinputsfromstructuresbelievedtobeinvolvedinreferredpain139.

Also,clonidinehasbeenshowntoinhibitNMDA-evokedresponsesinnociceptiveneuronslocated

inthetrigeminalnucleuscaudalis140,whichisabrainareaofcentralimportanceinmigraine

pathogenesis.Inanotheranimalexperiment,clonidineinhibitedthemigrationofcorticalspreading

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depression141,aphenomenonthatisbelievedtounderliemigraineaura131.Therefore,clonidinehas

severalplausiblemechanismsofactionthatcouldleadtoitsefficacyinmigraineprevention.

AlthoughitisnotcurrentlyapprovedforuseinmigrainebytheFDAnorHealthCanada,itisused

off-labelforthisindication.

Sillanpääreportedtheresultsofadouble-blind,placebo-controlled,2-armparallel-groupstudy

involvingthecomparisonofclonidinetoplaceboformigraineprophylaxisinchildrenwith

migraineupto15yearsofage142.Althoughitseemsimpliedthatthetrialwasrandomized,itisnot

explicitlystatedinthetext.Becausethepaperwaspublishedin1977withasingleauthorforwhom

nocurrentcontactinformationwastraceable,thestudywasincludedinthesystematicreview

despitetheunclearrandomizationstatus.Inthisstudy,28childrenreceivedclonidineatadoseof

25micrograms(mcg)dailyforthoseweighinglessthan40kgand25mcgbidforthoseweighing

over40kg,and29childrenreceivedplaceboforthe2-monthtreatmentperiod.Intheclonidine

group,thedosewasincreasedby25mcgforeachparticipantafterthefirstmonthoftreatment.The

reportingofoutcomesissuboptimalasitisunclearwhichoutcome(s)wereprimary.Also,insome

instanceshypothesistestsarereportedandinotherstheyarenot.Forthefrequencyofmigraines

outcome,whichisnormallytheprimaryoutcomeinsuchtrials,theredidnotappeartobe

significantdifferencesbetweenthegroups.Thegroupsalsodidnotdifferwithrespecttomigraine

intensitynorduration.Inthesubgroupsofpatientshavingafamilyhistoryofmigraineormigraine

withaura,thosetreatedwithclonidinehadsignificantlylowermigrainefrequenciesduringthe

treatmentperiod.Thoseintheclonidinegroupreportedmoreadverseevents:11participantson

clonidinevs.6participantsonplaceboreportedadverseevents.Intheclonidinegroup,themost

commonadverseeventwasfatigue,followedbynausea.Inthisstudy,nosamplesizecalculations

arereportedandgiventhesmallsamplesize,thetrialwaslikelyunderpoweredtodetectsmallbut

meaningfulclinicaldifferenceswhencomparingclonidinetoplacebo.Therewasahighriskof

reportingbiasgiventhathypothesistestswereonlyreportedforsomeoutcomes.Therewasalsoa

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highriskofattritionbiasgiventhat3patientswithdrewfromthestudyandallwereinthe

clonidinegroup.Theriskofselectionbiaswasuncleargiventhelackofclaritysurrounding

randomizationandallocationconcealment.Therefore,overall,thetrialhadahighriskofbias.

Basedonthisonestudywithhighriskofbias,itisdifficulttodrawconclusionsontheefficacy

ofclonidineforpediatricmigraineprevention.

3.3.6 Trazodone

Trazodoneisananti-depressantmedicationthatinhibitsthereuptakeofserotoninatthe

neuronalsynapse.Itsmechanismofactioninmigraineisunclear,thoughithasbeenpostulatedthat

theincreasedavailabilityofserotonincouldberelatedtoitsanti-migrainepotential143.Itis

currentlyonlyapprovedforuseinmajordepressivedisorderinbothCanadaandtheUSanditsuse

inmigraineisthereforeofflabel,evenintheadultpopulation.

Trazodonehasonlybeenassessedinonerandomizedstudyforthisindicationinthepediatric

population.Theefficacyoftrazodoneforthepreventionofmigraineinchildrenandadolescentshas

beenassessedinonesmallrandomized,double-blind,placebo-controlledcrossovertrialinvolving

40participantsaged7to18years144.Battistellaetalrandomizedparticipantstoreceivetrazodone

1mg/kg/daydividedtidorcolor-matchedplacebodailyfor12weeks.Awashoutperiodwasthen

initiatedandmaintainedfor4weeks,andparticipantswerethencrossedovertotheother

intervention.Afterthefirsttreatmentperiod,therewasnodifferencecomparingtrazodoneto

placebointermsofmigrainefrequency,andmigrainedurationwasinfactlongerinthetrazodone

group(16.1+1.4hrsvs.10.2+1.0,p<0.01).Inthesecondtreatmentphase,thetrazodonegrouphad

agreaterreductioninmigrainefrequency(trazodonereducedfrom2.1+0.2attacks/monthto

1.8+0.2vs.placeboincreasedfrom1.8+0.1to2.1+0.2,p<0.005)andduration(from10.7+1.3to

4.9+0.7vs.from11.9+1.3to13.1+1.3,p<0.001)ascomparedtotheplacebogroup.Noadverse

eventsarereportedinthemanuscriptandtheauthorsstatethatnoseriousadverseevents

occurred.Twopatientswithdrewfromthegroupinitiallyrandomizedtotrazodoneandthree

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patientswithdrewfromthegroupinitiallyrandomizedtoplacebo,duetoerrorsinmedication

administrationandonsetofnewillnesses.Nosamplesizecalculationsaregivenandthereforeitis

unclearhowthestudywaspoweredandforwhichoutcome.Themethodofrandomizationwasnot

describedandallocationconcealmentisnotmentionedinthetext,thereforeintroducinganunclear

riskofselectionbias.Thestudywasthusgivenaratingofunclearriskofbias.

Giventhatthisistheonlystudyontrazodoneforpediatricmigraineprophylaxisandgivenits

somewhatunusualresults(ie.superiorityoftrazodoneoverplaceboonlyseenduringsecond

treatmentphase),itwouldbeimprudenttodrawconclusionsontheefficacyoftrazodoneforthis

indication.

3.3.7 Nimodipine

Nimodipineisacalcium-channelblocker,inthesamecategoryasflunarizineandcinnarizine.As

withothermigraineinterventions,itsexactmechanismofactionisunclear.Arecentanimalstudy

foundthatnimodipineadministrationresultedindownregulationofcalcitoningene-related

peptide(CGRP)expressioninthetrigeminalnucleuscaudalis145.CGRPisthoughttoplayan

importantroleinmigrainepathophysiology:itslevelsriseduringmigraine,CGRPadministration

cantriggermigraines,andanewclassofmedicationscalledtheCGRPreceptorantagonistshold

promiseformigraineprophylaxis146.Therefore,thepotentialefficacyofnimodipineinmigraine

prophylaxiscouldbeexplainedbydownregulationofCGRPinthetrigeminalnucleuscaudalis,a

brainareathatiscriticalinmigrainepathogenesis.Inaddition,researchhasshownthatinhibition

ofL-typevoltage-gatedcalciumchannels,whichoccurswithnimodipine,decreasestherateof

corticalspreadingdepression147,whichisbelievedtounderliemigraineaura131.Therefore,there

areacoupleofpotentialmechanismsbywhichnimodipinemayeffectivelypreventmigraines.

NeitherHealthCanadanortheFDAapprovedtheuseofnimodipineformigrainepreventionin

adultsorchildren.

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Onlyonerandomizedstudyhasinvestigatedthepotentialrolefornimodipineinpediatric

migraineprophylaxis.TheBattistellaetalgrouprandomized37participantsaged7to18yearsto

nimodipine10-20mgdailytidortocolor-matchedplaceboinadouble-blind,2-arm,placebo-

controlled,crossovertrial148.SimilarlytotheotherBattistellaetaltrial,a4-weekwashoutperiod

occurredbetweenthetwotreatmentperiodsandeachtreatmentperiodwas12weeksinduration.

Afterthefirsttreatmentphase,thegroupsdidnotdifferintermsofmigrainefrequencynor

migraineduration.However,migrainefrequencywasreducedtoagreaterextentinparticipants

takingnimodipineduringthesecondtreatmentphase(from2.7+0.8attacks/monthto1.9+1.7vs.

from2.6+0.8to2.8+0.6,p<0.01),thoughnodifferencewasseenformigrainedurationinthatphase.

Threepatientsexperiencedmildtransientgastrointestinalsymptomsduringtheinitialdaysof

nimodipinetreatment,thoughnootheradverseeventswerereported.Themethodsof

randomizationandallocationconcealmentwerenotdescribed,introducingthepotentialfor

selectionbias.Theremayhavealsobeenattritionbiasas18.9%oftheparticipantswithdrewfrom

thestudyanditwasnotmadeclearforwhatreason(s)andwhichgroup(s)theseparticipants

belongedto.Therefore,theriskofbiaswasratedasunclearforthistrial.

Basedonthisonestudy,theefficacyandtolerabilityofnimodipineforpediatricmigraine

prophylaxiscannotbeestablished.

3.3.8 Cinnarizine

Cinnarizinehastwoprimarymechanismsofaction:itactsasacalcium-channelblockerandalso

hasantihistaminergicproperties149.Itspotentialmechanismofactionismigraineisnotknown.One

smallstudyfoundthatcinnarizineinducedserotoninreleasefromplateletsandinhibitedplatelet

aggregationinbothhealthyvolunteersaswellasmigraineurs150.However,giventhecomplex

pathophysiologyofmigraine,whichisstillnotfullyunderstood,itisunclearastowhetherthese

effectsseeninthissmallstudycouldunderliecinnarizine’spotentialmechanismofactionin

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migraine.Atthepresenttime,cinnarizinedoesnothaveHealthCanadanorFDAapprovalforusein

anyconditionincludingmigraine.

Onerandomizedtrialoncinnarizinewasincludedinthisreview.Ashrafietalrandomized62

childrenaged5to17yearstoreceiveeithercinnarizine1.5mg/kgdailyor50mgforthoseweighing

above30kg,orplacebofora12-weektreatmentperiod151.Therewasahigherresponserateinthe

cinnarizinegroupwith60%ofthecinnarizineparticipantsachievinga50%orgreaterreductionin

attackfrequencyascomparedtoonly31.3%oftheplaceboparticipants(p=0.023).Bothgroupshad

statisticallysignificantreductionsinheadachefrequencyovertimebutnogroupdifferenceswere

seen.Itappearsthatcinnarizinewasmoreeffectivethanplaceboinseveralofthesecondary

outcomes,includinginreducingmigraineintensityandduration.Threeparticipantsinthe

cinnarizinegrouphaddrowsinessascomparedtooneintheplacebogroupandonecinnarizine

participantgained2.5kgonthemedication.Giventhelackofdescriptionofallocationconcealment

inthemanuscript,thestudywasgivenanunclearriskofselectionbias,andthusanunclearriskof

biasoverall.Therefore,overall,thissmallstudyfoundevidencefortheefficacyandtolerabilityof

cinnarizineinthispatientpopulation,thoughfindingsneedtobereplicatedpriortodrawing

conclusionsonitsefficacy.

3.3.9 Dimethothiazine

Dimethothiazineisaphenothiazinemedicationinthecategoryofneurolepticantipsychotic

medications.ItisnotapprovedbyHealthCanadanortheFDAandisnotavailableinNorthAmerica,

thoughitisavailableinsomecountriesworldwide.Itspotentialmechanismofactioninmigraineis

unknown.

Asdescribedabove,MachínAltueñaetalcomparedtheefficacyofflunarizine,dimethothiazine

andplaceboinagroupof45childrenaged5to13years134.Thestudywasarandomized,double-

blind,parallel-grouptrialcarriedoutinSpain.Allofthegroupshadsimilarratesofimprovement:

93.3%ofthedimethothiazinegrouphadclinicalimprovementvs.86.7%oftheflunarizinegroupvs.

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80%oftheplacebogroup(p>0.05)andtherewerenosignificantdifferencesinthesecondary

outcomes.Themostcommonsideeffectwasweightgain,occurringin23.1%oftheflunarizine

group.Thestudywasratedashavingahighriskofbiasgivenhowsmallthegroupswereandthe

lackofsamplesizecalculations,introducingthepotentialforasignificantlackofpowertodetect

clinicallymeaningfulgroupdifferences.Nomentionismadeofallocationconcealmentinthe

manuscript,andthustherewasanunclearriskofselectionbias.Givenmethodologicalissueswith

thetrial,onecannotdrawconclusionsontheuseofdimethothiazineforthisindicationfromthis

onestudy.

3.3.10 Papaverine

Papaverineisavasoactivecompoundthathasbeenstudiedaspotentialinterventionfor

preventingmigraines.Inrats,papaverineappearstorevertcorticalspreadingischemiatotheless

severephenomenonofcorticalspreadingdepression152.Ashasbeenmentionedpreviously,

migraineauraisbelievedtobecausedbycorticalspreadingdepression131,andifpapaverine

lessensthisprocess,itcouldperhapsplayaroleinmitigatingmigraine.Papaverinedoesnothave

HealthCanadanorFDAapprovalforuseinmigraine.

Sillanpääetalcarriedouttheonlyrandomizedcontrolledtrialassessingtheefficacyof

papaverineinchildrenandadolescentswithmigraine153.Thirty-sevenparticipantsagedbetween6

and15yearswithmigraineorvascularheadacheswererandomizedtoreceiveeitherpapaverine,

startingatadoseof5mg/kgdailydividedbidortidanddoublingto10mg/kgdayinonemonthif

tolerated,orplacebo,fora2monthtreatmentperiod.Significantlymoreparticipantstaking

papaverinehadpainfreedomduringthetreatmentperiodascomparedtoplacebo(6participants

outof19randomizedtopapaverinevs.0participantsoutof18randomizedtoplacebo,p<0.001).

Althoughspecificnumericalresultsarenotgiveninthemanuscript,afigureandasentenceinthe

textalludetosignificantlybetterimprovementinmigrainefrequency,durationandintensityinthe

papaverinegroupascomparedtoplacebo(p<0.001).Theadverseeventprofilesarenotreportedin

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themanuscript.Thisstudyhadanoverallunknownriskofbiasgiventheprobabilityofselection

bias:nomentionwasmadeofallocationconcealment.Inaddition,therewasapotentialforattrition

bias,giventhatfiveparticipantswereexcluded:twoforadverseeventsthatwerenotdescribedand

threeduetoinadequatecompliancewiththeintervention.Thereisnomentionofwhichgroup(s)

theybelongedto,andthereforetheriskofattritionbiasisunknown.Basedonthisonesmalltrial,it

isnotpossibletomakeaconclusionontheefficacy,andespeciallythesafety,ofpapaverineasa

pediatricmigrainepreventativeintervention.

3.4. UnpublishedTrials

Aftersearchingtheclinicaltrialregistries,threeunpublishedrandomizedcontrolledtrialswith

potentialforeligibilitywereidentified(clinicaltrialregistrynumbers:IRCT2013092914809N1,

EUCTR2010-019947-21-ESandIRCT2013020412361N1).Theauthorswerecontactedabouttheir

trials,toinquireabouteligibilityandpublicationstatus:Dr.AfshinFayyazi,Dr.LalaJarinandDrs.

AhmadTalebianandBabakSoltani,forclinicaltrialsIRCT2013092914809N1,EUCTR2010-

019947-21-ESandIRCT2013020412361N1,respectively.Attemptsatcontactingtheauthorswere

madeelectronicallyviae-mailonthefollowingdates:July2nd2015,July14th2015andOctober22nd

2015.Unfortunately,noneoftheauthorsrepliedtothee-mails,andcontactwasthereforenot

made.Becauseoftheimpossibilityofknowingwhetherthesetrialswereindeedeligibleornot

basedonthelimitedinformationontheclinicaltrialregistries,andbecausetheresultsofthese

studieswereunavailable,thesetrialscouldnotbeincludedinthissystematicreview.Their

existenceintroducesthepossibilityofpublicationbiasintothisbodyofliterature.

3.5. Meta-Analyses

3.5.1 Riboflavinvs.Placebo

Twostudiesassessedtheefficacyofriboflavinforthepreventionofmigrainesinchildrenand

adolescents114,115.However,thestudiesweretooclinicallyheterogeneoustoallowforpoolingina

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meta-analysis.Themainpointsofdissentwererelatedto:1)thedosing:riboflavinwasdosedat

200mg/dayintheMacLennanetaltrial114andat50mg/dayintheBruijnetaltrial115,2)the

outcomes:therewasinadequateoverlapinthemeasuredoutcomesforpoolingofthedata.

Therefore,theresultsofthesestudiesaredescribedqualitativelyabove,butnostatisticalpooling

wascarriedoutontheriboflavindata.

3.5.2 Topiramatevs.Placebo

Althoughsixstudiesontopiramateforpediatricmigraineprophylaxiswereincluded,onlyfive

ofthesestudies120–122,124,125includedefficacydataandonlythreeofthesestudies120–122had

substantialenoughoverlapintheirreportedoutcomestoallowforpoolinginameta-analysis.Inan

attempttoincludetheothertwotopiramatestudies124,125withefficacydatainthemeta-analysis,

theauthors(LisaM.Ford125andPaulWinner124)werecontactedwithinquiriesaboutaccessto

potentiallyunpublisheddatathatwouldpermitinclusionoftheirtrialsinthemeta-analysis.Dr.

Fordindicatedtomethatthemanuscriptassociatedwiththepublishedabstract125doescontainthe

requesteddata,butthatitcouldnotbesharedatthistimegiventhatthemanuscriptisin

preparationforpublication(LisaFord,personalcommunicationoveremail,July15th2015).Three

attemptstocontactDr.Winner(July2nd2015,August11th2015andOctober22nd2015)were

unsuccessfulandthedatarequiredtoaddthatstudy124tothemeta-analysiswerenotobtained.In

thisway,themeta-analysisdoesnotfullyreflecttheextentofthedataontopiramateforpediatric

migraineprophylaxis.Eachofthestudieswithmissingdataconsistedofapooledanalysisofdata

frompreviouslypublishedtrials:theFordetal125pooledanalysiscomprised260childrenaged6to

17yearsfrom5separatetrialsandtheWinneretal124pooledanalysiscomprised49adolescents

aged12to17yearsfrom3separatetrials.Thus,thenumberofparticipantsfromthesetwostudies

waslargeandfailuretoincludethisdatainthemeta-analysiscertainlycompromisedtheprecision

oftheestimateoftheeffectsize.However,bothofthesestudiesexcludedfromthemeta-analysis

alsoshowedfavorableefficacyresultsfortopiramate,anditisnotexpectedthattheirinclusionin

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themeta-analysiswouldhaveresultedinachangeindirectionintheestimateoftheeffectsizenor

wouldweexpectadramaticallydifferentpointestimateoftheeffectsize.

Thethreestudies120–122includedinthemeta-analysiswereamenabletopoolinggiventhateach

ofthestudiesreportedonthepercentagechangeinthefrequencyofmigrainescomparingbaseline

tothetreatmentperiod.Becauseofsignificantclinicalheterogeneityinthedatafromthethree

includedstudies,arandomeffectsinversevariancemethodwasusedtoestimatetheestimateof

theeffectsize.Apooledpointestimateofthemeandifferencewith95%confidenceintervalswas

generatedusingRevMan.Themeandifferencewaschosentoestimatetheeffectgiventhatall

studiesusedthesamescaletomeasuretheoutcomeofchangeinmigrainefrequency,thatis,the

percentageona100-pointscale.

Theresultsofthemeta-analysiscomparingtheefficacyoftopiramatetoplacebointermsofthe

percentagereductioninmigrainefrequencyaredisplayedinFigure4.Theestimateofthemean

differenceis21.4%(95%CI:9.7-33.0%),whichcanbeinterpretedassuch:basedontheresultsof

thesethreetrials,topiramateisexpectedtoreducemigrainefrequency21.4%morethanplacebo

overthecourseoftreatment,andthisresultisstatisticallysignificant.

Figure4.Topiramatevs.placebo:pooledanalysisofthepercentage(%)reductioninmigrainefrequencycomparingbaselinetothetreatmentperiod

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3.5.3 Flunarizinevs.Placebo

Althoughthreetrialscomparedflunarizinetoplaceboforpediatricmigraineprophylaxis132–134,

therewerenosharedoutcomesbetweenthetrials.Therefore,itwasnotpossibletopoolresults

fromthesethreestudiesintoameta-analysis.

3.5.4 OtherInterventions

Alloftheotherinterventionsincludedinthissystematicreviewwereonlyassessedinisolated

studies,therebyprecludingtheuseofmeta-analysistopooldata.

4. DISCUSSION

Inthissystematicreviewandmeta-analysis,19eligiblearticleswereidentified,comprising12

interventionsforpediatricmigraineprophylaxis:butterbur,riboflavin,topiramate,valproicacid,

flunarizine,timolol,clonidine,trazadone,nimodipine,cinnarizine,dimethothiazineandpapaverine.

Onlythreeinterventionswereassessedinmorethanoneeligiblestudy:riboflavin,topiramateand

flunarizine.Theremaininginterventionswereonlystudiedinsingletrials,oftenofpoorquality

witheitherunclearorhighriskofbias.Giventhisandgivenexcessiveclinicalheterogeneityforthe

interventionsthatwerestudiedinmultipletrials,onlyonemeta-analysiswaspossible:topiramate

vs.placebo.Thismeta-analysisislimitedbythefactthatonlyhalfoftheeligiblestudieswere

amenabletopooling,givenalackofoverlappingoutcomesandhighclinicalheterogeneity.

Therefore,theresultsofthismeta-analysismustbeinterpretedinlightofthefactthatthepooled

resultsdonotreflecttheentirebodyofliterature.

Giventhelimitationsinvolumeandqualityofevidence,fewconclusionscanbedrawnfromthis

systematicreview.Asdescribedabove,topiramateappearstobesafeandeffectiveforthe

preventionofmigraineinthepediatricpopulation,basedonsixeligiblestudiesandonemeta-

analysiscomprisedofthreeofthesetrials.Bothbutterburandvalproicacidappeartohavelimited

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tolerabilityinthispopulationbasedonlimitedevidence.Theremaininginterventionsincludedin

thissystematicreview(ie.riboflavin,flunarizine,timolol,clonidine,trazadone,nimodipine,

cinnarizine,dimethothiazineandpapaverine)lackedthevolumeandqualityofevidencerequired

formakingconclusionsaboutefficacyandsafety.

Themostsignificantconclusionthatcanbedrawnfromthissystematicreviewpertainstothe

paucityofevidenceforinterventionsaimedatpreventingmigraineinchildrenandadolescents.

Tworelatedprojects,onesystematicreview154andonemeta-analysis155,withcomparable

objectivesandscopeotherthanthefactthatonlypharmaceuticalinterventionswereeligible,have

drawnsimilarconclusionsabouttheevidenceforpediatricmigraineprophylaxis.Thereisadire

needforhighquality,adequatelypoweredandwell-justifiedclinicaltrialsinthisbodyofliterature.

Oneofthechallengesincarryingouttrialsofinterventionsinthepediatricpopulationpertains

totheethicsoftreatingchildrenwithplacebo.Althoughitisgenerallyacceptedthatinterventions

mustbecomparedtoplaceboinordertoestablishefficacy,somegroupshavecalledthisphilosophy

intoquestion.Ithasbeenarguedthat,inthepediatricpopulation,itmaybemoreethicaltouseoff-

labelinterventionsthatarecommonlyprescribedinclinicalpracticeasactivecomparators,rather

thanusingplacebocomparators156.Inthiscontext,non-inferiorityhypothesesmaybemore

appropriatethansuperiorityhypotheses.Unfortunately,therearenoestablishednon-inferiority

marginsforcommonoutcomesusedinmigraineresearch.Onlyafewpublishedmigrainetrials

withadultparticipantshaveusednon-inferiorityhypotheses157–159,andneitheremployedawell-

justifiednon-inferioritymargin.Inordertoaddressthisgapintheliterature,theNon-Inferiority

MarginsinMigraine(NIMM)Researchsurveywasconceived.TheNIMMsurvey’srationale,

methodsandresultsaredescribedbelowinPartII.

Giventheneedforhighqualityevidenceinthisbodyofliterature,aclinicaltrialwithlowriskof

biasandadequatepowerwasdesigned.TheresultsoftheNIMMsurveywereusedtodeterminethe

samplesizeforthistrial,giventhatitiscomprisedofbothasuperiorityhypothesisandanon-

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inferiorityhypothesis.ThetrialprotocolisdescribedbelowinPartIII.WiththeNIMMsurveyand

theproposedclinicaltrial,weaimtostrengthenthebodyofevidenceontheefficacyof

interventionsforthepreventionofmigraineinchildrenandadolescents.

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THESISPARTII:SURVEYONNON-INFERIORITYMARGINSFORMIGRAINETRIALS:DeterminingaNon-InferiorityMarginforMigraineTrials:TheNon-InferiorityMarginsinMigraineResearch(NIMM)Survey

1. Background

Traditionally,clinicaltrialshavebeendesignedaroundwhatisreferredtoassuperiority

hypotheses160.Whensettingasuperiorityhypothesis,theinvestigatorsareattemptingtodisprove

thenullhypothesisthattwointerventionsdonotsignificantlydiffer,thatis,thegoalistoshowthat

oneinterventionissuperiortotheother.Superiorityhypothesesareestablishedbasedonsettinga

minimalclinicallyimportantdifference(MCID).TheMCIDisthedifferencebetweenthe

interventionsthatisfelttobesufficienttocallthenewinterventionclinicallysuperiortothe

comparativeintervention.

Althoughsuperiorityhypothesesarethemostwidelyusedindesigningclinicaltrialsandare

thusthemostfamiliartothescientificcommunity,theyarenotalwaysthemostappropriatetypeof

hypothesistoemployfortheclinicalquestion.Asthemedicalliteraturegrowsandtherangeof

evidence-basedtreatmentoptionsexpands,poweringastudybasedonthehypothesisthatone

interventionissuperiortothenextisnotalwaysthemostclinicallyrelevantorappropriateoption.

Forexample,inmanyareasofmedicine,thereareinterventionsthatareknowntobesafeand

effectivebasedonpriorevidence,andinvestigatorsmaywishtocomparetheseinterventionsto

newinterventionsthatarelessexpensive,easiertouseoraccess,orperhapsmoretolerableto

patients161.Inthesetypesofscenarios,themedicalcommunitywouldlikelyadoptthenew

interventionifitwasshowntobenolesseffectivethantheestablishedintervention,asopposedto

requiringittohaveevidenceforsuperioritytotheestablishedintervention.Theneedtoshow

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superiorityisobviatedbytherelativeadvantagesthatthenewinterventionhasoverthe

establishedintervention(e.g.cost,easeofuse,sideeffectprofile,etc).Therefore,designingthetrial

withthegoalofestablishingsuperiorityofthenewinterventionovertheestablishedintervention

wouldbeinappropriate,becauseifsuperiorityisnotshownstatistically,thenewinterventionmay

berejectedbythemedicalandscientificcommunities,eventhoughitmayfactbeaseffectiveasthe

establishedinterventionwhilstofferingrelativeadvantagesbeyondefficacy.Inthistypeof

situation,anon-inferiorityhypothesisismoreappropriatethanasuperiorityhypothesistothe

goalsofthetrialandismoreclinicallyrelevant.

Non-inferiorityhypothesesareusedwhentheobjectiveofthetrialistoshowthatanew

interventionisnoworsethantheestablishedinterventionrelativetoitsefficacyortolerability162.

Inordertoestablishanon-inferiorityhypothesisandgenerateanestimateofanappropriate

samplesizetotestthishypothesis,investigatorsmustdesignateanon-inferioritymargin(delta).

Essentially,non-inferiorityisbasedonshowingthatthedifferencefoundbetweentheestablished

interventionandthenewinterventionissmallerthanapre-definedmargin,thenon-inferiority

margin(seefigure5).Therefore,thenullhypothesisinanon-inferioritytrialisthatthenew

interventionisinferiortotheestablishedinterventiongivenadifferencebetweentheinterventions

thatisequaltothenon-inferioritymarginorlargerthanthenon-inferioritymargin.

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Figure5.Illustrationofthedifferencebetweenasuperiorityandnon-inferiorityhypothesis

Figure5.Illustrationoftheconceptofanon-inferiorityhypothesis.Aninterventionisconsiderednon-inferiorwhentheconfidenceintervalfortheestimateofitseffectdoesnotincludevaluesbelowthenon-inferioritymargin(–delta).Asthefigureillustrates,aconclusionofsuperioritycanstillbedrawnwithanon-inferiorityhypothesiswhentheconfidenceintervalfortheestimateoftheeffectofaninterventionisrestrictedtovaluesabovezero.

Theprocessofestablishinganon-inferioritymarginrequirescarefulconsideration.Choosingan

excessivemarginwillresultinclinicallyinferiorinterventionsbeingdeemednon-inferiorto

establishinginterventions,whereaschoosingtoosmallamarginwillresultinrejectionofan

interventionthatmaybeclinicallynon-inferior,andwillunnecessarilyinflatethesamplesizeofthe

trial160.Inaddition,non-inferioritymarginsshouldnotexceedtheMCID,forobviousethicaland

intuitivereasons.Guidelinesrecommendchoosingthemarginbasedonbothstatisticalandclinical

considerations163.Severaltechniquesforsettinganon-inferioritymarginhavebeendescribed.For

example,avarietyoftechniqueshavebeenproposedbasedontheuseofhistoricaldata162.One

suchtechniqueinvolvesretrievingdatafromtrialsthathavecomparedtheestablishedintervention

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toplacebo.Thedifferencebetweentheestablishedinterventionandplacebocanthusbeobtained,

andonecandetermineapercentageofthatdifferencethatwillbecalledthenon-inferiority

margin160.Althoughthishistoricalapproachtheoreticallyallowsonetoconcludethatanon-inferior

interventionisalsosuperiortoplacebo,amajorassumptionismadeintheprocess:thatthe

establishedinterventionwillhaveasimilareffectinthecurrenttrialstoitseffectinpriortrials162.

Thisassumptioncanneverbecompletelytrue,giventhatstudypopulations,trialset-upanddesign

issueswillalwayscreateheterogeneitybetweentrials.Anotherapproachisbasedontheopinions

ofexpertsand/orstakeholders.Inthisway,individualswithexpertiseinthefieldand/or

stakeholdersareconsultedabouttheiropinionsonanappropriatenon-inferioritymargin163.This

approach,whilesubjective,isarguablypreferableinthatthehypothesisofthetrialwillbedriven

byexpertorstakeholderconsensus,andtheresultsofthetrialarethereforemorelikelytobe

pertinenttotheknowledgeusersandconsequentlymorelikelytobeappliedintheclinicalcontext.

Unfortunately,itappearsthatthemajorityofnon-inferioritytrialsarepublishedwithoutan

adequatedescriptionorjustificationforthechoiceofthenon-inferioritymargin.Arecent

systematicreviewfoundthatonly23%ofnon-inferioritytrialsjustifiedtheirchoiceofanon-

inferioritymargin164.Thisflawintheliterature,coupledwiththeincreasingprevalenceofnon-

inferioritytrials161,164,isalarming.Severalreasonscouldexplainthisdeficiency:inadequate

trainingofinvestigatorsregardingtheconductandreportingofnon-inferioritytrials164,journals

notenforcingadherencetotrialreportingguidelines164,orperhaps,investigatorschoosingtoset

thenon-inferioritymarginthemselvesratherthanconsultinghistoricaldataorexpertcolleagues

giventhetimeandresourcerequirementsassociatedwiththeseapproaches.

Non-inferioritytrialsappeartobeunderusedintheareaofmigraineresearch.Onlyafew

publishedtrialsinthisareahavetestednon-inferiorityhypotheses157–159.Toourknowledge,none

ofthesetrialsprovidedajustificationforthechoiceofthemargin.Therefore,itappearsthat

headacheexpertshavenotyetbeensurveyedfortheiropinionsonclinicallyacceptablenon-

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inferioritymarginsforoutcomesusedinmigrainetrials.Resultsofsuchasurveywouldbevery

usefulinthedesignoffuturenon-inferioritytrials,giventhattheywouldprovideareferencefor

investigatorstouseinchoosingtheirnon-inferioritymargins.Furthermore,becausethe

InternationalHeadacheSocietyhaspublishedGuidelinesforControlledTrialsofDrugsin

Migraine165,thereareestablishedandacceptedstandardprimaryoutcomesthatshouldbeusedin

migrainedrugtrials,thusfacilitatingtheuseofnotonlyuniversalprimaryoutcomesbutalso

associatednon-inferioritymargins.

TheaimofthisstudyistosurveyNorthAmericanheadacheexpertsregardingtheiropinionson

acceptablenon-inferioritymarginsforprimaryoutcomesinmigrainetrials.

2. Objectives

2.1. Primaryobjectives

a. Toestablishaclinicallyacceptablenon-inferioritymarginfortherecommended

primaryoutcomeintrialsofmigraineprophylaxis165,thatis,thechangeinthe

numberofmigraineattackscomparingbaselinetothetreatmentperiod,througha

surveyofheadacheexpertsinNorthAmerica.

b. Toestablishaclinicallyacceptablenon-inferioritymarginfortherecommended

primaryoutcomeintrialsofacutemigrainetreatment165,thatis,thepercentageof

patientswhoareheadachefree2hoursaftertreatment,throughasurveyof

headacheexpertsinNorthAmerica.

2.2. Secondaryobjectives

c. Toestablishclinicallyacceptablenon-inferioritymarginsforimportantsecondary

outcomesintrialsofmigraineprophylaxis165throughasurveyofheadacheexperts

inNorthAmerica.Secondaryoutcomesofinterestwillbe:

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• Thechangeinthenumberofmigrainedayscomparingbaselinetothe

treatmentperiod

• Theintensityoftheheadacheasmeasuredbythe4-pointseverityscale

(0=noheadache,1=mildheadache,2=moderateheadache,3=severe

headache)

d. Toestablishclinicallyacceptablenon-inferioritymarginsforimportantsecondary

outcomesintrialsofacutemigrainetreatment165throughasurveyofheadache

expertsinNorthAmerica.Secondaryoutcomesofinterestwillbe:

• Thepercentageofpatientswhohaveamigrainerelapsewithin48hoursof

treatment

• Thepercentageofpatientswithsustainedpainfreedom(ie.painfreedom

2hoursaftertreatmentandmaintained48hoursaftertreatment)

3. Methods

3.1. StudyDesign&Protocol

TheNon-InferiorityMarginsinMigraineResearch(NIMM)surveywasdesignedtoestablish

clinicallyrelevantnon-inferioritymarginsthroughexpertopinionforoutcomescommonlyusedin

migraineclinicaltrialsandendorsedbytheInternationalHeadacheSociety’sGuidelinesfor

ControlledTrialsofDrugsinMigraine165.TheNIMMsurveycomprised11questions.Thefirstfive

questionspertainedtodeterminingparticipants’eligibilitytocompletethesurveyandto

characterizingparticipants(eg.adultvs.childneurologist,percentageofpracticedevotedto

research,etc–seeAppendixG).Theremainingsixquestionsaimedtodetermineparticipants’

opinionsaboutnon-inferioritymarginsforoutcomesusedinmigrainetrials.Theoutcomesof

interestforprophylactictreatmenttrialswere:thechangeinthenumberofmonthlymigraine

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attackscomparingbaselinetothetreatmentperiod,thechangeinthenumberofmonthlymigraine

dayscomparingbaselinetothetreatmentperiodandthechangeintheaveragemigraineintensity

comparingbaselinetothetreatmentperiod.Theoutcomesofinterestforacutetreatmenttrials

were:theabsolutepercentageofparticipantswhoarepain-free2hoursaftertheintervention,the

absolutepercentageofpatientswhohaveamigrainerecurrencewithin48hoursoftreatmentand

theabsolutepercentageofpatientswithsustainedpainfreedom.Withintheinitialfivequestions,

branchinglogicwasusedtonotifyparticipantsoftheirnon-eligibilitywhereapplicable.For

example,inquestion1,participantswereaskedwhatkindofpractitionertheyidentifyas:anadult

neurologist,achildneurologistor‘other’.Forparticipantsselecting‘other’,branchinglogicwas

usedtodisplayanotificationofnon-eligibility(seeAppendixG).

TheAmericanHeadacheSociety(AHS)andtheCanadianHeadacheSociety(CHS)were

contactedandaskedtodistributethesurveytotheirmembersviaemail.Thesurveywasapproved

fordistributionbybothsocieties.TheinitialemailsinvitingAHSandCHSmemberstocompletethe

surveyweredistributedinNovember2015.Follow-upemailsremindingpotentialparticipants

aboutthesurveyweresentonemonth(December2015)andtwomonths(January2016)following

theinitialinvitationemail.

ThesurveyswereadministeredanonymouslytoparticipantsusingResearchElectronicData

Capture(REDCap™).REDCap™isasecurewebapplicationwithasurveymodulethatallowsfor

bothsurveydesignanddistributioninthecontextofasecureplatform.Potentialparticipantswere

presentedwithanemail(seeAppendixE)thatbrieflyexplainsthesurveyandwereprovidedwitha

linktotheREDCap™survey(seeAppendixG).Anintroductionandconsentscriptwaspresentedto

interestedpartiesatthebeginningofthesurvey,andprovideddetailspertinenttotheconsent

process.Essentially,theintroductionscriptexplainedconceptspertinenttothestudyandthe

consentscriptexplainedthatcompletionofthesurveyisnotexpectedtoengenderanyspecific

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harmsorbenefits,thatidentifyinginformationwillnotbecollectedinthecontextofthisstudy,and

thatparticipationinthesurveyisprovidingimpliedconsentforparticipationinthestudy.

TheOttawaHealthScienceNetworkResearchEthicsBoardapprovedthestudyprotocol

(OHSN-REBProtocol#20150651-01H).

3.2. Inclusion&ExclusionCriteria

3.2.1 InclusionCriteria

a. Practicingadultorchildneurologist

b. Expertiseinheadachemedicine

3.2.2 ExclusionCriteria

c. CannotreadandunderstandEnglish

3.3. Statistics

DatawereexportedfromREDCap™intoSAS®4.0.Descriptivestatisticsweregeneratedfor

eachitem(frequenciesandpercentages).Chisquare(χ2)testsofgoodnessoffitwereemployedto

assessiftherewasasignificantdifferencebetweentheproportionsofresponseitemsforeach

question.

4. HumanProtection

4.1. TimeCommitment

Thetimecommitmentinvolvedinparticipatinginthesurveywastheonlyethicalconsideration

thatpertainstothisproject.Participantscompletedaten-itemsurvey,requiringatime

commitmentof5-10minutesforcompletion.

4.2. RisksInvolvedinParticipatingintheStudy

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Itwasnotanticipatedthatanyriskswouldbeassociatedwithstudyparticipation.Theonly

actionassociatedwithparticipationwassurveycompletion.Therewasnoexperimental

manipulation,treatmentnorphysicaltestingofstudyparticipants.

4.3. BenefitsAssociatedwithParticipatingintheStudy

Therewerenoanticipatedbenefitsassociatedwithstudyparticipation.Studyparticipantswere

notofferedanyincentivesforparticipationandwerenotexpectedtodirectlybenefitfrom

publicationofitsresults.Theremotebenefitofimprovingfuturenon-inferioritytrialdesignsmay

beconstruedasabenefittosomeparticipants.

5. Results

Intotal,120individualscompletedtheNIMMsurvey.Twentyonerespondentswereineligible

toparticipateinthesurveybasedontheirresponsestotheinitialscreeningquestions:20

individualsdidnotidentifyasaneurologist,andoneindividualindicatedthattheyhadno

experiencepracticingHeadacheMedicine.Afterexcludingtheseineligibleparticipants,thefinal

samplesizeforthesurveycomprised99respondents.

RespondentcharacteristicsaredisplayedinTable3.Themajorityofthesample(84.9%)was

comprisedofadultneurologistsand74%ofrespondentsreportedpracticingintheUSA.Themost

commontypeofpracticewasacademic,with47.5%ofrespondentsclaimingtopracticeinthis

setting,while34.3%oftherespondentsreportedpracticinginthecommunityandtheremainder

reportedpracticinginamixedmodel.Respondentshadvaryingdegreesofexperiencepracticing

HeadacheMedicine(seeTable1);interestingly,alargenumberofrespondents(44.9%)reported

over20yearsofpracticeexperience.Themajorityofrespondentsreportedspendinglessthan10%

oftheirtimeonresearchactivities(59.6%),while23.2%reportedspending10-25%oftheirtime

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onresearch,andtheremainderofthesamplereportedthatover25%oftheirtimewasspenton

research(seeTable3).

Table3.CharacteristicsofNIMMrespondents

Characteristic Totalnumberofrespondents(missing)

N(percentage)

TypeofNeurologistAdultNeurologistChildNeurologist

99(0)

84(84.9)15(15.1)

LocationofPracticeUSACanada

96(3)

71(74)25(26)

TypeofPracticeAcademicCommunityMixedacademic/communitymodel

99(0)

47(47.5)34(34.3)18(18.2)

YearsPracticingHeadacheMedicine0-5years5-10years10-15years15-20yearsOver20years

98(1)

16(16.3)17(17.4)7(7.1)14(14.3)44(44.9)

PercentageofTimeDevotedtoResearch<10%10-25%25-50%50-75%>75%

99(0)

59(59.6)23(23.2)9(9.1)4(4.0)4(4.0)

Themostcommonlyselectednon-inferioritymarginforthechangeinthenumberof

monthlymigraineattackscomparingbaselinetothetreatmentperiodwas1attackpermonth,with

39.4%oftherespondentschoosingthismargin(seeTable4).Theresponsesfortheoutcomeof

monthlyattackswerenotevenlydistributed(p<0.0001).Forthechangeinthenumberofmonthly

migrainedays,44.4%oftherespondentsselected1dayastheirpreferrednon-inferioritymargin

andthiswasthemostcommonlyselectedmargin,withtheresponsesforthisoutcomebeing

unevenlydistributed(p<0.0001).Respondentsmostcommonlyselected1.0astheirpreferrednon-

inferioritymarginforthechangeinmigraineintensityonthe4-pointratingscale,with31.3%

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indicatingthismarginastheirchoice.Onceagain,theresponsestothisquestionwereunevenly

distributed(p<0.0001).

Table4.Non-inferioritymarginresponsesforprophylacticmigrainetrials

Outcome Totalnumberofrespondents(missing)

Margin Frequencyofrespondentsselectingmargin(percentage)

Changeinthenumberofmonthlymigraineattackscomparingbaselinetothetreatmentperiod

99(0) 0.25 8(8.1)0.5 28(28.3)0.75 6(6.0)1.0 39(39.4)1.25 8(8.1)Other* 10(10.1)

Changeinthenumberofmonthlymigrainedayscomparingbaselinetothetreatmentperiod

99(0) 0.5 20(20.2)0.75 7(7.1)1.0 44(44.4)1.25 4(4.0)1.5 16(16.2)Other* 8(8.1)

Changeintheaveragemigraineintensitycomparingbaselinetothetreatmentperiod(wheretheintensityoftheheadacheismeasuredonthefollowing4-pointseverityscale:0=noheadache,1=mildheadache,2=moderateheadache,3=severeheadache)

99(0) 0.2 9(9.1)0.4 28(28.3)0.6 18(18.2)0.8 8(8.1)1.0 31(31.3)Other* 5(5.0)

*SeeAppendixH

Forthefirstacuteoutcome,theabsolutepercentageofparticipantswhoarepain-free2

hoursaftertheintervention,41.4%ofrespondentsfeltthat5%wasthemostappropriatenon-

inferioritymargin(seeTable5).Thelattermarginwasthemostpopularselection,andthe

responsestothisquestionwereunevenlydistributed(p<0.0001).Themostcommonlychosennon-

inferioritymarginforthepercentageofpatientswithamigrainerelapsewithin48hoursof

treatmentwas5%,with42.4%ofrespondentsindicatingthatthisoptionwastheirpreference.

Again,theresponsestothisitemwerenotevenlydistributed(p<0.0001).Finally,forthe

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percentageofpatientswithsustainedpainfreedomat48hours,5%wasonceagainthemost

popularresponseitem,with42.4%oftherespondentsselectingthismargin.Theresponsestothis

questionwerenotevenlydistributed(p<0.0001).

Table5.Non-inferioritymarginresponsesforacutemigrainetrials

Outcome Totalnumberofrespondents(missing)

Margin Frequencyofrespondentsselectingmargin(percentage)

Absolutepercentageofparticipantswhoarepain-free2hoursaftertheintervention

99(0) 2.5 17(17.2)5 41(41.4)7.5 5(5.0)10 25(25.3)12.5 7(7.1)Other* 4(4.0)

Absolutepercentageofpatientswhohaveamigrainerecurrencewithin48hoursoftreatment

99(0) 2.5 20(20.2)5 42(42.4)7.5 9(9.1)10 21(21.2)12.5 4(4.1)Other* 3(3.0)

Absolutepercentageofpatientswithsustainedpainfreedom(ie.thepercentageofpatientswhoarepainfree2hoursaftertheinterventionandremainpain-free48hoursaftertheintervention)

99(0) 2.5 18(18.2)5 42(42.4)7.5 8(8.1)10 22(22.2)12.5 5(5.1)Other* 4(4.0)

*SeeAppendixH

Basedonthemostcommonresponsesselectedforeachitem,expertopiniononappropriate

non-inferioritymarginsfortheoutcomesstudiedissummarizedinTable6.

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Table6.Expertopiniononappropriatenon-inferioritymarginsforcommonlyusedmigraineoutcomesProphylacticTrialOutcomesOutcome Margin Percentageofexperts

selectingmarginChangeinthenumberofmonthlymigraineattackscomparingbaselinetothetreatmentperiod

1day 39.4%

Changeinthenumberofmonthlymigrainedayscomparingbaselinetothetreatmentperiod

1day 44.4%

Changeintheaveragemigraineintensitycomparingbaselinetothetreatmentperiod(wheretheintensityoftheheadacheismeasuredonthefollowing4-pointseverityscale:0=noheadache,1=mildheadache,2=moderateheadache,3=severeheadache)

1.0point 31.3%

AcuteTrialOutcomesOutcome Margin Percentageofexperts

selectingmarginAbsolutepercentageofparticipantswhoarepain-free2hoursaftertheintervention

5% 41.4%


5% 42.4%

Absolutepercentageofpatientswithsustainedpainfreedom(ie.thepercentageofpatientswhoarepainfree2hoursaftertheinterventionandremainpain-free48hoursaftertheintervention)

5% 42.4%

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6. Discussion

TheNIMMsurveysummarizestheopinionsofneurologistswithexpertiseinHeadache

Medicineonappropriatenon-inferioritymarginsforoutcomescommonlyusedinclinicaltrialsof

interventionsformigraine.Thissurveyisuniqueinprovidingthemigraineresearchcommunity

withexpertopinionfromalargenumberofHeadacheMedicinespecialistsonoptimalnon-

inferioritymarginsformigrainetrialoutcomes.

Itisinterestingtonotethatthemajorityoftherespondents(59.6%)reportedspendingless

than10%oftheirtimeonresearchactivities.Thus,oursamplewascomprisedofparticipantswho

areprimarilyengagedinclinicalHeadacheMedicine.Webelievethatthisisastrengthofthestudy,

giventhatclinicalHeadacheMedicinespecialistsaretheprimaryknowledgeusersvis-à-visclinical

trialsonmigrainetreatments.Anotherinterestingfeatureofoursamplepertainstotheexperience

levelofparticipants:59.2%ofparticipantsreported15ormoreyearsofexperienceinpracticing

HeadacheMedicine.Inaddition,thevarioustypesofpracticemodels(ie.academicvs.community

vs.mixedmodel)wereeachwellrepresentedinthesample.Therefore,webelievethatoursample

ofparticipantswasoptimalinthatitwasdiverseandthecollectivedegreeofclinicalexperience

wassignificant,therebymakingtheconclusionsdrawnmorecredibletoawiderangeofend

knowledgeusers.

Weusedseveralevidence-basedstrategiesinordertomaximizeparticipation166.Weusedsocial

exchangetheoryindesigningtheemailinvitationbyhighlightingtheminimalcoststoparticipants

(ie.brevityofthesurvey)andthepotentialbenefitstofutureresearchstudies.Wedidnotcollect

anypersonalorsensitiveinformation.Wealsoattemptedtooptimizerecruitmentbysendingtwo

follow-upcommunicationstopotentialparticipants.Finally,itisknownthatsendingsurveys

throughrespectedorganizationscancontributetooptimizingparticipation166,andwewereableto

havetheNIMMsurveysentoutthroughtheAHSandCHS.

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Respondentsselectedmultiple-choiceoptionsinordertoindicatetheiropinionsonthenon-

inferioritymargins.Onecouldarguethatthepre-specificationofmultiplechoiceoptionsleadsto

biasedresults,bylimitingrespondentstoavailableoptions.However,eachsurveyitemhadan

“Other”responseoption,wherebyparticipantscouldselectamarginoutsideofthoselistedinthe

multiplechoiceoptions.Giventhelownumberofrespondentsselecting“Other”asanoption(range

from3.0-10.1%),andgiventheheterogeneityofthewrittenresponsesassociatedwiththe“Other”

option(seeAppendixH),itmaybereasonabletoconcludethatdesigningthesurveydifferently,for

example,withfreetextentryasopposedtomultiplechoiceoptions,wouldnothaveyielded

drasticallydifferentresults.Thedecisionwasmadetousemultiplechoiceoptionssoastosimplify

thesurveyforrespondentsandensurethatthesurveywouldyieldasetmarginforeachoutcome.

Designingthesurveywithfree-textentryofmarginsmayhaveavoidedthepotentialproblemof

biasingrespondentsintoselectingparticularmargins,butinterpretationoftheresultswouldhave

beencomplicatedinthatitlikelywouldnothavebeenpossibletoselectonepreferredmarginfor

eachoutcomeinavalidmanner.Asurveywithsimilaraimssampledexpertopiniononnon-

inferioritymarginsforanticoagulantstopreventvenousthromboembolismpost-orthopedic

surgeryusingfree-textentryasameansofselectingthepreferredmargins,andtheresultsshowed

averywiderangeofresponsesthatwouldbedifficulttoapplytopractice167.

Severaladditionallimitationsofthissurveyshouldbenoted.Therewasahighlikelihoodof

coveragebiasgiventhatAHSandCHSmembershiplistswereusedasthesamplingframe.Itislikely

thatHeadacheMedicinespecialistswhoaremembersoftheseorganizationsdiffersystematically

fromHeadacheMedicinespecialistswhoarenotmembersoftheseorganizations.Membersare

likelymoreinvolvedinacademicactivitiesgiventhattheseorganizationspromoteandsupport

academicendeavorssuchasscientificmeetingsandresearchcollaborations.Languageminorities

arelikelysystematicallyunderrepresentedintheAHSandCHSasallcommunicationsandmeetings

areheldinEnglish.Thesurveyalsohadasignificantpotentialfornon-responsebiasforseveral

76

reasons.Firstly,althoughitwasnotpossibletodeterminethetotalnumberofeligibleHeadache

MedicinespecialistswithintheAHSandCHS,wesuspectthatourresponseratewaslowbasedon

thetotalnumberofmemberswhoweresentthesurvey(eg.1,211AHSmembersweresentthe

survey).BecausethesurveywasonlysentinEnglish,languageminoritieswerelikelysystematically

underrepresentedamongstsurveyrespondents.Therewasalsoasignificantpotentialfor

measurementerrorinthissurvey.Thesurveytopicwascomplexandalthoughanattemptwas

madeatformulatingtheclearestpossiblequestions,thesurveywasnotpilotedanditistherefore

possiblethatsomerespondentsfoundthequestionschallengingtoanswer.Althoughoutcomes

wereselectedjudiciously,throughconsultationofinternationalguidelines,patientswerenot

consultedonthechoiceofoutcomes.Thepatientperspectiveisthereforelackinginthissurveyand

thisisanimportantlimitationofthestudy.Therecommendednon-inferioritymarginswere

selectedusingthemodeoftheresponses.Althoughusingthemodeallowedustosimplytranslate

theresultsofoursurvey,itarguablymaynotprovidetheidealrepresentationoftherangeof

responses.

Astheliteratureonmigrainetreatmentexpandsandmoreinterventionsareconsistently

showntohavesuperiorefficacytoplacebo,non-inferioritytrialswillplayanincreasinglyimportant

roleinexpandingourknowledgeofsafeandeffectivetreatmentsformigraine.Thisstudyprovides

auniqueperspectivefromalargeandexperiencedgroupofHeadacheMedicinespecialistsontheir

opinionsregardingnon-inferioritymarginsforoutcomesusedinmigraineclinicaltrials.Itishoped

thattheseresultsmaybeusedinthedesignoffutureclinicaltrials,sothatappropriatesamplesizes

maybecalculatedbasedinpartontherecommendednon-inferioritymarginsderivedfromthis

survey.

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THESISPARTIII:DESIGNOFARANDOMIZEDCONTROLLEDTRIAL

1. BACKGROUND

Aswassummarizedabove,migraineisexceedinglycommoninchildren,affecting

approximately8%ofallchildrenandadolescentsworldwide1.Migraineisalsoasignificantcauseof

disabilityinadults2andchildren6–8.Theliteraturereviewpresentedinthebackgroundsection

above(seethesispartI)combinedwiththedataobtainedthroughthesystematicreview(seethesis

partI)provideacomprehensiveoverviewoftheevidencebaseformigrainemanagementin

pediatrics.

Severalconclusionscanbereachedafterreviewingtheevidenceforpediatricmigraine

prophylaxis.Firstly,amongstallcategoriesofinterventions,thepharmaceuticalshavebeenthebest

studied.Thisisunsurprisinggiventhatfundingforpharmaceuticalresearchismorereadily

availablethanfundingfornon-pharmaceuticalresearch,whichtendstohavelesscommercial

value168.Amongstthepharmaceuticals,themostextensivebodyofliteraturepertainstotheefficacy

andsafetyoftopiramateforthepreventionofmigrainesinchildrenandadolescents.Sixstudies

haveexploredthisquestion120–125,andtopiramateappearstobemoreefficaciousthanplacebofor

thisindicationbasedonbothaqualitativeandquantitativereviewoftheevidence.However,

topiramatealsoappearstobelesstolerabletopatientsthanplacebo,withahostofrelatively

commonsideeffectsincludingcognitivesideeffects,weightlossandanorexia,paresthesiasand

upperrespiratorytractinfections.Inadditiontothesixtopiramatestudies,thesystematicreview

identifiedelevenothernutraceuticalorpharmaceuticalinterventionsthathavebeenstudiedin

randomizedtrialsforthisindication:butterbur104,riboflavin114,115,valproicacid127,flunarizine132–

134,timolol137,clonidine142,trazadone144,nimodipine148,cinnarizine169,dimethothiazine134and

papaverine170.Inadditiontotheseinterventionswithevidencefromrandomizedstudies,ahostof

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pharmaceuticalandnutraceuticalinterventionshaveonlybeenassessedinnon-randomized

studiesorlowqualityrandomizedstudiesthatdidnotqualifyforthesystematicreview:

magnesium53,coenzymeQ1054,fishoils55,combinationnutraceuticalinterventions57–59,

levetiracetam70,71,amitriptyline75–77,L-5-hydroxytryptophan56,cyproheptadine76,pizotifen171and

Botox78,79.

Oftheinterventionswithanevidencebaseotherthantopiramate,fewholdpromiseaspotential

first-lineinterventionsforthepreventionofmigraineinchildrenandadolescents.Avarietyof

limitationsexistforsomeoftheseinterventions.Severaloftheinterventionsarenotavailablein

Canada:nimodipine,cinnarizineanddimethothiazine.Nutraceuticalsareconsideredtobenatural

healthproductsandareregulateddifferentlybyHealthCanadathanpharmaceuticals172withless

stringentregulationsandsurveillanceascomparedtopharmaceuticals.Therefore,theroutine

clinicaluseofnutraceuticalsforthepreventionofpediatricmigraineislimitedbythelackof

stringencyinregulationsandqualitycontrol,withthefollowinginterventionsfallingintothis

category:butterbur,riboflavin,magnesiumcoenzymeQ10,fishoils,L-5-hydroxytryptophanand

combinationnutraceuticalagents.Afewoftheinterventionsthathavebeenstudiedforthis

indicationareassociatedwithsignificantsideeffectprofilesthatmaketheiruseasfirst-lineagents

lessappealingtobothphysiciansandpatients,namelyvalproicacid,pizotifenandflunarizine.Most

often,pediatriciansorpediatricneurologistsareprescribingprophylaxisforpediatricmigraine.

Severaloftheinterventionsthathavebeenstudiedareoflimitedfamiliaritytothesepractitioners,

andarethereforelesslikelytohavesuccessfuluptakeasfirst-lineinterventions:timolol,

papaverineandpizotifen.AlthoughpreliminaryevidenceforBotoxsuggeststhatitmightbe

efficaciousinchronicmigraine78,79,ithasnotbeenstudiedforprophylaxisofepisodicheadaches.

Manypractitionersuseamitriptylineasafirst-lineinterventionformigrainepreventioninthe

pediatricagegroup76.Itisthereforequitesurprisingthattheevidenceforitsuseisderived

exclusivelyfromnon-randomizedstudies75–77,withtheexceptionofonerandomizedstudy

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comparingitsefficacyalonetoitsefficacyincombinationwithcognitivebehaviortherapy35.This

lackofevidenceandthecommonalityofitsuserenderitanexcellentcandidateinterventionforthe

nextrandomizedcontrolledtrialinthearea.Infact,theChildhoodandAdolescentMigraine

Preventionstudy(CHAMP),currentlyunderway,iscomparingtheefficacyofamitriptyline,

topiramateandplaceboinarandomized,double-blind,parallel-groupdesign173.Giventhat

amitriptylineisalreadybeingstudiedinalarge,well-designedclinicaltrial,itwouldbedifficultto

justifythedesignofasecondrandomizedtrialaimingtoanswerthesamequestionwhenthereare

somanyotherimportantandunansweredquestionsinthisareaofresearch.

Oftheremaininginterventionswithoutlimitationstosuccessfuluptakeasdescribedaboveand

whichlackconsistentevidenceforefficacythusjustifyingstudyinarandomizedtrial,thatis,

clonidine,trazadone,papaverine,levetiracetam,andcyproheptadine,levetiracetamisthemost

likelytobedeemedclinicallyacceptabletothemedicalcommunityandtopatients.Aspreviously

mentioned,clonidinehasfallenoutoffavourasamigrainepreventiveagent,withrecentdatafrom

oneNorthAmericancentersuggestingthatitisveryinfrequentlyprescribedforthisindication174.

Additionally,thedatafromtheonerandomizedstudyonitsefficacyisunconvincing142anditwould

thereforenotbetheidealinterventiontoinvestresourcesintofurtherstudying.Trazodonealso

lackspromiseasafirst-linemigrainepreventiveagent,giventhatitappearstobeusedvery

infrequentlyincurrentclinicalpractice174,andgiventhattheonlystudyonitsefficacyforthis

indicationfailedtodemonstratethatithaspotentialbeyondplacebo144.TheFDAhasnotapproved

useofpapaverineandHealthCanadaisregulatingpapaverineasanewdrug175,acategorythat

appliestointerventionswithlimiteddataonefficacyandsafetyinCanadaduetoashortperiodof

saleorminimalsales.Giventhisandtheminimaldatafoundduringthissystematicreview,

papaverineisnotanauspiciousagenttobestudiedasamigrainepreventive.Cyproheptadine,

althoughrelativelycommonlyusedinmanycenters,tendstobeusedprimarilyinyoungerchildren,

andmuchlesscommonlyinadolescents76,174.Thereasonforitsminimaluseintheadolescentage

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grouplikelypertainsinparttoconventionalpracticepatterns,andinparttodatafromasmall

randomizedstudythatfoundittobelesseffectivebeyond9yearsofageascomparedtoitsefficacy

inyoungerchildren176.Therefore,cyproheptadineislesslikelytobeusedintheadolescentage

group,andgiventhatmigraineisthemostprevalentinthispediatricsubsetofpatients1,itwouldbe

wisertostudyanotherinterventionthatismorelikelytobeeffectiveinadolescentswithmigraine.

Incontrast,levetiracetamhasdemonstratedpromiseformigraineprophylaxisinnon-randomized

studies70,71,andhasarelativelystrongtolerabilityprofile.Asidefromtheapproximately10%rate

ofbehavioralandpsychiatricsideeffects,itisrelativelysafetouse,doesnotrequireregularblood

worksurveillanceandhasthelowesttoxicityrankingofallofthenewanticonvulsantmedications

onthemarket177.Inaddition,pediatriciansandpediatricneurologistsarefamiliarwith

levetiracetambecauseitiscommonlyusedforthetreatmentofepilepsy178.

Asisdescribedabove,onlytwonon-randomizedstudieshaveassessedtheefficacyof

levetiracetamforthepreventionofmigrainesinthepediatricpopulation70,71.Becauseofitsrelative

promisebasedonthispreliminarydataandbecauseofalackofsignificantbarrierstouptakeas

comparedtotheotherinterventionsidentifiedinthisreview,itisofinteresttoinvestigateits

efficacyandtolerabilityforthisindication.Inordertoavoidduplicationandtoensurethatno

currentstudiesareunderwaytoanswerthisquestion,clinicaltrialregistriesweresearchedfor

relevantprotocolsonJuly15th2015(theNationalInstitutesofHealth(NIH)clinicaltrialregistry:

clinicaltrials.govandtheWorldHealthOrganization(WHO)InternationalClinicalTrialRegistry

Program:http://www.who.int/ictrp/en/).Nopediatricstudieswerefound.Onlyonestudywas

identifiedthroughclinicaltrialregistrysearches(registrationnumber:NCT00203216)andthe

clinicalquestionwaslimitedtotheadultpopulationaged18yearsandover.Therefore,

levetiracetamshowspromiseformigrainepreventionbasedonnon-randomizeddata,islikelyto

havesignificantuptakeclinicallyiffoundtobeeffectiveforthisindication,andnocompeting

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randomizedstudiesarecurrentlyunderwaytoassessitsefficacyandtolerabilityintheprevention

ofpediatricmigraine.

Thegoaloftheproposedstudywillbetocomparetheefficacyandsafetyoflevetiracetamto

thatoftopiramateandplaceboforthepreventionofmigrainesinchildrenandadolescents,usinga

randomized,double-blind,placebo-controlled,3-arm,parallel-grouptrialdesign.

2. METHODS

2.1. StudyObjectives

Theprimaryandsecondaryobjectiveshavebeenchoseninordertocomplywiththe

recommendationsdetailedintheInternationalHeadacheSocietyGuidelinesforControlledTrialsof

DrugsinMigraine84.

2.1.1. PrimaryObjective

• Tocomparetheefficacyoflevetiracetam,topiramateandplacebofor

reducingthenumberofmigraineattacksfrombaselineascomparedtothe

final4-weektreatmentintervalinchildrenandadolescentswithmigraine.

2.1.2 SecondaryObjectives


reducingthenumberofmigrainedaysfrombaselineascomparedtothe

final4-weektreatmentintervalinchildrenandadolescentswithmigraine.


reducingtheaverageintensityofmigraineattacksinchildrenand

adolescentswithmigraine.

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• Tocomparetheresponderrates,definedastheproportionofpatients

withatleasta50%reductioninmigrainefrequencyduringthetreatment

period,oflevetiracetam,topiramateandplaceboinchildrenand

adolescentswithmigraine.


reducingthedisabilityassociatedwithmigrainesinchildrenand

adolescents.

• Tocomparethesafetyoflevetiracetam,topiramateandplaceboin

childrenandadolescentswithmigraine.

2.2. StudyDesign

Thisstudywillconstitutearandomized,double-blind,placebo-controlled,3-arm,parallel-group

trial.Thestudywillbeamulticentertrialgiventhatitwillnotbefeasibletorecruitadequate

numbersofpatientsfromonecenter.Anticipatingthateachcenterwillrecruitanaverageof15

patientsperyear,withatotalsamplesizeof328(seebelow),theplanwillbetohave11centers

recruitingpatientsfortwoyears.Eachcenterwillhavearesearchcoordinatorassignedtothe

project,whowillberesponsibleforpatientrecruitment,enrollment,schedulingpatientfollow-ups,

carryingouttelephonefollow-ups,dataentryandcommunicationwiththesiteinvestigator,the

steeringcommitteeandthedataandsafetymonitoringboard.Participantswillberecruitedovera

periodoftwoyears.Aftera1-monthbaselineperiod,participantswillberandomizedtoreceive

eitherlevetiracetam,topiramateorplaceboina1:1:1allocation.Thetreatmentperiodwillbegin

withan8-weektitrationperiod,followedbya16-weekmaintenanceperiod,followedbya4-week

weaningperiod.Thetrialwillterminateaftera4-weekpost-treatmentobservationperiod

followingtheweaningperiod.Telephonevisitswilloccurwiththesitestudycoordinatorandclinic

visitswilloccurwiththesiteinvestigator.Boththeclinicvisitsandthetelephonevisitswilloccur

monthlyandtheywillbeseparatedby2-weekintervals,suchthatpatientshaveapointofcontact

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withthestudyevery2weeks.Theonlyexceptiontothisalternatingschedulewillbeforthelast

visit,whichwillbeatelephonevisitratherthanaclinicvisit.Thestudyscheduletemplateis

displayedinfigure6.

Figure6.Studytimelines

*NB.Bluetimepointsareclinicvisitsandredtimepointsaretelephonevisits

2.3. EligibilityCriteria

Theeligibilitycriteriahavebeenchosenbasedontherecommendationsmadebythe

InternationalHeadacheSocietyintheirGuidelinesforControlledTrialsofDrugsinMigraine84.The

rationalefortheeligibilitycriteriaarelistedinAppendixI.

2.3.1 InclusionCriteria

1. MigrainewithoutauraormigrainewithauraasperInternational

ClassificationofHeadacheDisordersThirdEdition,BetaVersion(ICHD)

criteria86(seeTables7and8)

2. Age8.0-18.0years

BaselineTitration Maintenance WeanPost-Rx

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3. Migrainefrequencyof2-8attackspermonthinthreemonthretrospective

periodand1monthbaselineperiod,withdefinitionofattackasfollows:

i. Attacksareseparatedbyatleasta48hourheadache-freeinterval

4. Migraineshavebeenpresentforatleastoneyear

5. Abletocommunicatesufficientlywithparentsinordertoaccuratelycomplete

aheadachediaryandstudyquestionnaires

2.3.2 ExclusionCriteria

1. Otherheadachetypesarepresentandtheparticipantcannotdifferentiate

migrainefromtheotherheadache(s)

2. Fifteenormoreheadachedayspermonth(ie.chronicmigraine)

3. Overusingacutemigrainemedications:

i. Takingatriptanontenormoredayspermonth

ii. Takingacetaminophenoranon-steroidalanti-inflammatorymedicationon

fifteenormoredayspermonth

4. Takingamigraineprophylacticmedicationwithinthreemonthsofenrollment

5. Takinganantipsychoticorantidepressantmedicationwithinthreemonthsof

enrollment

6. ReceivedBotoxinjectionsformigrainewithinthepastthreemonths

7. Previoustrialoftopiramateorlevetiracetamformigraineprophylaxiswith:

i. Adequatedosing

ii. Atleastthreemonthsofprophylaxis

8. Historyofanaphylaxisorallergytotopiramateorlevetiracetam

9. Pregnant,lactatingorpositivepregnancytest

10. Sexuallyactiveandnotusingareliablebirthcontrolmethod

11. Historyofrenalcalculi

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12. Significanthepaticorrenalimpairment

13. Ontheketogenicdiet

14. Historyofepilepsy

15. HasapsychiatricdisorderasdefinedintheDiagnosticandStatisticalManual

ofMentalDisorders5thedition(DSMV)

16. Hasalcoholordrugdependence

17. Historyofsignificantbehavioralproblems

18. Historyofanotherchronicpaindisorder

Table7.ICHDcriteriaforpediatricmigrainewithoutaura

Criterion DescriptionA Atleast5attacksthatfulfillcriteriaB-DB Attackslasting2-72hours*C Twoofthefollowingfourcharacteristicsarepresent:

• Unilateralorbilaterallocation• Pulsatingquality• Moderateorseverepainintensity• Aggravatedbyorcausingavoidanceofphysicalactivity

D Duringattacks,atleastoneofthefollowingcriteriaaremet:• Nauseaand/orvomiting• Photophobiaandphonophobia

E NotbetterexplainedbyanotherICHDdiagnosis

*Untreatedorunsuccessfullytreated

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Table8.ICHDcriteriaforpediatricmigrainewithaura

Criterion DescriptionA Atleast2attacksmeetingcriteriaBandCB Oneormoreofthefollowingfullyreversiblesymptomsofaura:

• Visual• Sensory• Speechand/orlanguage• Motor• Brainstem• Retinal

C Twoofthefollowingfourcharacteristicsarepresent:• Atleastonesymptomofauraspreadsgraduallyoverfiveminutes

ormore,and/ortwoormoresymptomsoccurinsuccession• Eachindividualsymptomofauralastsbetweenfiveandsixty

minutes• Atleastonesymptomofauraisunilateral• Theauraisaccompaniedbyaheadacheorfollowedbyaheadache

withinsixtyminutesD NotbetterexplainedbyanotherICHDdiagnosisandtransientischemic

attackhasbeenexcluded

2.4. Interventions

Participantsmeetingalleligibilitycriteriaaftertheonemonthbaselineperiodwillbe

randomizedina1:1:1fashiontoeitherlevetiracetam,topiramateorplacebo.Allinterventionswill

beadministeredinanoralsolutionform,whichwillbepreparedbythesitepharmacy.The

solutionswillbematchedintasteandcolor,soastoensurethatblindingismaintainedbasedon

theappearanceoftheintervention.Theinterventionswillbetitratedinastandardwayduringthe

courseofthe8-weektitrationperiodfollowingrandomization.

Levetiracetamwillbeadministeredinanoralsolutionform,withaconcentrationof

100mg/mL.Participantsinthelevetiracetamgroupwillbetreatedwithatargetdoseof20-

40mg/kg/day,toamaximumof3000mg/day.Thistargetdosagewaschosenbasedonprescription

recommendations179andbasedonapreviousprospectiveopen-labelstudyontheefficacyof

levetiracetamforpediatricmigraineprophylaxis71.Thetitrationschedulewillbeasfollows:initiate

levetiracetamat5mg/kg/dayqHSforoneweek,thendoubleto10mg/kg/daydividedbidforone

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week,theincreaseto15mg/kg/daydividedbidforoneweek(ie.5mg/kgqAMand10mg/kgqHS),

thenincreasetotargetof20mg/kg/dayandifrequired,canthenincreasein5mg/kg/day

incrementsweeklyuptoamaximumdoseof40mg/kg/daydividedbid.Ifthepatientisresponding

welltotheintervention,thenthedoseoflevetiracetamwillbeheldat20mg/kg/day;increases

beyond20mg/kg/daywillonlybecarriedoutifnecessary.Althoughlevetiracetamisusually

initiatedat10mg/kg/dayandincreasedbiweeklyby10mg/kg/day,thedecisionwasmadeto

initiatethedoseat5mg/kg/dayandincreaseby5mg/kg/dayweeklyinordertoreflecttheweekly

titrationscheduleoftopiramate.Thesimilarweeklytitrationscheduleswillhelptomaintain

participantandphysicianblinding.

Topiramatewillbeadministeredinoralsolutionform,withaconcentrationof6mg/mL.

Participantsassignedtotopiramatewillhavetheirdosagetitratedupto2-3mg/kg/day,toa

maximumof200mgdaily,inaccordancewithdosingrecommendations179andpreviouspediatric

topiramatetrials120,173.Thetitrationwillcorrespondtothefollowing:1)forchildren8-12years:

initiateat15mgqHSforoneweek,thendoubleto15mgbidforoneweek,thenincreaseto25mg

bidforoneweek,thencontinuewith25mg/weekincreasesinthedose,upto2-3mg/kg/dayor

200mgmaximum,2)forchildrenagedover12years:initiateat25mgqHSforoneweek,then

doubleto25mgbidforoneweek,thenincreaseto25mgqAMand50mgqHSforoneweek,and

continuetitrationby25mgweeklyincreasesupto2-3mg/kg/dayorthe200mgdailymaximum(ie.

100mgbid)179.

Theplacebogroupwillbegivenamatchedplacebooralsolution.Theplacebogroupwillfollow

asimilartitrationscheduletotheinterventiongroups.Theywillbeinitiallygiven3mLofthe

placebosolutionqHS,whichwillbedoubledto3mLbidafteroneweek,andtheywillsubsequently

have3mL/weekincreasesupto6mLbid,or,ifrequired,theywillcontinuetohave3mL/week

increasesthroughoutthetitrationperiodtoamaximumof12mLbid.

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Iftolerabilityissuesariseforanyoftheinterventions,thentheinvestigatoronsitewillhavethe

libertytodeviatefromthetitrationscheduleasrequiredclinically.Theinvestigatorwillbeableto

holdoffadoseincrease,decreaseacurrentdoseorrecommenddiscontinuationshouldintolerable

adverseeventsoccur.Theinvestigatorwillremainblindedthroughout,andwillmakedecisions

basedontheclinicalscenariowhileremainingblinded.However,ifaseriousadverseeventoccurs

orifaclinicalscenarioarisesthatrequiresunblinding,thesiteinvestigatorwillcontactthe

pharmacydepartmenttobreaktheirblinding.

Eachinterventionwillbeweanedoverthecourseof4weeks,indecrementsof25%perweek.

Blindingwillbemaintainedduringtheweaningphaseandbeyond.Thestudyinvestigatorwillhave

theauthoritytodeviatefromtheweaningscheduleattheirdiscretion,shouldtheybelievethatitis

inthebestinterestofthepatienttodoso.Uponcompletionofthewean,atweek32,therewillbea

studyvisitwiththesiteinvestigator.Atthisvisit,thesiteinvestigatorwilldiscusstheneedfor

ongoingprophylaxiswiththepatientandfamily,andwillhavetheabilitytostartaprophylactic

interventionatthispointintime,ifclinicallyindicated.Follow-upforthemigraineswillbe

arrangedeitherwithachildneurologistatthatcenter,orwiththepatient’sfamilydoctor,as

appropriateanddependingonthepatientandfamily’spreference.

2.5. Outcomes

Apaper-basedheadachediarywillbemaintainedbyparticipantsfromthebeginningofthe

baselineperioduntiltheendofthefollow-upperiod.TheInternationalHeadacheSociety

GuidelinesforControlledTrialsofDrugsinMigrainerecommendthatheadachediariesbeusedto

trackalloutcomesinmigraineprophylaxistrials,andrecommendsimpleformatseitherin

electronicorpaperformthatonlytrackprimaryandsecondaryoutcomesandavoidextraneous

informationsoastonotoverwhelmparticipants84.Theheadachediarytemplatethatwillbe

employedforthepurposesofthistrialcanbefoundinAppendixJ.Asrecommendedbythe

InternationalHeadacheSociety,itonlymeasurestheprimaryandsecondaryoutcomes,withthe

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exceptionofalsoaskingparticipantstoreportontheuseofacuteabortivemedications.Although

theInternationalHeadacheSocietyrecommendsagainstacutemedicationusageasanoutcomein

parallel-grouptrials,theydostatethatthisoutcomeshouldbeincludedinheadachediaries84,and

thisiswhythiselementwasincludedinthetemplateheadachediary.

Thechoiceofprimaryandsecondaryoutcomeswasbasedontherecommendationsmadeby

theInternationalHeadacheSociety84.Theprimaryoutcomewillbethechangeinmonthlymigraine

attackscomparingthebaselineperiodtothefinal4weeksoftreatment.Migraineattackfrequency

waschosenastheprimaryoutcomegiventhatitislikelymoreaccuratethanmeasuringmigraine

days.Theproblemwithusingmigrainedaysforthefrequencyoutcomeliesinthefactthatthe

numberofdaysdependsonattackduration,whichismultifactorial(eg.acutetreatment

administered,timeofdayofattackonset).Thus,giventhatmigrainedaysareinfluencedby

migraineduration,thisisacompositeoutcome,makingmigraineattacksbettersuitedasthe

primaryoutcome.However,thechangeinmigrainedayscomparingbaselinetothefinal4-weeksof

treatmentwillbemeasuredasasecondaryoutcome,giventhattheInternationalHeadacheSociety

suggeststhatbothmigraineattackfrequencyandmigrainedaysshouldbemeasured84.

Othersecondaryoutcomesofinterestwerealsochosenbasedontherecommendationsmade

bytheInternationalHeadacheSociety84.Migraineintensitywillbemeasuredusinga4-pointscale,

asrecommendedintheguidelines:

• 0–noheadache

• 1–mildheadache

• 2–moderateheadache

• 3–severeheadache

Theintensityofthemigrainesinboththebaselineperiodsandthefinal4weeksoftreatment

willbeaveragedandcompared,suchthatachangeinaveragemigraineintensitywillconstitutethe

outcomemeasuredinthiscase.

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Inadditiontomeasuringthechangeinmigraineattackfrequencyandmigrainedayfrequency,

theresponderrateforeachgroupwillbecalculated.Theresponderrateisarecommended

outcomebytheInternationalHeadacheSociety,andcomprisesthepercentageofpatientsachieving

a50%orgreaterreductioninmigraineattackfrequencywhencomparingthebaselineperiodto

thefinal4weeksoftreatment84.Itisbelievedtobeapatient-centeredoutcome,giventhatpatients

oftenvaluetheabilityofamigraineprophylacticagenttoreducetheirmigrainefrequencybyat

leasthalf84.However,thereisnodatatosupportwhichmigraineoutcomesarethemostpatient-

centered,andintheabsenceofthisdata,relianceontheInternationalHeadacheSocietyGuidelines

ismostappropriate.

TheInternationalHeadacheSocietyGuidelinesalsohighlightthatmigraine-relateddisabilityor

qualityoflifecanbeusedassecondaryoutcomesinordertocapturetheglobalburdenofmigraine

onthepatient’slife.Thereisawell-validatedandwidelyusedmigraine-specificinstrument

availabletomeasuremigraine-relateddisabilityinthepediatricpopulation:thePediatricMigraine

DisabilityAssessmentScale(PedMIDAS)180.ThePedMIDASwasmodeledafteritsadultcounterpart:

theMIDAS.Itwasdevelopedtobesimpletouse,rapidtocompleteandsensitivetotheunique

lifestyleofchildrenandadolescents.ThePedMIDASiscomprisedof6questionsthatevaluatethe

patient’sabilitytofunctioninthepast90days.ScoresonthePedMIDASrangefrom0toa

theoreticalmaximumof540.Disabilityisassessedacrossthreecoredomains:schoolfunctioning,

homefunctioningandfunctioninginthesocialandplaydomains.PedMIDAShasgoodinternal

consistencyandreliability,withaCronbach’sαscoreof0.78andaPearsoncorrelationscoreof0.8

ontest-retest180.Inadditiontoitsvalidationintheoriginalclinicalsample,thePedMIDAShasalso

beenvalidatedinapopulation-basedsample8.ThePedMIDASalsohasapatient-basedgrading

systemdevelopedbytheoriginalgroupwhocreatedthequestionnaires:1)GradeI:scoresof0-10

indicatelittletonodisability,2)GradeII:scoresof11-30indicatemilddisability,3)GradeIII:

scoresof31-50indicatemoderatedisabilityand4)GradeIV:scoresabove51indicatesevere

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disability7.PedMIDASscoreswillbemeasuredatbaselineandattheendoftreatment,andthe

changeinthescorewillbecomparedbetweenthegroups.ThePedMIDASwillbeadministeredat

thebaselinevisit,atthecompletionofthemaintenanceperiod(atweek28)andattheendofthe

follow-upperiod(atweek36),overthetelephone.ThePedMIDASatbaselinewillbecomparedto

boththePedMIDASatweek28andatweek36.ThePedMIDASquestionnairecanbefoundin

AppendixK.

Adverseeventswillberecordedintheheadachediary.Theywillsubsequentlybecodedusing

theMedicalDictionaryforRegulatoryActivity(MeDRA®),whichisaninternationalmedical

terminologysystemdevelopedbytheInternationalConferenceonHarmonisationofTechnical

RequirementsforRegistrationofPharmaceuticalsforHumanUse.Adverseeventswillbeclassified

basedonthefollowingcategories:seriousornon-serious,expectedorunexpected,resolved,study-

related,possiblystudy-relatedorunrelatedtothestudy.Recordswillbekeptonparticipants

withdrawingfromthetrialduetoanadverseeventandonparticipantshavingtheirmedication

dosereducedortheirtitrationheldduetoadverseevents.

2.6. Randomization

Patientswhoareeligibleforparticipationandwhoconsenttoparticipationwillberandomly

assignedtoreceiveeitherlevetiracetam,topiramateorplaceboina1:1:1fashion.Thesiteresearch

pharmacistwillcontactacentralrandomizationserviceinordertocarryoutrandomization.The

centralrandomizationservicewillbeutilizedinordertoensurethatallsitesarerandomizinginthe

sameway,andinordertofacilitateallocationconcealment.Thecentralrandomizationservicewill

employacomputerrandomnumbergeneratortoassignparticipantstoaninterventiongroup.

Randomizationwillbestratifiedbycenterandbyage(8-13years,>13yearsto18years).Within

eachstratum,randomizationwilltakeplaceinblocksof4,6or8,withthesizeoftheblockbeing

randomlyselected.

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Theallocationwillonlybeknowntothecentralrandomizationserviceandtothesiteresearch

pharmacist,whowillhavenocontactwiththeinvestigators,researchpersonnelnorwiththe

participants.Thesiteresearchpharmacistwillmaintainapassword-protected,encrypted

electroniclistofpatientallocations.Thislistwillbemaintainedinordertohavetheinformation

accessibleonsiteforthepurposesofrapidaccessintheeventwhereaseriousadverseevent

occursandunblindingisrequired.

2.7. StudyVisits

Thestudyvisitscheduleisillustratedinfigure6.Eachhospitalvisitwillinvolveinteractionof

theparticipantwiththestudysiteinvestigator.Theinitialstudyvisitatweek0willcomprisea

completehistoryandphysicalexambythestudyinvestigator.Eligibilitycriteriawillbereviewedat

theinitialvisit.Ifapatientiseligibleforthestudy,thesiteinvestigatorwillcontactthesiteresearch

coordinatortofurtherdiscusstheprojectwiththepatientandfamily.Theresearchcoordinatorwill

explainstudyprocedurestothepatientandfamilyandwillseekinformedconsentfromeligible

participantsaged16yearsandoverandtheparentorguardian(seeAppendixL).Assentwillbe

soughtfromeligibleparticipantsunder16years(seeAppendixM).Consentingparticipantswillbe

senthomewithabrochureexplainingthestudy(seeAppendixN).Theresearchcoordinatorwill

explainthemigrainediaryindetailandwillgooverexamplesofhowtocompleteit.Participants

willbeinstructedtocompletethemigrainediaryonadailybasis,andwillbegiventipsonhowto

remembertocompletethediary(eg.setalarmonphone,leavediaryatthebedsideandcomplete

priortogoingtosleep,etc).

Subsequentstudyvisitswillinvolveweightmeasurements,physicalexamsasnecessary(eg.if

patientisexperiencingconcerningsideeffects)andintervalhistories.Anemphasiswillbeplaced

onreviewingtheheadachediary,interventioncomplianceandaddressinganyconcernsfromthe

patientorfamily.

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Duringthemonthlytelephonevisits,thesitestudycoordinatorwillreviewtheintervalhistory,

reviewcompliancewiththeheadachediaryandinterventionanddiscusssideeffectswiththe

patientandfamily.Wheresignificantconcernsarisewithsideeffectsorthepatient’shealth,the

studycoordinatorwillliaisewiththesiteinvestigatortoscheduleamoreexpedientfollow-up.

3. ProtectingAgainstSourcesofBias

3.1. SelectionBias

Inordertodecreasethepotentialforselectionbias,patientswillberandomizedusingacentral

randomizationservicethatbasesrandomizationonrandomnumbergeneration.Thismethodof

randomizationisconsideredtohavelowriskofselectionbias83.Inaddition,thereisalowriskof

selectionbiasrelatedtoallocationconcealmentwhenacentralrandomizationserviceisusedfor

thepurposesofrandomization83.Toensurethatthemostimportantcovariatesarebalanced

betweenthegroups,stratificationbasedoncenterandage(8-13years,>13yearsto18years)will

occurduringtherandomizationprocess.Othercovariates(ie.gender,baselinemigrainefrequency)

willbeaccountedforinlinearregressionmodels.

3.2. PerformanceBias

Thistrialwillbedouble-blind;onlythepharmacistswillknowthegroupassignment,whilethe

patients,families,studypersonnelandoutcomeassessorswillremainblinded.Thethree

interventionswillallbeadministeredinsolutionform,andthesolutionswillbematchedfortaste

andcolor.Inaddition,solutionvolumeswillbekeptrelativelyhomogeneousaswillthetitration

schedulesforeachintervention.Clinicalcarewillbeidenticalforallthreegroups.Inthisway,

severalattemptshavebeenmadetoensurethatblindingisbothestablishedandmaintained,in

ordertolimitthepotentialforperformancebias.

3.3. AttritionBias

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Participantswillhaveregularcontactwithstudypersonnel,withfollow-upsevery2weeks.

Thiswillensurethatanypatientandparentalconcernsarepromptlyaddressed.Inaddition,the

frequencyofin-hospitalfollow-upvisitswillbeminimizedbyprovidingtelephonefollow-upfor

50%ofthevisits,thusminimizingthenecessityforparticipantstodisplacethemselvesand

hopefullyoptimizingretention.Missingdatawillbeimputedusingmultipleimputation,which

shouldalsocontributetotheminimizationofattritionbias83.

3.4. DetectionBias

Theoutcomeswillprimarilybederivedfromtheparticipants’headachediaries.Giventhatthe

participantswillbeblindedandthateffortshavebeenmadetoensurethattheyremainblinded,

detectionbiasshouldbeminimized.Thesitestudycoordinatorswillassistincollectingsomeofthe

outcomes(eg.administrationofPedMIDASoverthetelephoneatthelastfollow-up).Study

coordinatorswillalsoremainblindedthroughoutthetrial.Therefore,theriskofdetectionbiasin

thisstudyshouldbelow,basedonhowtheoutcomesarebeingascertained.

4. STATISTICS

4.1. SampleSizeCalculations

Threeprimaryhypothesesofdifferingnaturesarebeingexploredintheproposedstudy:two

superiorityhypotheses,wherebytopiramateandlevetiracetamarehypothesizedtobesuperiorto

placebo,andanon-inferiorityhypothesis,wherebylevetiracetamishypothesizedtobenon-inferior

totopiramatewithrespecttotheprimaryoutcome.Giventhethreeprimaryhypotheses,two

separatesamplesizecalculationswerecarriedoutandthefinalsamplesizewaschosenbasedon

thelargerofthetworesults.

Theprimaryoutcomeinthistrialconsistsofthedifferencebetweentheaveragenumberof

monthlymigraineattacksatbaselineandtheaveragenumberofmonthlymigraineattacksinthe

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final4weeksoftreatment.Thisisacontinuousoutcome,characterizedbystandarddeviationasthe

measureofvariation.Allsamplesizecalculationswerecarriedoutusingapower(1–β)of0.8and

analpha(α)valueof0.05.Analyseswerecarriedouttakingintoaccounttheplannedgroup

sequentialdesignwithk=4intervals(seebelow).Thefollowingdatawereusedforthesamplesize

calculations:

• Topiramatevs.placebohypothesis:Theonlypediatricmigrainetrialcomparing

topiramateandplacebowithsimilareligibilitycriteriaandthesameprimaryoutcomeis

theWinneretaltrial120.Inthistrial,topiramateyieldedameanreductioninmigraine

attacksof2.6days,withastandarddeviation(SD)of2.6days,andplaceboyieldeda

meanreductionof2.0days,withaSDof3.1days.Nosamplesizecalculationswere

providedinthispediatrictrial.Adultrandomizedcontrolledtrialswithsimilareligibility

criteriaandassessingtheefficacyoftopiramatevs.placeboformigraineprophylaxis

usingthesameprimaryoutcomehavesetaminimalclinicallyimportantdifferenceof

1.19dayspermonth,withastandarddeviationof2.5daysfortheirsamplesize

calculations,basedonpilotdata181–183.Intheabsenceofdataonstakeholderopinion

regardingtheoptimalMCIDforthisoutcome,thedecisionwasmadetousethe

followingvaluesforthesamplesizecalculation,basedonthedatafromtheWinneretal

trialandtheadulttrials:1)topiramatemean:2.6,2)placebomean:1.41,3)SD:2.5.

Usingthesevalues,withatwo-tailedhypothesis,anαof0.05andapowerof0.8,a

samplesizeofN=71pergroupwascalculatedusingthePASS14software184(see

AppendixOforPASSreport).Planningforadrop-outrateof25%,thefinalsamplesize

topowerthetrialforthesuperiorityhypothesisis284.

• Levetiracetamvs.placebohypothesis:Asdescribedabove,twonon-randomizedstudies

evaluatedtheefficacyoflevetiracetamforpediatricmigraineprophylaxis70,71.Neitherof

thesestudiesusedacomparator,andbothwereobservational.Neitherusedreasonably

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similarinclusioncriteriatotheproposedstudy.Inlinewiththethirdhypothesis,

levetiracetamisexpectedtohavesimilarefficacytotopiramateforthisoutcome.

Therefore,aseparatesamplesizecalculationwasnotcarriedoutforthissecond

hypothesisasitwasassumedthattherequiredsamplesizewouldbesimilartothat

requiredforthefirstsuperiorityhypothesis.

• Topiramatevs.levetiracetamhypothesis:Inordertocalculateavalidsamplesizeforthis

thirdhypothesis,theNon-InferiorityMarginsinMigraineResearch(NIMM)surveywas

carriedout(seeabove).TheNIMMsurveyaskedexpertstoexpresstheiropinionson

optimalnon-inferioritymarginsforavarietyofcommonlyusedmigraineoutcomes.The

mostcommonlychosenresponseitemforthequestionregardingthenon-inferiority

marginfortheprimaryoutcomeinthistrial(ie.thechangeinthenumberofmigraine

attacks),was1attack,thatis,expertsfeltthatifaninterventionyielded1additional

attackpermonthorlessascomparedtothestandardintervention,thenitwouldbe

reasonabletoconsideritnon-inferior.Therefore,inordertocalculateasamplesizefor

thisnon-inferiorityhypothesis,thefollowingvalueswereused:1)non-inferiority

margin(delta):1,2)SD:2.5(asabove).Usingthesevalues,withanon-inferiority

hypothesis,whichisbydefinitionaone-tailedhypothesis,anαof0.05andapowerof

0.8,asamplesizeofN=82pergroupwascalculatedusingthePASS14software184(see

AppendixP).Planningforadrop-outrateof25%,thefinalsamplesizetopowerthe

trialforthenon-inferiorityhypothesisis328.Giventhatthiscalculationyieldedalarger

samplesizethanthesuperiorityhypothesiscalculation,thefinalsamplesizewillbe

328,soastomaintainadequatepowerforbothhypotheses.

4.2. PlannedStatisticalAnalyses

4.2.1 PrimaryHypotheses

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Therewillbethreeprimaryhypothesesintheproposedtrial:

1. Topiramatewillyieldagreaterdecreaseinthefrequencyofmigraineattackscomparing

baselinetothefinal4weeksoftreatmentascomparedtoplacebo.

2. Levetiracetamwillyieldagreaterdecreaseinthefrequencyofmigraineattackscomparing

baselinetothefinal4weeksoftreatmentascomparedtoplacebo.

3. Levetiracetamwillbenon-inferiortotopiramatewithregardstothechangeinmigraine

attackfrequencycomparingbaselinetothefinal4weeksoftreatmentascomparedto

placebo.

4.2.2 PrimaryOutcomeAnalysisPlan

AllanalyseswillbeperformedusingSAS®4.0.Demographiccharacteristicsforeachgroupwill

bepresenteddescriptivelyintabularform.

Theprimaryoutcomeinthisstudyisacontinuousoutcome:thechangeinmonthlymigraine

attackscomparingthebaselineperiodtothefinal4weeksoftreatment.Thegroupmeansforthis

outcomewillbecomparedusingusingaone-wayANCOVA.TheresponsevariablefortheANCOVA

willbethenumberofmonthlymigraineattacksinthefinal4weeksoftreatment,andanalysiswill

adjustforthenumberofmonthlymigraineattacksatbaselineasthecovariateofinterest.A

Bonferronicorrectionwillbeappliedinordertoaccountforthemultiplecomparisonscarriedout

post-hocintheeventwheretheinitialANCOVAissignificant(ie.topiramatevs.levetiracetam,

topiramatevs.placeboandlevetiracetamvs.placebo).

Inordertofurtherexploretheimpactofcovariatesontheprimaryoutcome,alinearregression

modelwillbeusedtomodeltheimpactofgroup,age,genderandbaselinemigrainefrequencyon

thechangeinmigrainefrequency.

4.2.3 SecondaryOutcomeAnalysisPlan

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Thefollowingcontinuoussecondaryoutcomeswillbeanalyzedinthesamewayastheprimary

outcome,withone-wayANCOVAscombinedwithBonferronicorrections(whereapplicablepost-

hoc)inordertocomparetopiramatevs.placebo,levetiracetamvs.placeboandtopiramatevs.

levetiracetam:

1. Thechangeinfrequencyinmigrainedayscomparingbaselinetothefinal4weeksof

treatment

2. Thechangeintheaveragemigraineintensitycomparingbaselinetothefinal4weeksof

treatment

3. ThechangeinPedMIDASscorecomparingbaselinetoweek28.

4. ThechangeinPedMIDASscorecomparingbaselinetoweek36.

ThefollowingdiscreteoutcomeswillbeanalyzedusingchisquaretestswithBonferroni

correctionsappliedinordertocomparetopiramatevs.placebo,levetiracetamvs.placeboand

topiramatevs.levetiracetam:

1. Theproportionofparticipantsachievinga50%orgreaterreductioninmigrainefrequency

whencomparingbaselinetothefinal4weeksoftreatment

2. Theproportionofparticipantswithanyadverseeventduringthetrial

3. Theproportionofparticipantswhowithdrewfromthetrialduetoadverseevents

4. Theproportionofparticipantswhohadtheirdosereducedortitrationheldduetoadverse

events

4.2.4 DealingwithMissingDataandApproachtoDataAnalysis

Missingdatawillbeimputedusingmultipleimputationtechniques.Becauseoneoftheprimary

hypothesesofthetrialisanon-inferiorityhypothesis,bothper-protocolandintention-to-treat

analyseswillbecarriedout.

4.2.5 InterimDataAnalyses

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Threeinterimdataanalyseswillbeplannedusingagroup-sequentialdesign:1)thefirst

analysiswilloccurwhen25%ofparticipantshavebeenrecruited;2)thesecondanalysiswilloccur

when50%oftheparticipantshavebeenrecruited;3)thethirdanalysiswilloccurwhen75%ofthe

participantshavebeenrecruited;4)thefinalanalysiswilloccurwhen100%oftheparticipants

havebeenrecruited.Intheinterimanalyses,onlytheprimaryoutcomeandthethreeoutcomes

relatedtoadverseeventswillbeanalyzed(ie.theproportionofparticipantswithadverseevents,

theproportionofparticipantswhowithdrewfromthetrialduetoadverseeventsandthe

proportionofparticipantswhohadtheirdosereducedortitrationheldduetoadverseevents).

TheO’BrienandFlemingmethod185willbeusedtocontroltheleveloftypeIerror(α)inthe

proposedtrial.Thealphawillbespentinthefollowingway,withpvaluecut-offsforeachanalysis

asfollows,given4plannedanalyses(k=4)atintervalsik(seeAppendixPforsourceofpvalues):

• Firstinterimanalysis(i1):p=0.00116

• Secondinterimanalysis(i2):p=0.00529

• Thirdinterimanalysis(i3):p=0.02532

• Finalanalysis(i4):p=0.04643

DetailsregardingtheboundariesusedforthetrialstoppingrulesareincludedinAppendixP.

5. TRIALMANAGEMENTISSUES

5.1. RecruitmentProcess

5.1.1 RecruitmentTargets

Eachoftheelevensiteswillbeexpectedtorecruitanaverageof15patientsperyearand

recruitmentwillproceedovertwoyears,sothateachsiterecruitsanaverageof30patients.

Siteresearchcoordinatorswillmaintainarecruitmentlogdetailingthenumberofpatients

assessedforstudyeligibility,thenumberexcludedwithstandardizedreasonsforexclusion,the

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numberwhoconsentedtoparticipationandthenumberwhowererandomizedtoanintervention.

Siteresearchcoordinatorswillsendrecruitmentlogstothetrial’ssteeringcommitteeonamonthly

basis.Inthisway,therewillbeanongoingassessmentastowhetherrecruitmenttargetsarebeing

met.Ifparticularsitesarestrugglingwithrecruitment,thetrialsteeringcommitteewillreachoutto

theaffectedsite(s)andworkonsolutionsaimedatimprovingtherecruitmentrate.

5.1.2 StrategiestoMaximizeRecruitmentandFollow-Up

Sitecoordinatorswillhostapresentationforallclinicalpersonnelinparticipatingclinicsafew

weekspriortoinitiatingsiterecruitment.Clinicalpersonnelwillbeinformedaboutthestudy,its

purpose,itsoveralldesignaswellasitsrecruitmentmethods.Posterswithconciseinformation

aboutthestudyandthesitecoordinator’scontactinformationwillbeplacedineveryclinicroom

andinmultiplelocationsineachparticipatingclinic.Thesitecoordinatorwillsendanemailto

clinicalpersonnelevery3months,whichwillbrieflydescribehowrecruitmentatthesiteis

proceedingrelativetothesite’srecruitmenttarget.Whereproblemswithrecruitmentarise,thesite

coordinatorwillliaisewiththetrialsteeringcommitteetodiscusssolutionstowardsimprovingsite

recruitment.

Participantswillbegivenbrochures(AppendixN)thatdetailstudyproceduresandwhatto

expectasthestudyunfolds.Havingthisinformationatthetimeofrecruitmentshouldimprove

participants’understandingoftheirroleinthestudyandhopefullyimproveretentionand

adherencelongterm.Biweeklyfollow-upswillbeinplace,thusgivingparticipantsthechanceto

havetheirconcernsaddressedexpediently.Ateachfollow-up,participantswillberemindedabout

studyproceduresandtheimportanceofadheringtotheirinterventionasprescribed.Thus,every

attemptwillbemadetokeeptheparticipantsinformedaboutthestudyandtheimportanceof

adherence.Maximizingparticipants’informationinthiswayisthoughttoimproveadherencein

clinicaltrials185.Also,only50%ofthevisitswillbeinclinic,whiletheother50%willbeconducted

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overthephone.Thisshouldplacealesserburdenoftransportationandtimeonparticipants,and

alsohopefullycontributetooptimalretention.

Atthe4-weekclinicvisit,whenpatientswillreceivetheirintervention,thesitestudy

investigatorwilldiscussmeansofensuringmedicationadherencewithparticipants(eg.settingan

alarmontheirphone,placingthemedicationbottleinanopportunelocationthatwillprovidea

visualremindertotakethemedication,etc).Ateachfollow-up,medicationcompliancewillbe

addressedwithparticipants.Ifissuesarise,thestudycoordinatororinvestigatorwillre-explore

meansofmaximizingadherencewiththeparticipant.

6. PERSONNELANDROLES

6.1. StudyPersonnel

6.1.1 SiteResearchCoordinators

Eachsitewillhaveasiteresearchcoordinator.Thetimecommitmentoftheresearch

coordinatorwillvaryasafunctionofthesiterecruitmenttarget:theresearchcoordinatorwillhave

anywherefrom0.1-0.4full-timeequivalents(FTE)devotedtothisparticularstudyandthenumber

ofFTEswilldependontherecruitmenttarget.Thesiteresearchcoordinatorwillhaveavarietyof

rolesinthestudy:1)participantrecruitment,2)enrollmentofeligibleandconsentingparticipants,

3)maintenanceofrecruitmentlogs,4)hostingapresentationforclinicpersonnelpriortoinitiating

thestudyinordertoinformstaffabouttheproject,5)settingupandmaintainingpostersinthe

clinicareawithinformationaboutthestudy,6)sendingemailstoclinicstaffevery3monthswith

studyandrecruitmentupdates,7)schedulingpatientfollow-upsandclinicvisits,8)carryingout

telephonefollow-ups,9)dataentry,10)documentingandclassifyingadverseevents,11)notifying

thetrialsponsorofanyseriousandunexpectedadverseeventsthatrequireexpeditedreportingto

HealthCanada,12)communicationwiththesiteinvestigator,13)communicationwiththesteering

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committee,14)communicationwiththedataandsafetymonitoringboard,and15)communication

withtheleadsitebiostatistician.Siteresearchcoordinatorswillmeetwithsiteinvestigatorsona

monthlybasis.Monthlyreportsdetailingsiterecruitmentstatistics,drop-outstatistics,adverse

eventsandissuesarisingwillbepreparedbythesitecoordinatorsandsenttothetrialsteering

committee.Thisinformationwillalsobecompiledandsenttothedataandsafetymonitoringboard

every3monthsandtotheleadsitebiostatisticianonamonthlybasis.Whentheleadsite

biostatisticianhasdeterminedthataninterimdataanalysisisrequired(ie.whenrecruitment

numbershavereachedthethresholdforinterimanalysis),siteresearchcoordinatorswillbe

requiredtocompletedataentryforrecruitedparticipants.Allsiteresearchcoordinatorswillenter

dataintoREDCaP™,whichisasecure,encryptedwebapplicationthatallowsresearcherstocollect

data,storedataandhasamultitudeofotherfunctions.TheuseofREDCaP™byallsiteswillallow

foralldatatobestoredinonelocation,whichwillfacilitateanalysesfortheleadsitebiostatistician.

6.1.2 SiteInvestigators

Siteinvestigatorswillberesponsibleforfilingresearchethicsboardapplicationsattheir

respectivesites.Siteinvestigatorswillalsocarryoutallclinicvisitswithparticipants,whichwill

involveweighingthepatients,carryingoutphysicalexamsasrequired,takinginterimhistories,

discussinginterventioncompliance,addressingpatientconcerns,inquiringaboutadverseevents,

andaddressinganyclinicalconcernsorissuesarising.Thedocumentationofadverseevents,and

notificationofthetrialsponsorofseriousandunexpectedadverseeventsthatrequireexpedited

reportingtoHealthCanada,willnotonlybetheresponsibilityoftheresearchcoordinator,butalso

ofthesiteinvestigator,giventhattheymaybeinformedofadverseeventsduringclinicvisits.Site

investigatorswillbeinregularcommunicationwithsiteresearchcoordinatorsaboutissuesarising

fromthestudy.Monthlymeetingsbetweenthesiteresearchcoordinatorandsiteinvestigatorwill

bearrangedinordertoensurethatissuesareaddressedandthatthecoresiteteamisworking

togethertomaximizerecruitmentandfollow-up.

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6.1.3 SiteResearchPharmacists

Thesiteresearchpharmacistswillberesponsibleforcoordinatingrandomization.Atthetime

ofrandomization,theresearchpharmacistwillcontactacentralrandomizationservice.Once

randomizedbythisservice,thesiteresearchpharmacistwillrecordtheparticipant’sallocationinto

apassword-protected,encryptedelectronicdocument.Thepharmacistwillprepareandpackage

thestudyinterventionsforparticipants.Participantswillvisitthesitepharmacyonamonthlybasis

andthesiteresearchpharmacistwilldispensetheinterventiontotheparticipantsatthistime.

6.1.4 LeadSiteResearchCoordinator

Theleadsiteresearchcoordinatorwillbeassignedallofthesamerolesasthesiteresearch

coordinators,inadditiontoseveralothertasks:1)servingastheprimarycontactpersonforthe

siteresearchcoordinatorsshouldquestionsabouttheprotocolortroubleshootingarise,2)

assistingtheprincipalinvestigatorwiththeleadsiteresearchethicsboardapplication,theHealth

CanadaClinicalTrialApplication,preparationofthetrialprotocolandotherrequired

documentationand3)sittingonthetrialsteeringcommittee.Giventhesignificanttime

commitmentrequiredtofulfillallofthesetasks,theleadsiteresearchcoordinatorwillhave1.0

FTEsdevotedtothisproject.

6.1.5 LeadSitePrincipalInvestigator

Theleadsiteprincipalinvestigatorwillhavethesameresponsibilitiesasthesiteinvestigators,

inadditiontotheirroleasprincipalinvestigatorandtrialsponsor.Inadditiontotheseroles,the

leadsiteprincipalinvestigatorwill:1)writethetrialprotocolandcreateprotocolbindersforall

siteswiththeassistanceoftheleadsiteresearchcoordinator,2)actasthetrialsponsorandobtain

fundingforthetrial,giventhatthiswillbeaninvestigator-initiatedtrial3)prepareandsubmita

ClinicalTrialApplicationtoHealthCanadaalongwiththeleadsiteresearchcoordinator,4)serveas

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theprimarycontactpointforsiteinvestigatorsshouldquestionsariseaboutresearchethicsboard

applications,thetrialprotocolortroubleshootingariseand5)sitonthetrialsteeringcommittee.

6.1.6 LeadSiteResearchPharmacists

Theleadsiteresearchpharmacistswillhavethesamerolesasthesiteresearchpharmacists.

6.1.7 LeadSiteBiostatistician

TheREDCaP™databasewillbedesignedbytheleadsitebiostatistician,inconsultationwiththe

leadsiteprincipalinvestigator.Theleadsitebiostatisticianwillbeinchargeofcarryingoutallof

thedataanalyses,forboththeinterimanalysesandthefinalanalysis.Monthlyreportswillbesent

totheleadsitebiostatisticianfromthesiteresearchcoordinatorsaboutrecruitmentstatistics,

drop-outstatistics,adverseeventsandissuesarisingatindividualsites.Theleadsitebiostatistician

willmergethedatafromthevarioussitesinordertoprepareacompiledreportforthemonthly

steeringcommitteemeetings.Inaddition,interimanalyseswillbetheresponsibilityoftheleadsite

biostatistician.Whenrecruitmenttargetsforinterimanalyseshavebeenreached,theleadsite

biostatisticianwillcontactthesiteresearchcoordinatorstoaskforalldataentrytobecompleted

onenrolledparticipants.Thisdatawillthenbeusedtocarryouttheinterimanalyses,andthe

biostatisticianwillprepareareportoninterimresultstobesubmittedtothedatasafetymonitoring

board.

6.2. DataandSafetyMonitoringBoard

Thedataandsafetymonitoringboard(DSMB)willcomprisethreeindividuals:1)a

biostatistician(notthesameindividualastheleadbiostatistician),2)aneurologist(notthesame

individualastheleadsiteprincipalinvestigator),3)anepidemiologistwithexpertiseinclinicaltrial

designandimplementation.TheDSMBwillmeetevery3months,duringwhichtimethereports

fromthesiteresearchcoordinatorswillbereviewed.ThiswillgivetheDSMBtheopportunityto

reviewadverseeventsandissuesarisingatthevarioussites.Inadditiontothescheduledmeetings,

105

meetingswilloccuronceinterimdataanalyseshavebeencompleted.Theleadsitebiostatistician

willprovidetheinterimdataanalysisreportstotheDSMB,andaninterimmeetingwillbe

scheduled.Atthesetimes,theDSMBwillreviewtheinterimefficacyandsafetydata.

Ifconcerningtrendsinadverseeventsarise,orifseriousadverseeventsoccur,theDSMBwill

contacttheresearchpharmacistsattheinvolvedsite(s)tobreakblindingoninvolvedparticipants

whennecessary.TheDSMBwillhavetheauthoritytorecommendearlytrialtermination,should

majorconcernsarisewithregardstoadverseeventsoratinterimanalyses.Intheeventwherethe

DSMBdoesrecommendearlytrialtermination,areportwillbepreparedbytheDSMB

biostatistician,whowillcommunicatetherecommendationverballyandinwritingtothetrial

steeringcommittee.

6.3. TrialSteeringCommittee

Thetrialsteeringcommitteewillcomprisetheleadsiteprincipalinvestigator,theleadsite

researchcoordinatorandtheleadsitebiostatistician.Thesteeringcommitteewillmeetmonthlyin

ordertoreviewtrialprogress.Themonthlyreportfromthebiostatistician,consistingofa

compilationofthesiteresearchcoordinatorreports,willbereviewed.Recruitmentnumbers,drop-

outs,adverseeventsandissuesarisingatthesiteswillbediscussedandreviewed.Where

necessary,actionpointswillbedevelopedinordertoimprovetrialimplementation.Asabove,

recommendationsfromtheDSBMwillbecommunicatedtothesteeringcommitteethroughthe

DSBM’sbiostatistician.

7. ETHICALCONSIDERATIONS

7.1. ClinicalEquipoiseRegardingLevetiracetamforPediatricMigraineProphylaxis

Asisdescribedabove,thereisclearuncertaintyintheliteratureregardingtheefficacyof

levetiracetamfortheprophylaxisofpediatricmigraine.Onlytwonon-randomizedstudies70,71have

106

assessedthesafetyandefficacyoflevetiracetamforthisindication.Levetiracetamhasneverbeen

comparedtoplacebonortotopiramateintheliterature.Inordertoestablishassaysensitivityfor

levetiracetamascomparedtoplacebo,whichhasnotyetbeendeterminedintheliterature,itis

necessarytocompareittoplaceboinadouble-blind,randomizedfashion.Inaddition,the

comparisonoflevetiracetamtotopiramatewillhelptoestablishitsnon-inferioritywithregardsto

efficacyandsafetyrelativetotheinterventionwiththehighestlevelofevidenceintheliterature.

Thetwointerventionshaveneverbeencomparedinthepast,andthereisthusuncertaintyasto

whetherlevetiracetamisnon-inferiortotopiramateforthepreventionofpediatricmigraine.

Therefore,thereisdefiniteclinicalequipoiseintheliteratureregardingthetwoprimary

hypothesesofthistrial,thatis:1)levetiracetamwillyieldagreaterdecreaseinthefrequencyof

migraineattackscomparingbaselinetothefinal4weeksoftreatmentascomparedtoplacebo,2)

levetiracetamwillbenon-inferiortotopiramatewithregardstothechangeinmigraineattack

frequencycomparingbaselinetothefinal4weeksoftreatmentascomparedtoplacebo.

7.2. InformedConsent

Informedconsentwillbeobtainedinwritten(seeAppendixL)andverbalformfromboth

participantsaged16yearsandoverandtheparent(s)orguardian(s)oftheparticipant.For

participantsyoungerthan16yearsofage,verbalandwritten(seeAppendixM)assentwillbe

obtained.Ifaparticipantovertheageof16yearsisdeemedcognitivelyunabletoprovideinformed

consent,thenassentwillbesoughtinlieuofconsent,andtheparent(s)orguardian(s)willprovide

informedconsent.TheconsentandassentformshavebeenwritteninaccordancewiththeTri-

CouncilPolicyStatement:EthicalConductforResearchInvolvingHumans186.Theresearch

coordinatorwillexplainimportantelementsoftheconsentprocesstotheparticipantandtheir

parent(s)orguardian(s)andwillbepresenttoanswerquestionsabouttheconsentform.

Participantsandtheirparent(s)orguardian(s)willalsobegiventheopportunitytotakethe

consentformhometofurtherdiscussthestudyandtheirpossibleinvolvement.Contact

107

informationfortheprincipalinvestigatorisavailableontheconsentform(seeAppendixL)andthe

principalinvestigatorwillbeavailabletoparticipantsandtheirparent(s)orguardian(s)for

questionsrelatedtoconsentshouldtheyarise.

7.3. SpecialConsiderationsinthePediatricPopulation

Inordertoimprovemigrainecareinchildrenandadolescents,itisnecessarytocarryoutwell-

designedclinicaltrialsofinterventionsforpediatricmigraine.Thisstudywilladdsignificantlyto

thebodyofevidenceinthepediatricmigraineprophylaxisliterature.Becausethisisastudy

involvingchildrenandadolescents,specialconsiderationswillbetakentoaddressconcernsrelated

tocarryingoutresearchonthisvulnerablepopulation.Therisk/benefitratiointhisstudyhasbeen

carefullyconsidered.Thereisasignificantanticipatedbenefittoparticipantsthroughparticipation

inthistrial:participantsfromallthreeinterventiongroupsareexpectedtobenefitfromreduced

migrainefrequencyovertime.Althoughtherearerisksofadverseeventsforbothtopiramateand

levetiracetam,theparticipantsandtheirparent(s)orguardian(s)willbenotifiedaboutthese

potentialrisksduringtheconsentprocess.Also,theriskofseriousadverseeventsforeachofthese

interventionsisverylow.

Becauseoftheyoungageoftheparticipants,bothaconsentandanassentprocesswillbe

available.Participantsundertheageof16yearsorthosewhoarenotcognitivelyabletoprovide

informedconsentwillbeguidedthroughanassentprocess.Theassentformwillbetailoredfor

youngerchildren,withamoreconcisepresentationandtheuseofsimplifiedlanguage.

7.4. PrivacyandConfidentiality

Theprivacyandconfidentialityofparticipantswillbeprotectedinavarietyofways.Contact

informationforparticipantswillbestoredinaseparatefiletothedatacollectionfiles.Storageof

contactinformationisrequiredinorderfortheresearchcoordinatortohavetheabilitytocontact

participantsfortelephonefollow-ups.Thisinformationwillbestoredinanencrypted,password-

protectedelectronicfilethatwillbedivorcedfromanyoftheotherstudydata.Inaddition,the

108

researchpharmacistswillmaintainanencrypted,password-protectedelectronicfileofparticipant

groupassignments,whichwillincludeparticipantnamesandcontactinformation.Thisisnecessary

inordertoensurethatunblindingcanoccurshouldaseriousadverseeventbereported.The

remainingstudydatawillbeenteredbythesiteresearchcoordinatorsintoREDCaP™,which,as

describedabove,isaweb-based,secureandencrypteddatastoragesoftwarethatiswidelyusedfor

researchpurposes.TheREDCaP™databasewillcontainonlyde-identifieddata:studyidentification

numbers,generatedatrandom,willbeusedfordatastorage.Noidentifierswillbeincludedinthe

database.

109

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177. WillsB,ReynoldsP,ChuE,etal.ClinicalOutcomesinNewerAnticonvulsantOverdose:APoisonCenterObservationalStudy.JMedToxicol2014;10:254–60.

178. BourgeoisFT,OlsonKL,PoduriA,MandlKD.ComparisonofDrugUtilizationPatternsinObservationalData:AntiepilepticDrugsinPediatricPatients.PaediatrDrugs2015;17(5):401-10.

179. LexicompOnline®,Pediatric&NeonatalLexi-Drugs®,Hudson,Ohio:Lexi-Comp,Inc.;January29,2015.

180. HersheyA,PowersS,VockellA,LeCatesS,KabboucheM,MaynardM.Developmentofaquestionnairetoassessdisabilityofmigrainesinchildren.Neurology2001;57:2034–9.

181. BrandesJ,SaperJ,DiamondM,etal.Topiramateformigraineprevention.Pharmacotherapy2006;26(3):375–87.

182. SilbersteinSD,NetoW,SchmittJ,JacobsD.Topiramateinmigraineprevention.Headache2005;45(Suppl1):S57–65.

183. DienerH-C,Tfelt-HansenP,DahlofC,etal.Topiramateinmigraineprophylaxis:Resultsfromaplacebo-controlledtrialwithpropranololasanactivecontrol.JNeurol.2004;251(8):943–50.

184. PASS14PowerAnalysisandSampleSizeSoftware(2015).2015;Availablefrom:ncss.com/software/pass

185. FriedmanL,FurbergC,DeMetsD.FundamentalsofClinicalTrials.4thEdition.NewYork,USA:Springer;2010.

186. CanadianInstitutesofHealthResearch,NaturalSciencesandEngineeringResearchCouncilofCanadaandSocialSciencesandHumanitiesResearchofCanada,Tri-CouncilPolicyStatement:EthicalConductforResearchInvolvingHumans,December2010.

120

ThesisAppendix

8. AppendixA.Electronicsearchstrategiesforidentificationofstudies

MEDLINESearchStrategy:1.expMigraineDisorders/2.statusmigra*.mp.3.migraine*.tw.4.or/1-35.pc.fs.6.prophyl*.mp.orprevent*.ti,ab.7.Amitriptyline/8.expBotulinumToxins/9.Clonidine/10.expCyproheptadine/11.Domperidone/12.flunarizine/ortrazodone/13.Piracetam/14.Metoclopramide/15.Nimodipine/16.Papaverine/17.Pizotyline/18.Propranolol/19.Timolol/20.Topiramate.mp.21.ValproicAcid/22.5-Hydroxytryptophan/23.expFattyAcids,Omega-3/24.Q10.ti,ab.25.Coenzyme.mp.26.Riboflavin/27.Magnesium/28.Petasites/orbutterbur*.tw.29.expGinkgolides/30.or/5-2931.4and3032.((randomizedcontrolledtrialorcontrolledclinicaltrial).pt.orrandomized.ab.or

placebo.ab.orclinicaltrialsastopic.sh.orrandomly.ab.ortrial.ti.)not(expanimals/nothumans.sh.)

33.(child*oradolescent*orinfan*).mp.34.31and32and3335.removeduplicatesfrom34EmbaseSearchStrategy:

121

1.expmigraine/2.statusmigrainosus.mp.3.migrain*.tw,kw.4.AliceinWonderlandSyndrome.tw.5.or/1-46.prophyl*.mp.orprevent*.ti,ab.7.prophylaxis/8.amitriptyline/9.botulinumtoxin/10.clonidine/11.cyproheptadine/12.domperidone/13.flunarizine/14.trazodone/15.piracetam/16.metoclopramide/17.nimodipine/18.papaverine/19.pizotifen/20.propranolol/21.timolol/22.topiramate/23.valproicacid/24.5hydroxytryptophan/25.omega3fattyacid/26.ubidecarenone/27.riboflavin/28.magnesium/29.butterbur/30.ginkgolide/31.or/6-3032.5and3133.(random$orfactorial$orcrossover$orcross-over$orplacebo$or(doubl$adjblind$)or

(singl$adjblind$)orassign$orallocat$orvolunteer$).mp.orcrossover-procedure/ordouble-blindprocedure/orrandomizedcontrolledtrial/orsingle-blindprocedure/

34.limit32to(childorpreschoolchild<1to6years>orschoolchild<7to12years>oradolescent<13to17years>)

35.(pediatricorpaediatricorchild$ornewborn$oradolescen$orinfan$orneonat$oryouth$orteen$orbaby$orbabies$orpreschool$orpre-school$orelementaryschool$orelementarystudent$orkindergartenornurseryschool$orgradeschool$orpublicschool$orhighschool$orhighschool$orschoolchild$).mp.

36.32and33and(34or35)37.limit36toembase38.removeduplicatesfrom37CENTRALSearchStrategy:1.migrain*.tw,kw.2.prophyl*.mp.orprevent*.ti,ab.

122

3.(AmitriptylineorBotoxorClonidineorCyproheptadineorDomperidoneorFlunarizineorTrazadoneorLevetiracetamorMetoclopramideorNimodipineorPapaverineorPizotifenorPropranololorTimololorTopiramateorValproicAcidorL-5-hydroxytryptophanorOmega-3orCoenzymeQ10starthereorRiboflavinorMagnesiumorButterburorGinkgolide).tw.

4.1and(2or3)5.(pediatricorpaediatricorchild$ornewborn$oradolescen$orinfan$orneonat$oryouth$

orteen$orbaby$orbabies$orpreschool$orpre-school$orelementaryschool$orelementarystudent$orkindergartenornurseryschool$orgradeschool$orpublicschool$orhighschool$orhighschool$orschoolchild$).mp.

6.4and57.removeduplicatesfrom6

123

9. AppendixB.SystematicReviewIncludedStudiesEligibilityForms

ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist

StudyID#:Oelkers-Ax2008Screenedby:SLO

Table1:InclusionCriteria

Characteristic Yes(Include)

No(Exclude)

Unsure(Discuss)

StudyDesignIsthestudyaclinicaltrial? x Wasthestudyrandomized? x Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18

andunder?x

Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?

x

WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?

x

InterventionsWasthetreatmentapharmacologicornutraceutical

intervention(orinterventions)takendailytopreventmigraines?

x

Comparison Wasthereaplaceboascomparison? x

Table2:ExclusionCriteria

Characteristic Yes

(Exclude)No

(Include)Unsure(Discuss)

StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?

x

Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?

*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).

Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure

124


StudyID#:MacLennan2008Screenedby:SLO



No(Exclude)

Unsure(Discuss)


andunder?x


x


x



x



Characteristic Yes(Exclude)

No(Include)

Unsure(Discuss)


x


*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure

125


StudyID#:Bruijn2010Screenedby:SLO



No(Exclude)

Unsure(Discuss)


andunder?x


x


x



x




No(Include)

Unsure(Discuss)


x


x



126


StudyID#:Winner2005Screenedby:SLO



No(Exclude)

Unsure(Discuss)


andunder?x


x


x



x




No(Include)

Unsure(Discuss)


x




127


StudyID#:Lakshmi2007Screenedby:SLO



No(Exclude)

Unsure(Discuss)

StudyDesignIsthestudyaclinicaltrial? X Wasthestudyrandomized? X Wasthestudyeithersingleordoubleblind? X ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18

andunder?X


X


x



x




No(Include)

Unsure(Discuss)


x




128


StudyID#:Lewis2009Screenedby:SLO



No(Exclude)

Unsure(Discuss)


andunder?X


X


x



x




No(Include)

Unsure(Discuss)


x




129


StudyID#:Pandina2010Screenedby:SLO



No(Exclude)

Unsure(Discuss)


andunder?X


X


x

InterventionsWasthetreatmentapharmacologicintervention(or

interventions)takendailytopreventmigraines?x




No(Include)

Unsure(Discuss)


x


*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure

130


StudyID#:Winner2006PooledAnalysisScreenedby:SLO



No(Exclude)

Unsure(Discuss)


andunder?x


x


x



x




No(Include)

Unsure(Discuss)


x




131


StudyID#:Apostol2008Screenedby:SLO



No(Exclude)

Unsure(Discuss)

StudyDesignIsthestudyaclinicaltrial? X Wasthestudyrandomized? X Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18

andunder?X


X


X



x




No(Include)

Unsure(Discuss)


x




132


StudyID#:Sorge1988Screenedby:SLO



No(Exclude)

Unsure(Discuss)


andunder?x


x


x



x




No(Include)

Unsure(Discuss)


x




133


StudyID#:Sorge1985Screenedby:SLO



No(Exclude)

Unsure(Discuss)


andunder?x


x


x



x




No(Include)

Unsure(Discuss)


x


x



134


StudyID#:Noronha1985Screenedby:SLO



No(Exclude)

Unsure(Discuss)


andunder?x


x


x



x




No(Include)

Unsure(Discuss)


x


x



135


StudyID#:Sillanpää1977Screenedby:SLO



No(Exclude)

Unsure(Discuss)


andunder?x


x


x



x




No(Include)

Unsure(Discuss)


x




136


StudyID#:Battistella1993Screenedby:SLO



No(Exclude)

Unsure(Discuss)


andunder?x


x


x



x




No(Include)

Unsure(Discuss)


x


x



137


StudyID#:Battistella1990Screenedby:SLO



No(Exclude)

Unsure(Discuss)


andunder?x


x


x



x




No(Include)

Unsure(Discuss)


x


x



138


StudyID#:Ford2014Screenedby:SLO



No(Exclude)

Unsure(Discuss)


andunder?x


x


x



x




No(Include)

Unsure(Discuss)


x




139


StudyID#:Ashrafi2014Screenedby:SLO



No(Exclude)

Unsure(Discuss)


andunder?x


x


x



x



Characteristic Yes(Exclud

e)

No(Inclu

de)

Unsure(Discuss)


x




140


StudyID#:MachínAltueña1987Screenedby:SLO



No(Exclude)

Unsure(Discuss)


andunder?x


x


x



x




No(Include)

Unsure(Discuss)


x




141


StudyID#:Sillanpää1978Screenedby:SLO



No(Exclude)

Unsure(Discuss)


andunder?x


x


x



x




No(Include)

Unsure(Discuss)


x




142

10. AppendixC.SystematicReviewIncludedStudies‘CharacteristicsofStudies’

Tables

ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies

StudyID#:Oelkers-Ax2008StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,partlydouble-blind,3-armparallel-grouptrial

• 8weekbaselineperiodfollowedby12weektreatmentphasefollowedby8weekpost-treatment/follow-upphase

• PatientswererecruitedusingadvertisementsfromthecatchmentareaoftheHeidelbergUniversityhospital

Participants • Childrenaged8-12withmigrainemeetingICHDcriteria• Allhadatleast1yrhistoryofmigraine• Hadtoreport2ormoremigraines/monthin3months

precedingenrollmentandduringthebaselineperiod• Higherbaselinemigrainefrequencyinthebutterburgroup

(9.8+7.6vs.5.5+4.4vs.5.0+2.5,p=0.409)Interventions • Petadolex®:20patientsrandomizedtoreceive50mg/dayif

8-9yoor50mgbidif10-12yowithadoseincreaseto75mg/dayfor8-9yoorif10-12yo75mgbidat8weeksifsuboptimalresponseinthefirst8weeksoftreatment

• Placebo:19patientsrandomizedtoplacebo,witha“doseincrease”at8weeksifsuboptimalresponse

• Musictherapy:24patientsrandomizedto12weeklysessionsofmusictherapyinvolvingmusic-aidedrelaxationtraining,bodyawarenesstechniquesandconflicttraining

Outcomes • Primaryoutcome:Allthreegroupshadastatisticallysignificantreductioninheadachefrequencycomparingbaselinetopost-treatmentandfollow-upinbothas-treatedandintention-to-treatanalyses(ITT)(seeTable3).Inpost-treatment,musictherapywassuperiortoplacebo(p=0.042inITT)buttherewasnodifferencebetweenplaceboandbutterbur.At6monthspost-treatment,bothmusictherapy(p=0.018)andbutterbur(p=0.042)weresuperiortoplacebo.

• Secondaryoutcome:Responderrates,thatisthoseachievinga50%orgreaterreductioninmigrainefrequency,werehighestinthemusicgroupatpost-treatment(p=0.01),butdidnotdifferbetweenthegroupsatthe6monthfollow-up.

• Adverseevents:Nodifferenceinadverseeventsbetweengroupsnorstudyperiods;butterburgroupmostlyreported

143

gastrointestinalsymptoms,dermalorallergicsymptomsNotes • Higherdrop-outrateininterventiongroups:5%inthe

placebogroupvs.25%inbutterburgroupvs.29%inthemusictherapygroup

144


StudyID#:MacLennan2008StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,double-blind,2-arm,parallelgroupclinicaltrial

• Patientswerefollowedfora4-weekbaselineperiodandtreatedfor12weeks

• Recruitmentthroughlocalschools,theEDortheoutpatientdepartmentoftheChildren’sHospitalofWestmead,Australia

Participants • Childrenaged5-15yearswithmigrainemeetingICHDcriteria• Participantshadtohavemigraineforatleast3monthswith

monthlymigrainefrequencybetween2and8attacks/month• Participantsalsohadtohaveatleastonemigrainein4week

baselineperiod• Nosignificantdifferencesfoundbetweenthegroupsat

baselineInterventions • Riboflavin:27participantswererandomizedtoriboflavin

200mgdaily• Placebo:21participantswererandomizedtoplacebo

Outcomes • Thetrialwasstoppedaftera12monthinterimdataanalysisduetolackofevidenceforadifferencebetweenthegroups

• Primaryoutcome:Therewerenogroupdifferenceintheproportionofparticipantsachievinga50%orgreaterreductioninmigrainefrequency(66.6%ofplacebovs.44.4%ofriboflavin,p=0.125)

• Secondaryoutcomes:Nochangeinmigraineintensityineithergroup,meannumberofdayswithassociatedsymptomsdecreasedforplacebobutnotforriboflavin,bothgroupshadadecreaseinnumberoftreatedmigraineattacks

• Adverseevents:Onechildtakingriboflavinhadanincreaseinthenumberoftensionheadaches,and4childrenintheriboflavingroupnotedachangeintheirurinecolor

Notes • Thereisnonoteaboutwhattypeofstoppingruletheyusedintheinterimdataanalysisanditisquestionableastowhetherearlyterminationwaswarranted.

145


StudyID#:Bruijn2010StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,double-blind,cross-overstudy

• 4weekbaselineperiodfollowedby16weektreatmentperiodfollowedby4weekwashoutperiodfollowedbyanother16weektreatmentperiod

• Recruitmentfrom2hospitalsintheNetherlandsParticipants • Childrenaged6-13yearswithmigrainemeetingICHDcriteria

• Participantshadtohaveatleast2migrainespermonthatbaseline

• Therewerenosignificantbaselinedifferencesbetweenthegroups

Interventions • Riboflavin:20patientsrandomizedtoreceiveriboflavin50mgdailyforfirsttreatmentperiod

• Placebo:22patientsrandomizedtoreceivematchedplacebo(containingcarotene)capsulesforfirsttreatmentperiod

Outcomes • Primaryoutcome:Thegroupsdidnotdifferwithregardstochangeinmigrainefrequency(p=0.44)

• Secondaryoutcomes:Noothermeasuredoutcomessignificantlydifferedbetweenthegroups

• Noadverseeventswerereportedineithergroup• Analysisforperiodofcarry-overeffectwasinconclusive

Notes • Thestudywaspoweredtodetectadifferenceof0.6SDbetweenthegroupsintermsoftheprimaryoutcome

146


StudyID#:Winner2005StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,double-blind,placebo-controlled,2-armparallel

grouptrialwith2:1assignmenttotheinterventiongroup• Comprisedof4weekbaselineperiodfollowedby8week

medicationtitrationperiodfollowedby12weekmaintenanceperiod

• Recruitmentfrom17medicalcenterintheUSParticipants • Childrenaged6-15yearswithmigrainemeetingICHDcriteria

• Required3-10migrainedays/monthin4weekbaselineperiodand3monthsprecedingstudyentry

• Chronicmigraineexcluded• Therewerenosignificantdifferencesbetweenthegroupsat

baselineInterventions • Topiramate:112patientsrandomizedtotopiramate,ata

startingdoseof15mgdaily,whichwastitratedupasneededto200mgdailyor2-3mg/kg/day,whicheverwasachievedfirst

• Placebo:50patientsrandomizedtoplacebowithidentical“titration”scheduletotopiramate

Outcomes • Primaryoutcome:Intheintention-to-treatanalysis,thetopiramategroupshowedatrendtowardsagreatermeanreductioninmigrainefrequencyduringthetreatmentperiodascomparedtotheplacebogroup(2.6+2.6daysvs.2.0+3.1days,p=0.061);thedifferencebetweenthegroupswasstatisticallysignificantintheper-protocolanalysis(2.8+2.4vs.2.2+2.1,p=0.033)

• Secondaryoutcomes:thetopiramategrouphadagreaterreductionthanplaceboinmigrainedaysduringthelasttreatmentmonthascomparedtothebaselineperiod;nodifferenceinproportionofparticipantshaving50%orgreaterreductioninmigrainefrequency,buthigherproportionoftopiramategroupwith75%orgreaterreductioninmigrainefrequency;

• Adverseevents:nosignificantdifferenceinincidenceofadverseeventsinplacebovs.topiramategroup;4seriousadverseeventsintopiramategroup

Notes • 16%ofpatientsintheplacebogroupvs.20.5%ofpatientsinthetopiramategroupdroppedoutofthestudy

147


StudyID#:Lakshmi2007StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,double-blind,placebo-controlled,2-arm

parallel-groupstudy• Comprisedofa4-weektitrationperiodfollowedbya12-week

maintenanceperiod• CarriedoutinoutpatientdepartmentofthePostgraduate

InstituteofMedicalEducationandResearchinIndiaParticipants • Childrenaged8-14yearswithmigrainemeetingICHDcriteria

• Participantshadtohave2ormoremigrainespermonthinthe3monthsprecedingenrollment

Interventions • Topiramate:22randomizedtotopiramateatastartingdoseof25mgdailywithweekly25mgincreasestoamaximumof50mgbid

• Placebo:22randomizedtoplaceboOutcomes • Primaryoutcome:Thetopiramategrouphadagreater

decreaseinmigrainefrequencycomparingbaselinetotheendofthestudy(from16.14+9.35to4.27+1.95vs.from13.38+7.48to7.48+5.94,p=0.025)

• Secondaryoutcomes:Therewasahigherproportionofpatientsinthetopiramategroupshowinga50%orgreaterreductioninmigrainefrequencyfollowingtreatmentascomparedtoplacebo;nodifferenceinthemeanchangeinmigrainedurationormeanmigraineseverity;nodifferenceinrescuemedicationusebetweenthegroups;greaterdecreaseinPedMIDASdisabilityscoreinthetopiramategroup;greaterimprovementinschoolabsenteeisminthetopiramategroup

• Adverseevents:Thereweremoreadverseeventsinthetopiramategroup,withweightloss,lossofappetite,paresthesiasandlackofconcentrationinschoolbeingthemostcommon

Notes • Onlyonepatientlosttofollow-upineachgroup

148


StudyID#:Lewis2009StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,placebo-controlled,double-blind,3-arm,

parallel-groupstudy• Comprised9weekbaseline(1weekscreening,4week

washoutofprophylacticmedicationsand4weekbaselineperiod)followedby16weektreatmentperiodfollowedby2weektaperandthen4weekexitphase

• Recruitmentfrom31USandnon-USsitesParticipants • Adolescentsaged12-17yearswithmigrainemeetingICHD

criteria• Participantshadtohavemigrainesforaminimumof6

months• Participantshadtohave3-12migrainedays/monthinthe3

monthsprecedingenrollmentInterventions • Lowdosetopiramate:35patientsrandomizedtotopiramate

initiatedat25mg/dayuptoamaximumof25mgbidasneededover4weeksandthenmaintainedfor12weeks

• Highdosetopiramate:35patientsrandomizedtotopiramateinitiatedat25mg/dayuptoamaximumof50mgbidasneededover4weeksandthenmaintainedfor12weeks

• Placebo:33patientsrandomizedtoplaceboforthetreatmentperiod

• NB.Allpatientsreceived4tablets/daythroughout,withthetabletsconsistingofeitherplacebo,25mgtopiramateoracombinationthereof

Outcomes • Primaryoutcome:Thehighdosetopiramategrouphadasignificantlargerdecreaseinmigrainefrequencywhencomparingthelast12weeksoftreatmenttobaselineascomparedtoplacebo(72.2%vs.444%,p=0.016),buttherewasnosignificantdifferencecomparinglowdosetopiramateandplacebo(p=0.798)

• Secondaryoutcomes:Morethan50%ofparticipantstreatedwithhighdosetopiramateweremigraine-freeduringthelast4weeksoftreatment;highdosetopiramatebutnotlowdosetopiramatewassuperiortoplaceboinreducingmigrainefrequencyduringthelast4weeksoftreatmentascomparedtobaseline;mostsecondaryanalysesalsofoundthathighdosetopiramatewassuperiortoplacebobutnotlowdosetopiramate

• Adverseevents:Thereweremoreadverseeventsinthetopiramategroupsascomparedtotheplacebogroup(74%

149

vs.48%),withthemostcommonadverseeventsinthetopiramategroupsbeingupperrespiratorytractinfections,paresthesiasanddecreasedappetite;therewere2seriousadverseeventsinthehighdosetopiramategroupthatweredeemedunlikelytoberelatedtotreatmentbytheinvestigators

Notes • None

150


StudyID#:Pandina2010(analysisofsubsetofthedatafromLewis2009)StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,placebo-controlled,double-blind,3-arm,

parallel-groupstudy• Comprised9weekbaseline(1weekscreening,4week

washoutofprophylacticmedicationsand4weekbaselineperiod)followedby16weektreatmentperiodfollowedby2weektaperandthen4weekexitphase

• Recruitmentfrom31USandnon-USsitesParticipants • Adolescentsaged12-17yearswithmigrainemeetingICHD

criteria• Participantshadtohavemigrainesforaminimumof6

months• Participantshadtohave3-12migrainedays/monthinthe3

monthsprecedingenrollmentInterventions • Lowdosetopiramate:35patientsrandomizedtotopiramate

initiatedat25mg/dayuptoamaximumof25mgbidasneededover4weeksandthenmaintainedfor12weeks

• Highdosetopiramate:35patientsrandomizedtotopiramateinitiatedat25mg/dayuptoamaximumof50mgbidasneededover4weeksandthenmaintainedfor12weeks

• Placebo:33patientsrandomizedtoplaceboforthetreatmentperiod

• NB.Allpatientsreceived4tablets/daythroughout,withthetabletsconsistingofeitherplacebo,25mgtopiramateoracombinationthereof

Outcomes • Primaryoutcome:ThiswasreportedintheLewisetal2009publication.Inthispaper,thefocuswasoncognitiveandmoodsideeffects.

• Outcomesforthispublication:Ascomparedtoplacebo,thehighdosetopiramategrouphadsmallincreasesintheirpsychomotorreactiontimes;thehighdosetopiramategroupalsohadadecreaseinthenumberofuniquewordstheycouldgenerate;nootherchangeswereseenincognitivescoresontheCANTABassessment(ie.memory,learning,visualprocessing);noneofthegroupsdifferedsignificantlyinthechangesseenintheirProfileofMoodStatesscores

Notes • None

151


StudyID#:Winner2006PooledAnalysisStudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Analysisfrom3adultsstudieswheredataonadolescent

participantsaged12-18yearswaspooled• Allthreeadulttrialsweredouble-blind,randomized,parallel-

group,placebo-controlledstudies• Recruitmentfrom150differentsitesinNorthAmerica,

EuropeandAsia• Compriseda2-weekwashoutperiod,followedbya4-week

baselineperiod,followedbyan8-weektitrationphaseandthenan18-weekmaintenancephase

Participants • Analysisisrestrictedtoadolescentparticipantsaged12-18yearswithmigrainemeetingICHDcriteria

• Participantshadtohave3-12migraines/monthinthe3monthspriortoenrollmentandinthebaselineperiod

• TherewerenomajorbaselinedifferencesbetweenthegroupsInterventions • Lowdosetopiramate:Twoofthestudiesrandomizedatotal

of11participantstotopiramate50mgdaily• Mediumdosetopiramate:Allthreestudieshadagroup

randomizedtotopiramate100mgdaily,comprising13participants

• Highdosetopiramate:Allthreestudieshadagrouprandomizedtotopiramate200mgdaily,comprising13participants

• Placebo:Allthreestudieshadaplaceboarm,comprising12participants

• Propranolol:Onestudyusedpropranololasanactivecomparatorinsteadofthelowdosetopiramate

• NB.Allgroupsontopiramatestartedatadoseof25mgdaily,with25mg/weekincreasesuntilthemaximumdosefortheirassignedgroupwasreached

Outcomes • Primaryoutcome:Thetopiramate100mgdailyand200mgdailygroupshadsignificantlygreaterreductionsinmigrainefrequencycomparingthetreatmentperiodtobaselineascomparedwithplacebo(63%and65%comparedto13%reductions,p<0.04)

• Secondaryoutcomes:Nosignificantdifferenceswereseenforthesecondaryoutcomes

• Adverseevents:Therewerenomeaningfuldifferencesinthefrequencyofadverseeventsbetweenthegroups;therewerenoseriousadverseeventsinanyofthetopiramategroups;weightlossappearedtobemorecommonfortopiramate;the

152

mostcommonadverseeventswereupperrespiratorytractinfections,paresthesiasandweightloss;7patientsontopiramatevs.2patientsonplacebohadcognitivesideeffects

Notes • None

153


StudyID#:Apostol2008StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,double-blind,placebo-controlled,4-armparallel

grouptrial• Comprisedof2weekwashoutperiod,followedbya4week

baselineperiodfollowedby2weektitrationperiodfollowedby10weeksofmaintenancetreatment

• Recruitmentfrom38differentUScentersParticipants • Adolescentsaged12-17withmigrainemeetingICHDcriteria

• Participantshadtohave3-12migraines/monthin3monthperiodpriortostudyentry

• Nostatisticallyorclinicallysignificantbaselinedifferencesbetweenthegroups

Interventions • Lowdosedivalproex:83participantsrandomizedtodivalproex250mgdaily,whichwasmaintainedthroughouttitrationandmaintenance

• Mediumdosedivalproex:74participantsrandomizedtodivalproex500mgdaily,whichstartedatadoseof250mgdailyduringthe2-weektitrationanddoublesubsequentlyforthe10-weekmaintenance

• Highdosedivalproex:75participantsrandomizedtodivalproex1000mgdaily,whichstartedatadoseof500mgdailyduringthe2-weektitrationanddoubledsubsequentlyforthe10-weekmaintenance

• Placebo:73participantsrandomizedtoplaceboOutcomes • Primaryoutcome:Therewasnodifferencebetweenanyof

thedivalproexdosesandplacebointermsofthechangeinmigrainefrequencycomparingbaselinetothe12weektreatmentperiod

• Secondaryoutcomes:Noneofthesecondaryoutcomesshowedanydifferencewhencomparinganyofthedivalproexdosestoplacebo

• Adverseevents:Therewerenogroupsdifferencesinthefrequencyofadverseevents;themostcommonsideeffectsforthedivalproexgroupswereupperrespiratorytractinfections,somnolenceandfatigue

Notes • Usedaneffectsizederivedfromanadultstudy,whichisperhapsnotappropriategiventhatchildrenareknowntohaveamoredramaticplaceboresponsethanadults.

154


StudyID#:Sorge1988StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Double-blind,placebo-controlledcrossovertrial

• RecruitmentfromHeadacheCenterat11ndMedicalSchoolofNaples

• Comprised4-weekbaseline,followedby12-weektreatmentperiod,followedby4-weekwashoutperiod,followedbycross-overtoanother12-weektreatmentperiod

Participants • Childrenaged5-11yearsofagewithmigrainemeetingVahlquist’scriteria

• Participantshadtohaveminimumof6monthsofmigraines• Therewerenosignificantdifferencesbetweenthegroupsat

baselineInterventions • Flunarizine:35patientswererandomizedtofirstreceive

flunarizine5mgdailyfortheinitialtreatmentperiod,andthentheyreceivedmatchedplacebo

• Placebo:35patientswererandomizedtofirstreceivedmatchedplacebofortheinitialtreatmentperiod,andthentheyreceivedflunarizine5mgdaily

Outcomes • Primaryoutcome:Bothgroupshadastatisticallysignificantreductioninmigrainefrequencyduringtheirtreatmentwithflunarizine(p<0.001inbothgroups)ascomparedtotheplacebophases

• Secondaryoutcomes:Thedurationofmigraineattackswasreducedby3monthsofflunarizineingroupAandby2monthsofflunarizineingroupBandthiswassignificantlydifferentfromtheplacebophases(p<0.001inbothgroups)

• Adverseevents:Thereisnodetailaboutwhichadverseeventsoccurredinwhichgroups;themostcommonsideeffectsweredrowsinessandweightgain,whichoccurredin9.5%and22.2%,respectively

Notes • 7patientswithdrewfromthestudy;2duringtheflunarizinephaseand5duringtheplacebophase

155


StudyID#:Sorge1985StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Double-blind,placebocontrolled,2-arm,parallel-groupstudy

• RecruitmentfromtheHeadacheCenteroftheNaplesIIedMedicalSchool

• Baselineperiodfollowedbyrandomizationtoaninterventionfor3months

Participants • Childrenundertheageof18yearswithmigrainemeetingtheVahlquistcriteria

• Baselinecharacteristicsweresimilarbetweenthegroups,exceptthattheflunarizinegrouphadshortermigrainesatbaseline(2.76+1.13hours/migrainevs.2.95+2.47hours/migraine)

Interventions • Flunarizine:24participantswererandomizedto3monthsofflunarizine5mgqHS

• Placebo:24participantswererandomizedto3monthsofplacebo

Outcomes • Primaryoutcomenotexplicitlydefined• Attrialcompletion,theflunarizinegrouphadsignificantly

lessfrequentheadachesthantheplacebogroup(p<0.001)duringthetreatmentperiod

• Theflunarizinegrouphadsignificantlyshortermigrainesduringthetreatmentperiodascomparedtoplacebo(p<0.05),buttheyalsohadshortermigrainesatbaseline

• Adverseevents:Thereisnodetaileddescriptionofadverseevents,onlyamentionthat3patientswithdrewfromtheflunarizinegroupduetosideeffects,namelygastrointestinalsymptoms,drowsinessandfatigue)andamentionthatthemostcommonsideeffectswereweightgainandsleepiness(butnodetailsaboutfrequencypergroup)

Notes • 3participantswithdrewfromflunarizinegroupbecauseofsideeffectsand3participantswithdrewfromplacebogroupduetolackofefficacy

156


StudyID#:Noronha1985StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Thiswasadouble-blind,randomizedcross-overstudy

• Thesiteofrecruitmentisnotlisted,butpresumablyrecruitmentwasfromasiteinEnglandgiventheauthor’slocation

• Comprised4-weekbaselineperiod,followedby8weeksoftreatment,followedby4-weekwashoutperiod,followedby8weeksoftreatmentwithalternateagent

Participants • Childrenaged5to16yearswithmigrainemeetingtheVahlquistcriteria

• Participantshadtohaveahistoryofatleast2attacks/month,thoughitisunclearhowlongofahistorywasrequired

• ParticipantshadsimilarbaselinemigrainefrequenciesInterventions • Timolol:9patientswererandomizedtofirstreceivetimolol

5mgdailyandthenwerecrossedovertoplacebo• Placebo:8patientswererandomizedtofirstreceiveplacebo

thentimolol5mgdailyOutcomes • Itisunclearwhichoutcome(s)wereprimary

• Therewasnodifferencebetweentimololandplaceborelativetoreducingmigrainefrequency,migraineseveritynorduration

• Therewasasimilarprogressivedecreaseinthefrequencyofmigrainesinbothgroups

• Adverseeventsarenotdetailedbeyondthestatementmadeabout2patientsdroppingoutduringthetimololphaseduetosideeffects,namelyheadacheandvomiting

Notes • 2patientsexcludedgiventhattheydroppedoutfromtimololsideeffects

157


StudyID#:Sillanpää1977StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Double-blind,placebo-controlled,2-arm,parallel-grouptrial

• Althoughitseemsimpliedthatthetrialwasrandomized,itisnotclear

• Patientsweretreatedfor2months,andthenhadameanfollow-upof7.9months

• PatientswererecruitedfromthePediatricOutpatientDepartmentsinTurkuorTempere,Finland

Participants • Childrenuptoage15yearswithmigraineorotherparoxysmalvascularheadaches(categorizedassuchifonemigrainecriterionwasmissing;ie.analogoustoprobablemigraineinICHDcriteria)accordingtoVahlquist’scriteria

• Thegroupshadsimilarbaselineheadachetypesandheadachefrequencies

Interventions • Clonidine:28participantsrandomizedtoclonidine25microgramsdailyforchildren<40kgand25microgramsbidforchildren>40kg;after1month,thedosewasincreasedby25microgramsforallpatientsinthisgroup

• Placebo:29participantsrandomizedtoplaceboOutcomes • Itisunclearwhichoutcome(s)wereprimary

• Hypothesistestingresultsarenotreportedformostoftheoutcomes

• Inbothgroups,1/3oftheparticipantswereheadache-freeduringtreatment

• 57%ofclonidineparticipantsand42%ofplaceboparticipantshadonly1or2headachesduringtheentirestudy(nopgiven)

• Therewerenostatisticallysignificantdifferencesbetweenthegroupsintermsofheadacheintensityorduration(nopgiven)

• Participantswithmigrainewithaurawhoreceivedclonidinehadlessfrequentandlessintenseheadachesduringtreatmentascomparedtoplacebo(p<0.05)

• 14participantsonclonidinevs.10participantsonplacebohadlessneedforrescuemedication(nopgiven)

• 11participantsonclonidinevs.6participantsonplaceboreportedadverseevents;themostcommonsideeffectsforclonidinewerefatigueandnausea

Notes • Nosamplesizecalculationsarereported;3drop-outsarereported,allfromtheclonidinegroup

158


StudyID#:Battistella1993StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized*,double-blind,placebo-controlled,2-arm,

crossovertrial• 4weekrun-inperiod,followedby12weektreatmentperiod,

followedby4weekwashoutperiod,followedbysecond12weektreatmentperiod(withotherintervention)

Participants • 40childrenaged7-18yearswithmigrainewithoutauraasperICHDcriteria

• Allhadmigraineforatleast6months• Hadtoreportatleast3migrainespermonth

Interventions • Trazodone:20patientsrandomizedtoreceivetrazadone1mg/kg/daydividedtidforfirstphaseoftreatment

• Placebo:20patientsrandomizedtoreceiveplaceboforthefirstphaseoftreatment

Outcomes • Primaryoutcome:Therewasnodifferencebetweenthegroupsinreductionofmigrainefrequencyinthefirsttreatmentphase;inthesecondtreatmentphase,thetrazadonegrouphadagreaterreductioninfrequencythantheplacebogroup(trazodonereducedfrom2.1+0.2attacks/monthto1.8+0.2vs.placeboincreasedfrom1.8+0.1to2.1+0.2,p<0.005)

• Secondaryoutcome:Attheendofthefirsttreatmentphase,thetrazodonegrouphadahigherdurationofmigrainethanplacebo(16.1+1.4hrsvs.10.2+1.0,p<0.01);attheendofthesecondtreatmentphase,thetrazodonegrouphadagreaterreductioninmigrainedurationthanplacebo(from10.7+1.3to4.9+0.7vs.from11.9+1.3to13.1+1.3,p<0.001)

• Adverseevents:Noseriousadverseeventsreported;nodetailsgivenaboutpotentialnon-serioussideeffects

Notes • 5patientswithdrew(2fromonegroupand3fromtheother)*NB.Authorcontactedtoensurethatthetrialwasrandomizedasmanuscriptwasvague

159


StudyID#:Battistella1990StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized*,double-blind,placebo-controlled,2-arm,

crossovertrial• 4weekrun-inperiod,followedby12weektreatmentperiod,

followedby4weekwashoutperiod,followedbysecond12weektreatmentperiod(withotherintervention)

Participants • 37patientsaged7to18yearswithmigrainewithorwithoutauraaccordingtotheAdHoccriteria

• Patientswererequiredtohaveatleast1migraine/monthinthe6monthsprecedingthetrial

Interventions • Nimodipine:18patientsrandomizedtonimodipine10mgto20mgtidforthefirsttreatmentperiod

• Placebo:19patientsrandomizedtocolour-matchedplaceboforthefirsttreatmentperiod

Outcomes • Primaryoutcome:Therewasnodifferencebetweenthegroupsinreductionofmigrainefrequencyinthefirsttreatmentphase;inthesecondtreatmentphase,thenimodipinegrouphadagreaterreductioninfrequencythantheplacebogroup(from2.7+0.8attacks/monthto1.9+1.7vs.from2.6+0.8to2.8+0.6,p<0.01)

• Secondaryoutcome:Therewasnodifferencebetweenthegroupsinreductionofmigrainefrequencyineithertreatmentphase

• Adverseevents:3patientshadmildabdominaldiscomfortwithnimodipineininitialdaysoftreatment

Notes • 7patientswithdrewforreasonsnotrelatedtotheinterventions;theauthorsdonotspecifywhichgroup(s)theybelongedto

*NB.Authorcontactedtoensurethatthetrialwasrandomizedasmanuscriptwasvague

160


StudyID#:Ford2014StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Analysisfrom5studieswheredataonparticipatingchildren

aged6-17yearswereanalyzed(ie.onlypediatricpatientsanalyzed)

• Allthreetrialsthatinvolvedarandomized,double-blind,placebo-controlled,parallel-groupdesign

• Alltrialsweremulticenter• Thetrialsrangedfrom16-26weektreatmentperiods,

including4-8weektitrationperiods• NB.Manydetailsarelackingasthisanalysiswasonly

availableinconferenceabstractformParticipants • Analysiswasrestrictedtopediatricpatientsaged6-17years

meetingICHDcriteriaformigraineInterventions • Atotalof309patientswereanalyzed,buttheabstractdoes

notreporthowmanybelongedtoeachgroup• Topiramate:Varioustopiramatedosinggroupswere

included:topiramate2-3mg/kg/day,50mgdaily,100mgdailyor200mgdaily

• Placebo:Allstudieshadaplaceboarm• Propranolol:Oneofthestudieshadanactivecomparatorarm

involvingpropranolol160mgdailyOutcomes • Noprimaryoutcomesspecified

• Percentreductioninmigraineattackrate:inTOPMAT-MIG-3006trialthetopiramate100mgdailywassuperiortoplacebo(p=0.0164);inCAPS-122thetopiramateandplacebogroupsdidnotdiffer;inTOPMAT-MIGR-001/002/003therewasatrendtowardstopiramate100mgdailybeingsuperiortoplacebo

• 50%responderrate:inTOPMAT-MIG-3006thetopiramate100mgdailyhadasignificantlyhigherresponderrate(p=0.0048),butnodifferencesinresponderratescomparingtopiramatewithplacebointheotherstudies

• Adverseevents:Mostcommonsideeffectswereinfluenza-likesymptoms,languageproblemsandparesthesias

Notes •

161


StudyID#:Ashrafi2014StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Double-blind,placebo-controlled,2-arm,parallel-groupRCT

• 4weekpre-randomizationphaseand12weeksforthetreatmentphase

• ParticipantswererecruitedfromtheChildren’sMedicalCenterinTehran,Iran

Participants • Children5-17yearswithmigraineaspertheICHDcriteria• Allhadatleast6monthsofmigraine• Allhadatleast4attackspermonthinthe6monthspreceding

enrollment• Noclinicallysignificantdifferencesbetweenthegroupsin

baselinecharacteristicsInterventions • Cinnarizine:30participantsrandomizedtocinnarizine

1.5mg/kg/dayforthoseweighinglessthan30kgand50mgdailyforthoseweighing30kgormore

• Placebo:32participantswererandomizedtoplaceboOutcomes • Primaryoutcomes:Thereweremoreparticipantsachievinga

50%ormorereductioninheadachefrequencyinthecinnarizinegroupascomparedwithplacebo(60%vs.31.3%,p=0.023);bothcinnarizineandplaceboyieldedsignificantdecreasesinthemonthlymigrainefrequencyovertime,butnogroupdifferenceswerereported(cinnarizine:baseline8attacks/month,at1monthreducedto5,4.5at2monthsand4at3months,p<0.001;placebo:baseline8attacks/month,at1monthincreasedto12,reducedto6.5at2monthsand6at3months,p<0.001)

• Secondaryoutcomes:Headacheseveritywasreducedtoagreaterextentafter3monthsoftreatmentinthecinnarizinegroup(p<0.001);headachedurationwassignificantlyreducedinthecinnarizinegroupascomparedtotheplacebogroup(p=0.042)

• Adverseevents:Noseriousadverseeventsineithergroup;3cinnarizineparticipantvs1placeboparticipanthaddrowsiness;1cinnarizineparticipanthadsignificantweightgain(2.5kg)resultingintheneedtoreducethedose

Notes •

162


StudyID#:MachínAltueña1987StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,double-blind,three-arm,placebo-controlled

clinicaltrial• Nobaselineperiod,randomizedto4monthtreatmentperiod

Participants • Childrenaged5to13yearswithmigrainemeetingAdHoccriteria

• Noneofthechildrenhadbeenpreviouslytreated• Baselinedemographicsnotdescribed

Interventions • Flunarizine:15patientsrandomizedtoflunarizine0.15mg/kgoncedaily

• Dimethothiazine:15patientsrandomizedtodimethothiazine1mg/kg/daydividedbid

• Placebo:15patientsrandomizedtoplaceboOutcomes • Primaryoutcome:Clinicalimprovementwasseenin93.3%of

thedimethothiazinegroupvs.86.7%oftheflunarizinegroupvs.80%oftheplacebogroup(p>0.05)

• Secondaryoutcomes:Inthedimethothiazinegroup,35.7%hadcompleteimprovementand64.3%hadpartialimprovementvs.intheflunarizinegroup38.4%hadcompleteimprovementand61.5%hadpartialimprovementvs.intheplacebogroup41.7%hadcompleteimprovementand59.3%hadpartialimprovement(nosignificantdifferencesbetweenthegroups);41.3%reductioninmigrainefrequencyinthedimethothiazinegroupvs.46.8%influnarizinegroupvs.45.8%inplacebogroup(nosignificantdifferences);nosignificantdifferencesinchangeinmigraineintensitynorduration

• Adverseevents:23.1%offlunarizinepatientsgainedweight,1patient(groupnotmentioned)hadIgAdeficiencybutnootherbiochemicalabnormalitieswerenoted

Notes • TranslatedfromSpanish

163


StudyID#:Sillanpää1978StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Thiswasadouble-blind,placebo-controlled,2-armparallel-

group,randomizedtrial• Thetreatmentperiodwas2monthsinduration;nobaseline

periodisdescribedinthetext• Patientswererecruitedfromtheoutpatientdepartmentsof

twohospitalsinFinlandParticipants • Patientsaged6-15yearswithmigraineasperVahlquist

criteriaorvascularheadache(meetingonlyoneVahlquistcriteria)

• Participantswererequiredtohaveatleast2headaches/month

• Therewerenosignificantdifferencescomparingbaselinecharacteristicsbetweenthegroups

Interventions • Papaverine:19participantsrandomizedtopapaverine5-10mg/kg/daydividedbidortid,startingatadoseof5mg/kg/dayanddoubledto10mg/kg/dayafter1month

• Placebo:18participantsrandomizedtoplaceboOutcomes • Noprimaryoutcomewasspecified

• 6/19papaverineparticipantsvs.0/18placeboparticipantswerepain-freeduringtreatment(p<0.001)

• Headachefrequency,intensityanddurationweresignificantlymorereducedinthepapaverinegroupascomparedtoplacebo(p<0.001)

• Adverseevents:notreportedNotes • 5patientswereexcluded(twobecauseofsideeffectsand

threeduetointerventioncomplianceissues;groupsnotspecified)

164

11. AppendixD.SystematicReviewIncludedStudies‘RiskofBiasAssessment’Tables

ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment

StudyID#:Oelkers-Ax2008Reviewedby:SLOFinalqualityrating:Highriskofbias

RiskofBiasTable

Bias Author’sjudgment Supportforjudgment Hig

hriskofbias

Lowriskofbias

Unclearriskofbias

Randomsequencegeneration(selectionbias)

x

Fromtext:“Patientswereallocatedtooneofthethreetreatmentgroupsafterbaselinebycomputerizedrandomization”

Allocationconcealment(selectionbias)

x Fromtext:“Randomizationwasaccomplishedbythefirstauthor(notinvolvedinpatientcontacts)whoassignedthesubjectnumbersinascendingnumericalsequence(blockrandomizationa9)tothesubjectswhoqualifiedforrandomization”

Blindingofparticipantsandpersonnel(performancebias)

x Thisstudywaspartiallydouble-blind,meaningthatthoseonplacebovs.butterburwereblinded,buttherewasnowayofmaintainingblindingforthemusicgroup.

Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)

x Alloutcomeswereself-reportedinaheadachediary,exceptadverseeventsthatwerereportedatvisits.Again,themusictherapygroupwasunblinded.

Blindingofoutcomeassessment–objectivemeasures(detectionbias)

Noobjectivemeasureswerestudied.

Incompleteoutcomedata(attritionbias)

x

Thereweremoredrop-outsinthemusictherapyandbutterburgroupsthanintheplacebogroup.TheydiddoanITTanalysis.

Selectivereporting(reportingbias)

x

Noconcernforthathere.

Otherbias x Therewasaclinicallymeaningful

165

differencebetweenthegroups.Butterburhadalmostdoublethebaselinemigrainefrequency.

166


StudyID#:MacLennan2008Reviewedby:SLOFinalqualityrating:Lowriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

Fromtext:“Randomizationwasperformedbythebiasedcointechnique.ThecomputergeneratedlistofrandomnumberswascreatedandadministeredbythehospitalPharmacyDepartment”.


x GiventhatthePharmacydepartmentweretheonesusingtheallocationsequencesoftwarethereislowriskofbiasforallocationconcealment.


x Thestudywasdoubleblindandeffortsweremadetomaintainblinding.Fromtext:“Theriboflavinandplacebocapsuleswereproducedbythesamemanufacturertoobtainanidenticalappearance.Asriboflavinisbrightorange,anorangefooddyewasusedinthemanufactureoftheplacebo”


x “EachfamilycollectedtheircapsulesdirectlyfromthePharmacy,andtreatmentallocationwasconcealedtotheparticipantsandinvestigatorsforthedurationofthestudy.Onlythedatamonitoringcommitteecouldviewunblindeddata,andtheydidnothaveanycontactwithstudyparticipants”


Noobjectiveoutcomesassessed


x

“Efficacyanalysiswasperformedonanintention-to-treatpopulationthatincludedallrandomizedpatients”


Noneidentified

Otherbias x Itisunclearwhatkindofstoppingruletheyusedfortheirinterimanalysis.

167


StudyID#:Bruijn2010Reviewedby:SLOFinalqualityrating:unclearriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x Themethodofrandomizationisnotdetailedbeyondreferencetoa“randomizationkey”.


x Fromthetext:“Treatmentallocationwasconcealedfromtheparticipantsandinvestigatorsforthedurationofthestudy.Thehospitalpharmacistsguardedtherandomizationkey”


x Effortsweremadetoblindandmaintainblinding.Forexample,becauseriboflavincandiscolortheurine,carotenewasaddedtoplacebo.Also,fromtext:”Toevaluateblinding,atthelastvisitparentswereaskedwhichtreatmenttheybelievedthattheirchildhadreceivedinwhichphase,andthereasonsfortheirassumptions”


x Asabove,effortsweremadetoblindthepatientswhoreportedtheoutcomesthroughtheirheadachediaries.


x Noobjectiveoutcomeswereassessed.


x

4patientsdroppedoutofthegroupassignedtoplaceboinitiallyandnonedroppedoutofthegroupassignedtoriboflavininitially.However,intention-to-treatanalyseswereused.


x Noevidenceforreportingbias.

168

Otherbias x Noneidentified

169


StudyID#:Winner2005Reviewedby:SLOFinalqualityrating:Unclearriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

Fromtext:“medicationcodeschedulegeneratedbeforethetrial”.Itisunclearhowthecodewasgenerated.


x Itseemsasthoughtheallocationsequencewaskeptfromthoseinvolvedinthestudy:“Aphysiciandrugassignment/inventory(PDA)thatlistedtheuniquemedicationcodenumberwassuppliedtoeachinvestigator.Theinvestigatorenteredthesubject’sidentificationinformationinnumericalorder,therebyassigningthesubjectto1of2treatmentgroups”


x Fromtext:“Treatmentassignmentswerenotrevealedtostudypatients,investigators,clinicalstaff,orstudymonitorsuntilallpatientshadcompletedthestudyandthedatabasehadbeenfinalized”


x Asabove.


x

Noobjectiveoutcomes


x

16%ofpatientsintheplacebogroupvs.20.5%ofpatientsinthetopiramategroupdroppedoutofthestudy.Also,ITTanalyseswereused.

Selectivereporting

x

Noneidentified

170

(reportingbias)Otherbias x Noneidentified

171


StudyID#:Lakshmi2007Reviewedby:SLOFinalqualityrating:Lowriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

Fromtext:“Arandomnumbertablewasusedtodrawuprandomizedblocksofsubjectsforallocationtoeacharmofthestudy,andarandomizationsequencewasgenerated.”


x Fromtext:“Theoriginalsequenceandthecodenumberswereplacedinsealedenvelopesandopenedonlyafterthedataanalysiswascompleted”


x Fromthetext:“Thesubjectsthemselves,theirparents,thepersonengagedininterviewingandadministeringthedrugs,bothatenrollmentandfollow-up,wereallblindedtotheassignment.Dispensingboththedrugandtheplaceboinidenticalformswithsimilarappearance,pack-aging,taste,andotherfactorsfurtherensuredthisimplementation”


x Asabove


x

Therewerenoobjectiveoutcomes


x

Therewasonlyonedrop-outineachgroupandbothwereattributedtofinanciallimitations.


x

Noevidenceofselectivereporting.


172


StudyID#:Lewis2009Reviewedby:SLOFinalqualityrating:Lowriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

Fromtext:“Subjectswereassignedrandomlybyusingpermutedblocksandacomputer-generatedschedule,withstratificationaccordingtoage(12–14yearsand15–17years).Centralrandomizationwasimplementedinthisstudy.”


x Therewaslowriskofallocationconcealmentfailuregiventhatcentralrandomizationwasused.


x Thestudywasdouble-blindandeffortsweremadetomaintainblinding:“Treatmentwastakenintheformofidentical-appearingcapsulesattheendoftheprospectivebaselineperiod(day1)”


x Asabove


x Noobjectiveoutcomesinthisstudy


x

Intention-to-treatanalyseswereusedanddrop-outratesweresimilaracrossgroups.


x

Noneidentified


173


StudyID#:Pandina2010(analysisofsubsetofthedatafromLewis2009)Reviewedby:SLOFinalqualityrating:lowriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

FromLewis2009text:“Subjectswereassignedrandomlybyusingpermutedblocksandacomputer-generatedschedule,withstratificationaccordingtoage(12–14yearsand15–17years).Centralrandomizationwasimplementedinthisstudy.”


x Therewaslowriskofallocationconcealmentfailuregiventhatcentralrandomizationwasused.


x Thestudywasdouble-blindandeffortsweremadetomaintainblinding(fromLewis2009text):“Treatmentwastakenintheformofidentical-appearingcapsulesattheendoftheprospectivebaselineperiod(day1)”


x Asabove


x SomeofthefeaturesoftheCANTABwereobjective(ie.reactiontime)andthetestwascompletedbytheparticipants,whowereblinded.


x

Intention-to-treatanalyseswereusedanddrop-outratesweresimilaracrossgroups.


x

Noneidentified


174


StudyID#:Winner2006PooledAnalysisReviewedby:SLOFinalqualityrating:Unclearriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

Fromtext:“randomizedinequalproportionsto1of4treatmentgroupsaccordingtoacomputer-generatedrandomizationschedule”


x Nomentionofallocationconcealment(originalstudiesaccessed)


x Alltrialsweredouble-blindandthepatientsreportedtheoutcomes.


x Asabove.


x

Noobjectiveoutcomes.


x

Nineteenpatientsoutofthe51totalwithdrewfromthestudy.Thetextdoesnotsaywhichgroup(s)theybelongedto.However,intention-to-treatanalyseswereused.


x Noneidentified.


175


StudyID#:Apostol2008Reviewedby:SLOFinalqualityrating:Unclearriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

Thereisnodetaileddescriptionofhowtherandomsequencewascreated:“Therandomizationschedulewaspreparedbythesponsor’sstatisticsdepartmentpriortothestartofthestudy”


x Thereisnodescriptionastohowallocationwasconcealed.


x Thetrialwasdouble-blindandeffortsweremadetomaintainblinding:“StudymedicationconsistedofunmarkedDVPXER250mgtabletsandmatchingplacebotabletsprovidedinsetsof4bottles”


x Asabove,participantswereblindedandtheyreportedalloutcomes.


x Therewerenoobjectiveoutcomesinthisstudy.


x

Intention-to-treatanalyseswereused.


x

Noevidenceofreportingbias


176


StudyID#:Sorge1988Reviewedby:SLOFinalqualityrating:Highriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

Therearenodetailsabouthowtherandomsequencewascreated.


x Thereisnomentionastohowallocationwasconcealed.


x Fromtext:‘Flunarizineandplacebowereidenticalinshapeandcolour.Bothpatientsandphysicianswereblindedwithregardtomedication.”


x Thepatientsreportedontheoutcomesandtheywereblinded.


x

Therewerenoobjectiveoutcomesinthisstudy.


x

2patientswithdrewfromtheflunarizinegroupand5withdrewfromtheplacebogroup.NoITTanalyseswereused.


x Noneidentified.


177


StudyID#:Sorge1985Reviewedby:SLOFinalqualityrating:Highriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

Nodescriptionofrandomsequencegeneration.


x Nomentionofallocationconcealment.


x Thestudyislabeledasdouble-blindthoughnofurtherdetailsaregiven.


x Giventhatthepatientsreportedtheoutcomesandthattheywereblinded,thereshouldbealowriskofdetectionbias.


Noobjectiveoutcomesinthisstudy.


x

Threepatientswithdrewfromeachgroup:3fromplaceboforlackofefficacyand3fromtheflunarizinegroupforsideeffects.NoITTanalyseswereused.Giventhatthereasonsforwithdrawalweredifferent,therewashighriskofattritionbias.


x

Noneevident.

Otherbias x Noneidentified.

178


StudyID#:Noronha1985Reviewedby:SLOFinalqualityrating:Highriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

Thewaythatrandomizationwascarriedoutisnotdescribed.


x Allocationconcealmentisnotdescribed.


x Thetrialisdescribedasbeing“double-blind”thoughnodetailsaregiven.


x Thetrialwasdouble-blindandparticipantsreportedontheoutcomes.


x

Therewerenoobjectiveoutcomesinthisstudy.


x

Twopatientswithdrewduetosideeffectsdeemedtoberelatedtotimolol.Nointention-to-treatanalyseswereused.Althoughtwopatientsisasmallnumber,therewereonly17patientsinthetrialsoitisnotnegligible.


x Noneidentified.

Otherbias x Noneidentified.

179


StudyID#:Sillanpää1977Reviewedby:SLOFinalqualityrating:Highriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

Itisunclearifthetrialwasrandomized.Itappearstobeimpliedinthefollowingsentence:“Whenthecodewasbrokenattheendofthestudy…”,butisneverexplicitlystated.


x Notdescribed


x Thepatientswereblindedandreportedontheoutcomes.


x Asabove.




x

3drop-outsreported;allfromtheclonidinegroup


x

Someofthehypothesistestingisnotreported(ie.nopvaluesgivenforsomeoutcomes).


180


StudyID#:Battistella1993Reviewedby:SLOFinalqualityrating:Unclearriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

Thestudywasrandomizedbutthemethodofrandomizedisnotspecified


x Nomentionofallocationconcealment


x Thetrialwasdouble-blindandeffortsweremadetomaintainblinding(eg.thecolorofplacebowasidenticaltotrazadone)


x Thetrialwasdouble-blindandpatientsreportedontheoutcomes




x

12.5%ofpatientswithdrew(2/5fromgroupthatreceivedtrazadonefirstand3/5fromgroupthatreceivedplacebofirst;withdrawalsduetodrugadministrationerrorsoronsetofnewdiseases)


x

Noneevident


181


StudyID#:Battistella1990Reviewedby:SLOFinalclassrating:Unclearriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

Thetrialwasrandomizedbutthemethodofrandomizationisnotdescribed


x Thereisnomentionofallocationconcealment


x Thestudywasdouble-blindandeffortsweremadetomaintainblinding(eg.theplacebowascolor-matchedtonimodipine)


x Asabove,thetrialwasdouble-blindandthepatientsreportedtheoutcomes




x 18.9%ofthepatientswithdrewanditisnotmadeclearwhytheywithdrewandwhichgroup(s)theybelongedto


x

Noneidentified


182


StudyID#:Ford2014Reviewedby:SLOFinalqualityrating:Unclearriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

Allstudieswererandomized.


x Unclearifallstudieshadallocationconcealment.


x Allstudiesweredouble-blind


x Participantsreportedonalloutcomesandtheywereblinded


Therewerenoobjectiveoutcomesinthesestudies


x Nomentionofpediatric-specificdrop-outrates


x

Noneidentified


183


StudyID#:Ashrafi2014Reviewedby:SLOFinalqualityrating:Unclearriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

Thiswasarandomizedstudyusingarandomnumbertable


x Thereisnomentionofallocationconcealment


x Thiswasadouble-blindstudyandeffortsweremadetomaintainblinding:“Bothcinnarizineandplaceboformulationsweredispensedtothepatientsinidenticalenvelopeswithsimilarappearance.Cinnarizineandplacebopillswereidenticalinshape,color,andtaste”


x Thepatientswereblindedandtheyreportedontheoutcomes.




x

6patientslosttofollowupfromthestudy(4inthecinnarizinegroupand2intheplacebogroup)duetorelocationorearlydiscontinuationofthestudyintervention


x

Noneidentified


184


StudyID#:MachínAltueña1987Reviewedby:SLOFinalqualityrating:Highriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

Thiswasarandomizedstudy,thoughthemethodofrandomizationisnotdescribed.


x Nomentionofallocationconcealmentinthetext.


x Itisunclearifthestudywasblindedornot,althoughitisimpliedtobeso.


x Becausetheblindingstatuswasnotexplicitlydetailed,itisunclearifdetectionbiascouldexistforself-reportedoutcomes.




x

Nodrop-outsreported.


x

Noneidentified.

Otherbias x Therearenosamplesizecalculationsgivenandthestudywasverylikelyunderpoweredtodetectclinicallymeaningfulgroupdifferences

185


StudyID#:Sillanpää1978Reviewedby:SLOFinalqualityrating:Unclearriskofbias

RiskofBiasTable


hriskofbias

Lowriskofbias

Unclearriskofbias


x

Thisstudywasrandomizedbutthemethodofrandomizationisnotdescribed.


x Thereisnomentionofallocationconcealment.


x Thestudywasdouble-blind.


x Theparticipantswereblindedandreportedontheoutcomes.


Noobjectiveoutcomes.


x Fivepatientswereexcluded(twobecauseofsideeffectsandthreeduetointerventioncomplianceissues).Thegroup(s)thattheybelongedtowerenotdescribed.


x

Noneidentified


186

12. AppendixE.EmailInvitationtoPotentialParticipants

Dear____________________, Youarereceivingthisemailbecauseyouhavesignificantexpertisein

HeadacheMedicine.WearecarryingoutabriefsurveyamongstHeadacheMedicinespecialistswiththegoalof

determiningclinicallyrelevantnon-inferioritymarginsforoutcomescommonlyusedinmigraineclinicaltrials.Wearehopingthattheresultsofthissurveycanbeappliedtothedesignoffuturenon-inferioritymigrainetrials,andthattheymayhelptoimprovethequalityofthedataandtheclinicalrelevanceofstudyresults.

Yourparticipationinthesurveyiscompletevoluntary.Thesurveywilltakenomorethan5-

10minutestocomplete.Youcanaccessthesurveythroughthefollowinglink:_________________________________________________________________________________________________

Weunderstandthatyouareverybusy,butweurgeyoutoconsidertakingthetimetocomplete

thissurveyasitmayhelptoimprovefutureresearchintheareaofmigrainetreatment.Thankyouforyourtimeandconsiderations.Sincerely,TheNIMMSurveyStudyGroupSerenaOrr,MD,MScCandidateDariushDowlatshahi,MD,PhD,FRCPCSuzanneChristie,MD,FRCPCTimothyRamsay,PhDDavidDodick,MD,FRCPC,FACP,FAHSJonathanGladstone,MD,FRCPC

187

AppendixF.EmailInvitationtoPotentialParticipants

Dear____________________, Thisisareminderemailregardingyourparticipationinabriefsurvey.You

arereceivingthisemailbecauseyouhavesignificantexpertiseinHeadacheMedicine.WearecarryingoutabriefsurveyamongstHeadacheMedicinespecialistswiththegoalof

determiningclinicallyrelevantnon-inferioritymarginsforoutcomescommonlyusedinmigraineclinicaltrials.Wearehopingthattheresultsofthissurveycanbeappliedtothedesignoffuturenon-inferioritymigrainetrials,andthattheymayhelptoimprovethequalityofthedataandtheclinicalrelevanceofstudyresults.

Yourparticipationinthesurveyiscompletevoluntary.Thesurveywilltakenomorethan5-

10minutestocomplete.Youcanaccessthesurveythroughthefollowinglink:_________________________________________________________________________________________________

Weunderstandthatyouareverybusy,butweurgeyoutoconsidertakingthetimetocomplete

thissurveyasitmayhelptoimprovefutureresearchintheareaofmigrainetreatment.Thankyouforyourtimeandconsiderations.Sincerely,TheNIMMSurveyStudyGroupSerenaOrr,MD,MScCandidateDariushDowlatshahi,MD,PhD,FRCPCSuzanneChristie,MD,FRCPCTimothyRamsay,PhDDavidDodick,MD,FRCPC,FACP,FAHSJonathanGladstone,MD,FRCPC

188

13. AppendixG.Non-InferiorityMarginsinMigraineResearch(NIMM)Survey

IntroductionScript:“Clinicaltrialscanbedesignedaroundavarietyofhypothesistypes.Traditionally,superiorityhypotheseshavebeenused,wherebytheaimistoshowthatoneinterventionissuperiortotheother.Non-inferiorityhypothesesareaimedatshowingthatanewinterventionisnotworsethananestablishedintervention.Non-inferiorityhypothesesaremoreappropriatewhenanewinterventionischeaper,easiertouseorhasabettersideeffectprofilethantheestablishedintervention,becauseadegreeofinferiorefficacycanbeacceptedinthecontextofotherrelativeadvantagesassociatedwiththenewintervention.Theuseofnon-inferiorityhypothesesinclinicaltrialsisincreasing.Todate,onlytwomigrainetrialshaveemployednon-inferiorityhypotheses.

Inordertoproperlydesignandpoweranon-inferioritystudy,anon-inferioritymarginmust

bedeterminedaprioriinordertocalculateasamplesize.Anon-inferioritymarginissetfortheprimaryoutcome.Itconstitutesanumberbelowwhichwewouldconsiderthenewinterventiontobeclinicallyinferiortotheestablishedintervention.Inotherwords,itisthemarginabovewhichthenewinterventionwouldbeconsiderednotworsethantheestablishedintervention,andabovewhichtheinterventionwouldbeclinicallyacceptabletopractitionersandpatients.Anacceptedwayofsettinganon-inferioritymarginisbysamplingopinionsfromexpertsinthefieldorotherstakeholders.Inthisprocess,expertsorstakeholdersareaskedtoexpresstheiropiniononanacceptablenon-inferioritymarginforaparticularclinicalquestion.

Youarebeingaskedtocompletethissurveybecauseyouhaveexpertiseintreatingmigraines.

Throughthissurvey,wearehopingtoestablishnon-inferioritymarginsforcommonlyusedandacceptedoutcomesinmigraineinterventiontrials,soastoimprovethedesignoffuturenon-inferioritytrialsinmigrainetherapeutics”.

ConsentScript:“Ifyouchoosetocompletethissurvey,youwillbeprovidingimplicitconsentfor

ustousethisdataforthepurposesofcompilingsurveyresults.Thisdatamayalsobeusedinfutureabstracts,publicationsand/oracademicpresentations.Yourresponsesarecompletelyanonymousandwillnotbetracedbacktoindividualrespondents.Wewillnotbecollectinganypersonalidentifyinginformationnorpersonalhealthinformationaspartofthisstudy.Researchrecordswillbekeptfor10years,asrequiredbytheOHSN-REB.Attheendofthestoragetime,allelectronicrecordswillbesecurelydeleted.Wedonotanticipatethatyouwillsufferanyharmfromparticipationinthisstudy.Wedonotforeseeanyrisksassociatedwiththisstudy.Youwillnotreceiveanydirectbenefitfromparticipation.Thesurveyconsistsof10multiplechoicequestionsandwillrequire5-10minutesofyourtimetocomplete.Youcanchoosetonotparticipate.Yourparticipationinthisstudyisvoluntary.Youmaydecidetocompletethesurveynowandwithdrawyourdataatalatertime,withoutaffectingyourcurrentorfutureemploymentatTheOttawaHospitalResearchInstitute.Therearenoconflictsofinteresttodeclarerelatedtothisstudy.Ifyouhaveanyquestionsaboutthisstudy,orifyoufeelthatyouhaveexperiencedastudy-relatedinjuryorillness,pleasecontactDr.SerenaOrrat(613)737-7600ext.1605.

TheOttawaHealthScienceNetworkResearchEthicsBoard(OHSN-REB)hasreviewedthis

protocol.TheBoardconsiderstheethicalaspectsofallresearchstudiesinvolvinghumanparticipantsatTheOttawaHospitalResearchInstitute.Ifyouhaveanyquestionsaboutyourrightsasastudyparticipant,youmaycontacttheChairpersonat613-798-5555,extension16719.”

189

Non-InferiorityMarginsinMigraineResearch(NIMM)Survey

1. Whatkindofpractitionerareyou?£ Adultneurologist£ Childneurologist£ Other*

If‘other’wasselected,branchinglogicwasusedtodisplaythefollowing: Youselected"Other"forpractitioner.Youarenoteligibleforthissurvey. Pleaseconfirm.

£ IamNOTaNeurologist(adultorchild)andIamNOTeligibleforthissurvey.£ IamaNeurologist(adultorchild)andIameligibleforthissurvey(eligible)

2. WheredoyoupracticeHeadacheMedicine?

£ Canada£ UnitedStates

3. InwhatsettingdoyoupracticeHeadacheMedicine?

£ Academicpractice£ Communitypractice£ Mixedacademic/communitypractice

4. ForhowmanyyearshaveyoubeenpracticingHeadacheMedicine?

£ 0-5years*£ 5-10years£ 10-15years£ 15-20years£ Over20years

*If‘0-5years’wasselected,branchinglogicwasusedtodisplaythefollowing:

“IfyouhavenotbeenpracticingHeadacheMedicine(i.e.practicing0years),thenyoumaynothavesufficientexpertiseintheareatomeeteligibilitycriteriaforthissurvey.Pleaseindicatewhichstatementappliestoyou”

£ IhaveNOTbeenpracticingHeadacheMedicineandIdoNOThaveHeadache

Medicineexpertisethroughotherexperience(eg.research,etc)(ineligible)£ IhaveNOTbeenpracticingHeadacheMedicinebutIhaveHeadacheMedicine

expertisethroughotherexperience(eg.research,etc)(eligible)£ IhavebeenpracticingHeadacheMedicine(eligible)

5. Whatpercentageofyourtimeisdevotedtoresearch?

£ Under10%£ 10-25%£ 25-50%£ 50-75%£ Over75%

190

6. Whatdoyouthinkwouldbeanacceptablenon-inferioritymarginforthefollowingoutcomeusedinmigraineprophylaxistrials:thechangeinthenumberofmonthlymigraineattackscomparingbaselinetothetreatmentperiod?

£ Areductionof0.25attackspermonth(ie.ifthenewinterventionyields0.25attacks

permonthmorethantheestablishedintervention,oranythinglessthan0.25attacksmore,itisnon-inferior)

£ Areductionof0.5attackspermonth(ie.ifthenewinterventionyields0.5attackspermonthmorethantheestablishedintervention,oranythinglessthan0.5attacksmore,itisnon-inferior)


£ Areductionof1attackpermonth(ie.ifthenewinterventionyields1attackpermonthmorethantheestablishedintervention,oranythinglessthan1attacksmore,itisnon-inferior)


£ Other–Pleasespecifyyoursuggestednon-inferioritymarginforthisoutcome:____________________________________________________________________

7. Whatdoyouthinkwouldbeanacceptablenon-inferioritymarginforthefollowingoutcome

usedinmigraineprophylaxistrials:thechangeinthenumberofmonthlymigrainedayscomparingbaselinetothetreatmentperiod?

£ Areductionof0.5dayspermonth(ie.ifthenewinterventionyields0.5daysper

monthmorethantheestablishedintervention,oranythinglessthan0.5daysmore,itisnon-inferior)

£ Areductionof0.75dayspermonth(ie.ifthenewinterventionyields0.75dayspermonthmorethantheestablishedintervention,oranythinglessthan0.75daysmore,itisnon-inferior)

£ Areductionof1daypermonth(ie.ifthenewinterventionyields1daypermonthmorethantheestablishedintervention,oranythinglessthan1daymore,itisnon-inferior)




8. Whatdoyouthinkwouldbeanacceptablenon-inferioritymarginforthefollowingoutcomeusedinmigraineprophylaxistrials:thechangeintheaveragemigraineintensitycomparingbaselinetothetreatmentperiod(wheretheintensityoftheheadacheismeasuredonthefollowing4-pointseverityscale:0=noheadache,1=mildheadache,2=moderateheadache,3=severeheadache)?

191

£ Areductionof0.2pointsinaverageintensity(ie.ifthenewinterventionyieldsareductioninintensitythatis0.2pointslessthantheestablishedintervention,oranythinglessthan0.2pointsless,itisnon-inferior)




£ Areductionof1pointinaverageintensity(ie.ifthenewinterventionyieldsareductioninintensitythatis0.6pointslessthantheestablishedintervention,oranythinglessthan0.6pointsless,itisnon-inferior)


9. Whatdoyouthinkwouldbeanacceptablenon-inferioritymarginforthefollowingoutcomeusedintrialsofacutemigraineinterventions:theabsolutepercentageofparticipantswhoarepain-free2hoursaftertheintervention?

£ 2.5%fewerparticipants(ie.if2.5%feweroftheparticipantsreceivingthenewinterventionarepain-freeascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder2.5%exists,itisnon-inferior)

£ 5%fewerparticipants(ie.if5%feweroftheparticipantsreceivingthenewinterventionarepain-freeascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder5%exists,itisnon-inferior)


£ 10%fewerparticipants(ie.if10%feweroftheparticipantsreceivingthenewinterventionarepain-freeascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder10%exists,itisnon-inferior)




usedintrialsofacutemigraineinterventions:theabsolutepercentageofpatientswhohaveamigrainerecurrencewithin48hoursoftreatment?

£ 2.5%moreparticipants(ie.if2.5%moreoftheparticipantsreceivingthenewinterventionhavearecurrenceascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder2.5%exists,itisnon-inferior)

£ 5%moreparticipants(ie.if5%moreoftheparticipantsreceivingthenewinterventionhavearecurrenceascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder5%exists,itisnon-inferior)

192


£ 10%moreparticipants(ie.if10%moreoftheparticipantsreceivingthenewinterventionhavearecurrenceascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder10%exists,itisnon-inferior)




usedintrialsofacutemigraineinterventions:theabsolutepercentageofpatientswithsustainedpainfreedom(ie.thepercentageofpatientswhoarepainfree2hoursaftertheinterventionandremainpain-free48hoursaftertheintervention?

£ 2.5%fewerparticipants(ie.if2.5%feweroftheparticipantsreceivingthenewinterventionhavesustainedpain-freedomascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder2.5%exists,itisnon-inferior)

£ 5%fewerparticipants(ie.if5%feweroftheparticipantsreceivingthenewinterventionhavesustainedpain-freedomascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder5%exists,itisnon-inferior)


£ 10%fewerparticipants(ie.if10%feweroftheparticipantsreceivingthenewinterventionhavesustainedpain-freedomascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder10%exists,itisnon-inferior)


Other–Pleasespecifyyoursuggestednon-inferioritymarginforthisoutcome:

___________________________________________________

193

14. AppendixH.NIMMResponsesin“Other”Category

Item Outcome “Other”Responses6 Changeinthenumberof

monthlymigraineattackscomparingbaselinetothetreatmentperiod

• “Areductionof1.5migrainedaypermonth(ie.ifthenewinterventionyields1daypermonthmorethantheestablishedintervention,oranythinglessthan1.5daymore,itisnon-inferior).Shouldalwaysusemigrainedaysandnotattacksorepisodes.Measuringattacksisinsensitivegiventhehighvariabilityinattackdurationbetweenandwithinindividuals”.

• “1ifepisodicmigraine”• “Idon'tthinkwehaveasufficientbodyofevidencein

themigraineprophylaxisliteraturetosupportnon-inferioritytrialsatall.Thatis,it'snotreallyanappropriatestudydesignwhensomanyofthestudiesofmedicationswecurrentlyuseproducedsuchaslightdecreaseinnumberofheadacheattacksordaysvsplacebo.ThePREEMPTstudyisagoodexample:thetreatmentgrouphad1.8migrainedayspermonthascomparedtoplacebo.Andwethinkthatonabotulinumtoxinisoneofthemosteffectivepreventivetreatmentswehave.Intermsoforaltreatments,itlookslikevalproateisthemosteffectwehave,andthatshowedareductionof2.4migrainedayspermonth.Giventhesenumberscomparedtoplacebo,Iwouldarguethatwedon'thaveatreatmentthat's'established'tothepointthatwecanuseitasthereferenceinanon-inferioritytrial.Ithinkwearestillatthestageofneedingtodoplacebo-controlledtrials.IwillalsopointoutthatthatIHSGuidelinesforcontrolledtrialsofdrugsinmigrainerecommendsincludingaplacebogroup”.

• “Achangein1attackpermonthisclinicallymeaningless.Lookforachangein2-4attackspermonth”

• “Iwouldgowithapercentagelike20%-Ithinkthequestionappliedbothtofrequentmigraineorchronicmigraine”

• “.2attackspermonth”• “50%orgreaterreductioninheadacheattack

frequency”• “Numberofattacksalonecannottellusifthereisa

differenceorinourcasenon-inferiority.Itwilldependonwhatthestatisticalanalysisshows.”

• “Areductionofatleast2attackspermonth”7 Changeinthenumberof

monthlymigrainedayscomparingbaselinetothetreatmentperiod

• “0.25”• “5”• “Pleaseseemyanswertothepreviousquestion”.

194

• “2-4days”• “Iwouldgowithapercentagelike20%-Ithinkthe

questionappliedbothtofrequentmigraineorchronicmigraine”

• “greaterthan4headachedays”• “50%orgreaterreductioninheadachedayfrequency”• “Numberofmigrainedaysalonecannottellusifthere

isadifferenceorinourcasenon-inferiority.Itwilldependonwhatthestatisticalanalysisshows”.

8 Changeintheaveragemigraineintensitycomparingbaselinetothetreatmentperiod(wheretheintensityoftheheadacheismeasuredonthefollowing4-pointseverityscale:0=noheadache,1=mildheadache,2=moderateheadache,3=severeheadache)

• “Noprophylactictrialhasevershownasignificantreductioninmigraineintensity.Usinga4-pointordinalscaledoesnotprovidethesensitivitysufficienttodetectadifference.ItsameaninglessoutcomemeasureinprophylactictrialsusingthisGlaxoSmithKlinescaleforacutetherapytrials”.

• “Again,Idon'tthinkwehaveaconsistentenoughresponseinthetreatmentswecurrentlyuse,ascomparedtoplacebo,tobeabletorunanon-inferioritytrial”.

• “3pointsormore”• “intensitybyitselfwillnotmatter”• “Thechangeofaveragemigraineintensityalone

cannottellyouifthereisadifferenceorinourcasenon-inferiority.Itwilldependonwhatthestatisticalanalysisshows”.

Absolutepercentageofparticipantswhoarepain-free2hoursaftertheintervention

• “Iwouldhaveresultscomparedbyseverityattimethefirstdoseistaken.ThishasaneffectthatIrecallisaslargeasyourpercentagesabove.Youcannotassumethatrandomizationwillachieveequaldistributionofheadacheseverityatthetimeofheadachetreatment-oncethisiscontrolledfor-10%”

• “20%”• “25%fewer”• “Theabsolutepercentageofpainfreedomalone

cannottellyouifthereisadifferenceorinourcasenon-inferiority.Itwilldependonwhatthestatisticalanalysisshows”.


• “20%”• “25%more”• “Theabsolutepercentageofmigrainerecurrencein

48halonecannottellyouifthereisadifferenceorinourcasenon-inferiority.Itwilldependonwhatthestatisticalanalysisshows”.

Absolutepercentageofpatientswithsustainedpainfreedom(ie.thepercentageofpatientswhoarepainfree2hoursaftertheinterventionand

• “20%”• “20%fewer”• “10%above.Overalldependsonwhetheryouinclude

placeborun-in(singleblindphasebeforerandomizationtoactivecomparators)”

195

remainpain-free48hoursaftertheintervention)

• “Theabsolutepercentageofpatientswithsustainedpainfreedomalonecannottellyouifthereisadifferenceorinourcasenon-inferiority.Itwilldependonwhatthestatisticalanalysisshows”.

196

15. AppendixI.RCTEligibilityCriteriaRationale

Theeligibilitycriteriafortheproposedrandomizedcontrolledtrialwerechosenforavarietyof

reasons,allofwhichfallintooneofthefollowingcategories(seeTable):1)compliancewiththe

InternationalHeadacheSocietyGuidelinesonControlledtrialsofDrugsinMigraine,2)safety,that

is,ensuringthatexposuretooneoftheactiveinterventionsdoesnotresultinanadverseevent,and

3)ensuringthatparticipantshaveabilitytoparticipateinthetrialandrespondtointerventions.

Theupperlimitoftheagecriterion,thatis,thatparticipantsmustbebetween8.0and18.0years,

waschoseninordertolimitthestudytopediatricpatients.Thelowerlimitoftheagecriterionwas

chosenbasedonthelowerlimitofasimilarlarge,well-designedpediatrictrialthatisunderway173

andbecauseitcanbemoredifficulttodiagnosemigraineaccuratelyinyoungerchildren.

Table.RationaleforSpecificInclusionandExclusionCriteria

Rationale InclusionCriteria ExclusionCriteriaCompliancewith

theInternationalHeadacheSocietyGuidelinesonControlledTrialsofDrugsinMigraine

• MigrainewithoutauraormigrainewithauraasperInternationalClassificationofHeadacheDisordersThirdEdition,BetaVersion(ICHD)criteria

• Migrainefrequencyof2-8attackspermonthinthreemonthretrospectiveperiodand1monthbaselineperiod

• Migraineshavebeenpresentforatleastoneyear

• Otherheadachetypesarepresentandtheparticipantcannotdifferentiatemigrainefromtheotherheadache(s)

• Fifteenormoreheadachedayspermonth(ie.chronicmigraine)

• Overusingacutemigrainemedications

• Takingamigraineprophylacticmedicationwithinthreemonthsofenrollment

• Takinganantipsychoticorantidepressantmedicationwithinthreemonthsofenrollment

• Pregnant,lactatingorpositivepregnancytest

Safety N/A • Historyofanaphylaxisorallergytotopiramateorlevetiracetam

• Pregnant,lactatingorpositivepregnancytest

• Sexuallyactiveandnotusingareliablebirthcontrolmethod

• Historyofrenalcalculi• Significanthepaticorrenal

impairment• Ontheketogenicdiet

197

• Hasalcoholordrugdependence• Historyofsignificantbehavioral

problems• Hasapsychiatricdisorderas

definedintheDiagnosticandStatisticalManualofMentalDisorders5thedition(DSMV)

Ensuringthatparticipantshaveabilitytoparticipateintrialandrespondtointerventions

• Abletocommunicatesufficientlywithparentsinordertoaccuratelycompleteaheadachediaryandstudyquestionnaires

• Overusingacutemigrainemedications

• Takingamigraineprophylacticmedicationwithinthreemonthsofenrollment

• Takinganantipsychoticorantidepressantmedicationwithinthreemonthsofenrollment

• ReceivedBotoxinjectionsformigrainewithinthepastthreemonths

• Previoustrialoftopiramateorlevetiracetamformigraineprophylaxis

• Historyofepilepsy• Hasapsychiatricdisorderas

definedintheDiagnosticandStatisticalManualofMentalDisorders5thedition(DSMV)

• Hasalcoholordrugdependence• Historyofanotherchronicpain

disorderOther • Age8.0-18.0years

198

16. AppendixJ.RCTHeadacheDiaryTemplate

Participantnumber:____________________Month:____________________Year:_____________________

Date 1 2 3 4 5 6 7 8 910 11 1213 14 1516 1718 19 2021 2223 24 2526 27 2829 3031

Didyouhaveaheadachetoday?

Yes

No

Wasthisheadacheamigraine?Ifyes,pleaseanswerquestionsbelow.

Yes

No

Howbadwasthemigraine?Pleaserecordtheworstpainthatyoufeltwiththismigraine.

Mild

Moderate

Severe

Atwhattimedidthemigrainestart?

StartTime

Atwhattimedidthemigraineend?Ifintonextday(s),extendarrowintodaywhereitendedandindicatetimeitendedthere.

EndTime

Didyouexperienceanyofthefollowingsymptomstoday?Tickallthatapply.

Increasedappetite

Decreasedappetite

Fatigue Problemsconcen-trating

Tinglingsensations

Changesinbehavior

Aggression Paranoia Problemsthinking

Other(pleaseindicatewhatthesymptomwas)

199

Didyoutakeanyofthesemedicationstorelievethemigrainetoday?Indicatehowmanydosesyoutooktodayinthebox.Acetamino-phen

Ibuprofen Naproxen Ketorolac Diclofenac Indo-methacin

Suma-triptan

Almotriptan Rizatriptan Eletriptan Naratriptan Frova-triptan

Zolmi-triptan

Other(pleaseindicatename)

200

17. AppendixK.PedMIDASQuestionnaire

PedMIDAS

Thefollowingquestionstrytoassesshowmuchtheheadachesareaffectingday-to-dayactivity.

Youranswersshouldbebasedonthelastthreemonths.Thereareno“right”or“wrong”answersso

pleaseputdownyourbestguess.

1. Howmanyfullschooldaysofschoolweremissedinthelast3monthsduetoheadaches?

__________________

2.Howmanypartialdaysofschoolweremissedinthelast3monthsduetoheadaches(donot

includefulldayscountedinthefirstquestion)?___________________

3.Howmanydaysinthelast3monthsdidyoufunctionatlessthanhalfyourabilityinschool

becauseofaheadache(donotincludedayscountedinthefirsttwoquestions)?___________________

4.Howmanydayswereyounotabletodothingsathome(i.e.chores,homework,etc.)duetoa

headache?___________________

5.Howmanydaysdidyounotparticipateinotheractivitiesduetoheadaches(i.e.,play,goout,

sports,etc.)?____________________

6.Howmanydaysdidyouparticipateintheseactivities,butfunctionedatlessthanhalfyour

ability(donotincludedayscountedinthe5thquestion)?___________________

TotalPedMIDASScore:____________________

201

18. AppendixL.TrialInformedConsentFormforParentsandParticipantsAged16

andOver

Title:OptimizingMigraineProphylaxisinPediatrics(OMPPTrial):ARandomizedControlled

TrialComparingtheEfficacyofLevetiracetam,TopiramateandPlaceboforPreventingMigrainesinChildrenandAdolescents

PrincipalInvestigator: Dr.SerenaOrr,MD,MScCandidate,PediatricNeurologyResident

Children’sHospitalofEasternOntario 401SmythRoad Ottawa,ON,Canada,K1H8L1 Phone:(613)737-7600ext.1605

1. IntroductionYouarebeinginvitedtoparticipateinaresearchstudy.Inthisstudy,wearetryingto

determineifthemedicationstopiramateandlevetiracetammighthelptopreventmigrainesinchildrenandadolescents.

Inordertoparticipateinanyresearchstudyyouhaveto:a)understandwhatisinvolvedin

participating,b)understandtherisksandbenefitsofparticipatingandc)makeaninformeddecisiontovoluntarilyacceptordeclineparticipation.Thisprocessiscalled‘informedconsent’.Thisformismeanttohelpyouunderstandthestudysothatyoucanmakeaninformeddecisiontotakepartinthestudyornot.

Youmaycomeacrosswordsinthisconsentformthatyoudonotunderstand.Pleaseaskthe

studyresearchcoordinatororstudyinvestigatortoexplainanythingthatyoudonotclearlyunderstand.Youcantaketimetoreadthroughanunsignedcopyofthisconsentformsothatyoucanthinkaboutit.Youcanalsodiscussitwithfamilyorfriendsbeforemakingadecision.

Youarebeingaskedtojointhisstudybecauseyouhavemigraineheadaches.Wearelooking

forinformationfromchildrenandadolescentswhoDOHAVEmigraineheadaches.Theresearchcoordinatorhasreviewedtheeligibilitycriteriaandhasdeterminedthatyouaresuitableforparticipationinthisstudy.

2. PurposeoftheStudy

Migrainesareverycommoninchildrenandadolescents,andcanhavealargeimpactontheir

day-to-daylives.Childrenandadolescentswithfrequentmigrainescanconsidertwotypesoftreatment:treatingtheheadacheswhentheycomeandtakingamedicationeverydaytopreventmigrainesinthefirstplace.Althoughseveraldifferentmedicationsareusedtopreventmigraines,wedon’thavealotofinformationaboutwhichonesarethemosteffective,becausetherearen’tverymanyresearchstudiesthathavebeendoneinthisarea.

Inthisstudy,wearetryingtocomparetwomedications,levetiracetamandtopiramate,toa

placebomedication,inordertodetermineifthesemedicationscanhelptopreventmigraines.

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3.OverviewoftheStudyPreventativemedicationsaregiventopatientstotryanddecreasethenumberofmigraines

theyarehaving.Notonlyshouldthesemedicationsworktodecreasethemigraines,buttheymustalsobetolerabletothepatients;thatis,theymustnothavetoomanyunpleasantsideeffects.

Severalstudiessuggestthattopiramateissafeandeffectiveinpreventingmigrainesinchildren

andadolescents.Levetiracetamhasnotbeenstudiedasmuchastopiramateformigraines,butpreliminarystudiessuggestthatitmighthelptopreventthem.Levetiracetamiscommonlyusedtotreatseizuresinchildrenandadolescents,andhasbeenfoundtobesafeinthatcontext.

Inthisstudy,wewouldliketocomparetopiramate,levetiracetamandplacebotodetermine

howwelltheseinterventionsworktopreventmigraines.Participantswillberandomlyassignedtobetreatedwitheithertopiramate,levetiracetamorplacebo.Aplaceboisamatchingpillthatdoesnotcontainanyactiveingredients.Whenresearchersaretryingtostudywhetheradrugworksornot,theymustcompareittoplacebo.Thishelpstoaccountforthefactthatmanypatientstendtodobetterjustbytakingapillorbyparticipatinginaresearchstudy.

Inordertocomparethesethreeinterventions,participantsinthisstudywillberandomly

assignedtoreceive24weeksoftreatmentwitheithertopiramate,levetiracetamorplacebo.Thismeansthateachpersonparticipatinginthisstudywillhaveanequalchanceofgettingeitheroftheinterventions,andthatthedecisionaboutwhoreceiveswhichinterventionisrandom.

4.StudyInclusion&ExclusionCriteriaA.InclusionCriteria

Inordertoparticipate,youmustmeetallofthefollowingcriteria:6. MigrainewithoutauraormigrainewithauraasperInternationalClassificationofHeadache

DisordersThirdEdition,BetaVersion(ICHD)criteria7. Age8.0-18.0years8. Migrainefrequencyof2-8attackspermonthinthreemonthretrospectiveperiodand1

monthbaselineperiod,withdefinitionofattackasfollows:a. Attacksareseparatedbyatleast48hourheadache-freeinterval

9. Migraineshavebeenpresentforatleastoneyear10. Abletocommunicatesufficientlywithparentsinordertoaccuratelycompleteaheadache

diaryandstudyquestionnaires

B.ExclusionCriteriaInordertoparticipate,youmustmeetNONEofthefollowingcriteria:19. Otherheadachetypesarepresentandtheparticipantcannotdifferentiatemigrainefrom

theotherheadache(s)20. Fifteenormoreheadachedayspermonth(ie.chronicmigraine)21. Overusingacutemigrainemedications:

a. Takingatriptanontenormoredayspermonthb. Takingacetaminophenoranon-steroidalanti-inflammatorymedicationonfifteen

ormoredayspermonth

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22. Takingamigraineprophylacticmedicationwithinthreemonthsofenrollment23. Takinganantipsychoticorantidepressantmedicationwithinthreemonthsofenrollment24. ReceivedBotoxinjectionsformigrainewithinthepastthreemonths25. Previoustrialoftopiramateorlevetiracetamformigraineprophylaxiswith:

a. Adequatedosingb. Atleastthreemonthsofprophylaxis

26. Historyofanaphylaxisorallergytotopiramateorlevetiracetam27. Pregnant,lactatingorpositivepregnancytest28. Sexuallyactiveandnotusingareliablebirthcontrolmethod29. Historyofrenalcalculi30. Significanthepaticorrenalimpairment31. Ontheketogenicdiet32. Historyofepilepsy33. HasapsychiatricdisorderasdefinedintheDiagnosticandStatisticalManualofMental

Disorders5thedition(DSMV)34. Hasalcoholordrugdependence35. Historyofsignificantbehavioralproblems36. Historyofanotherchronicpaindisorder5.StudyProceduresIfyoudecidetoparticipateinthisstudy,youwillfirstentera4weekbaselineperiod,during

whichyouwillcompleteaheadachediaryandhaveabaselineassessmentwiththestudydoctor.Ifyoucontinuetomeetoureligibilitycriteriaafterthat4weekperiod,youwillberandomlyassignedtoeitherreceivetopiramate,levetiracetamorplacebofor24weeks,followedbya4weekperiodduringwhichwewillslowlytakeyouoffthemedication.Neitheryou,thestudycoordinatornorthestudydoctorwillknowwhichmedicationyouaretaking.Theresearchpharmacistwillmaintainapassword-protectedlistwiththisinformationincasethereisaneedforyou,thestudycoordinatororthestudydoctortohaveaccesstothatinformationatanypointintime.Thepurposeofnotknowingwhichmedicationyouaretakingistomakesurethatanyeffectofthemedicationthatweobserveisduetothemedicationitselfandnotwhatyou,thestudydoctororthestudycoordinatorexpectthemedicationtobelike.

Duringthefirst8weeksofthestudy,thestudydoctorwilladjustthedoseofthemedicationto

reachadosethatworksbesttopreventyourmigrainesandistolerabletoyouintermsofsideeffects.Youwillthentakethemedicationfor16moreweeks.Afterthe16weeksarecomplete,themedicationwillbetaperedoffover4weeks.Onceyouareoffthemedication,therewillbeanother4weekperiodforfollow-up.Duringthestudy,youwillbeaskedtofilloutadailyheadachediaryinordertokeeptrackofyourmigraines.Youwillhavemonthlytelephonecheck-inswiththestudyresearchcoordinatorandmonthlyvisitswiththestudydoctorintheclinic.

Ateachstudyvisit,youwillseethestudydoctor.Yourweightwillbetakenandyouwillreport

onhowyouarefeeling(ie.howyourheadachesareandwhetheryouarehavinganynewsymptomsthatmightbesideeffects).Ifneeded,youwillhaveaphysicalexam.Thestudydoctorwillalsoreviewyourheadachediarytoseehowthingsaregoingwithyourmigraines.

Duringeachmonthlytelephonecheck-in,thestudyresearchcoordinatorwillcontactyoutoask

youhowthingsaregoingwiththemedicationandyourheadaches.Thecoordinatorwillreviewyouruseoftheheadachediaryandwillaskyouaboutprogresswithyourheadachesaswellasothersymptomsthatcouldberelatedtothemedication.

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Throughoutthestudy,youwillbeabletotakemedicationslikeTylenolorAdviltotreat

migrainesastheycome.Youwillbeaskedtonottakeanyothermedicationeverydaytopreventmigraines,becauseitisimportantforustoseewhattheeffectsofthesemedicationsarealone,withouttheaddedeffectofotherdailymedicationstakentopreventmigraines.

6.PossibleRisksInvolvedinParticipatinginthisStudyTopiramateandlevetiracetamarebothcommonlyusedmedications,andbothhavebeenfound

tobesafetouseinchildrenandadolescents.Eachdoeshavepotentialsideeffects,someofwhichareweightloss,decreasedappetite,changesinbehaviororconcentrationandaverysmallincreaseintheriskofgettingkidneystones.Theplacebomedicationwillnotcontainactiveingredients.However,somepeoplestillexperiencerelieffromtheirheadacheswithplacebo,anditisalsopossibletohavesideeffectsfromplacebo.Throughoutthestudy,youwillbecloselymonitoredformedicationsideeffects,andthedosingofyourmedicationcanbeadjustedifyougetanysideeffectsthatyoucannottolerate.

7.PossibleBenefitsInvolvedinParticipatingintheStudyIfyouparticipateinthisstudy,youmightreceiveamedicationthatsignificantlyhelpsto

preventyourmigraines.Youwillreceivethismedicationfor24weeksatnocost.Theinformationgainedfromthisstudywillhelpustoimprovethecareofchildrenandadolescentswithmigraine.Yourinvolvementwillpotentiallybenefitmanychildrenandadolescentsinthefuture,becauseoftheinformationthatwewillgainfromthisstudy.

8.VoluntaryParticipationandWithdrawalYourdecisionaboutwhetherornottoparticipateinthisstudyisvoluntary.Youcanchooseto

participate,oryoucanchoosetowithdrawfromthestudyforanyreasonwithoutpenaltyorlossofbenefitstowhichyouareotherwiseentitledandwithoutanyeffectonyourfuturemedicalcare.

Therewillbenoconsequencesofyourdecisiontowithdrawfromthestudy.Youcandecidenottobeinthestudywithoutlosinganymedicalbenefitsyouwouldotherwise

receive.Ifyoudoenterthestudy,youcanleavethestudyatanytimewithoutlossofanymedicalbenefitsoranyotherpenalty.Ifyouleavethestudy,yourusualmedicalcarewillnotbeaffectedinanyway.

9.PaymentforInjuryandHarmIntheeventthatyousufferinjuryasadirectresultofparticipatinginthisstudy,normallegal

rulesofcompensationwillapply.Bysigningthisconsentform,youareinnowaywaivingyourlegalrightsorreleasingtheinvestigatorsfromtheirlegalandprofessionalresponsibilities.

10.CompensationIfyoutakepartinthisstudy,youwillnotbepaidorrewardedinanyway.Youwillnotbe

compensatedforanydiscoveriesmadeasaresultofthisstudy.11.Confidentiality

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Onlyyou,thestudydoctor,thestudycoordinatorandmembersoftheNeurologyclinicwhoare

treatingyouwillknowthatyouareinvolvedwiththisstudy.Becausethestudycoordinatorwillbecontactingyouonamonthlybasisoverthephone,wewillneedtocollectyourcontactinformation.Wewillstorethisinformationinapassword-protected,encryptedelectronicfile.Theremainingrecordskeptforthisstudywillidentifyyoubyanumber,notbyname,nordateofbirth.Allinformationobtainedduringthisstudy,includingyourmedicalrecords,personaldataandresearchdata,willbekeptstrictlyconfidentialexceptasrequiredbylaw.Yournameormaterialidentifyingyouasastudyparticipantwillnotbereleasedwithoutwrittenpermission,exceptwhenitisrequiredorpermittedbylaw.Anypersonalinformationthatleavesthehospitalorclinicwillbecodedsothatyoucannotbeidentifiedbyname.Youwillnotbeidentifiedinanypublicationorpresentationofthisstudy.Thestudyrecordswillberetainedforaperiodof7yearsasperCanadianregulations.CHEOinternalmonitoringresearchstaffmayreviewchartsandmedicalrecordsforqualityimprovementpurposes.

12.ContactPersonsTheCHEOResearchEthicsBoardsisacommitteeofthehospitalthatincludesindividualsfrom

differentbackgrounds.TheBoardreviewsallresearchthattakesplaceatthehospital.Itsgoalistoensurethattherightsandwelfareofpeopleparticipatinginresearchareprotected.TheBoard’sworkisnotintendedtoreplaceaparentorchild’sjudgmentaboutwhatdecisionsandchoicesarebestforthem.ThisstudyhasbeenreviewedandapprovedbytheCHEOResearchEthicsBoard.YoumaycontacttheChairoftheResearchEthicsBoard,forinformationregardingpatients’rightsinresearchstudiesat:(613)737-7600ext.3272,althoughthispersoncannotprovideanyhealth-relatedinformationaboutthestudy.Ifyouhaveanyquestionsaboutparticipationinthisstudy,orifyoufeelthatyouhaveexperiencedastudy-relatedinjury,pleasecallDr.Orrat(613)737-7600ext.1605.

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CONSENTIhavereadthisconsentformanditscontentswereexplained.Myquestionshavebeen

answered.IgiveconsentvoluntarilytoparticipateinthisstudyandIwillreceiveasignedanddatedcopyofthisconsentformformyrecords.

BysigningthisinformedconsentformIamauthorizingsuchaccesstomypersonaldataas

describedinthiscontent.IamawarethatIcanrequestacopyoftheresultsofthisstudyuponitscompletion,ifIwishto

doso.NameofSubject(Printed)Date:mm/dd/yyyy_________________________________________________________________________________________________Signature

ofSubjectDate:mm/dd/yyyy(orParent/LegalGuardian)_________________________________________________________________________________________________Signature

ofParent/LegalGuardianDate:mm/dd/yyyy_________________________________________________________________________________________________SignatureofInvestigatorDate:mm/dd/yyyy_________________________________________________________________________________________________SignatureofPersonConductingConsentDiscussionDate:mm/dd/yyyy

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19. AppendixM.TrialAssentFormforParticipantsAgedLess16Years

Title:OptimizingMigraineProphylaxisinPediatrics(OMPPTrial):ARandomizedControlled

TrialComparingtheEfficacyofLevetiracetam,TopiramateandPlaceboforPreventingMigrainesinChildrenandAdolescents

PrincipalInvestigator: Dr.SerenaOrr,MD,MScCandidate,PediatricNeurologyResident

Children’sHospitalofEasternOntario 401SmythRoad Ottawa,ON,Canada,K1H8L1 Phone:(613)737-7600ext.1605Thisformmaycontainwordsyoudonotunderstand.Pleaseaskthestudydoctorto

explainanythingyoudonotunderstand.Ifyouwishtotalktothestudydoctorpleaseask.1.Whatisthisstudyabout?Thisisaresearchstudy.Researchstudiesaredonewhenwearetryingtofindoutmoreabout

something.Wearetryingtofindoutmoreabouthowtotreatheadachescalledmigraines.Youarebeingaskedtoparticipateinthisstudybecauseyouhavemigraines.Wearehopingtofigureoutifthemedicationstopiramateandlevetiracetamworktopreventmigrainesinkids.

2.DoIhavetobeinthisstudy?No.Youdonothavetobeinthisstudyifyoudon’twantto.Evenifyousaythatyouwanttobeinthisstudy,youcanchangeyourmindlater.Ifyouchange

yourmind,pleasetellyourdoctorortheresearchcoordinator.Theycananswerquestionsyouhaveaboutthestudybeforeyoumakeupyourmind.Youcantalktoyourmom,ordad,orthepersonwholooksafteryouaboutit.Theycanreadyoutheinformationtheresearchcoordinatorgavethemtohelpyoumakeupyourmind.

Ifyouwanttobeinthisstudy,youwillhavetosignthisform.3.Whatwillhappenduringthestudy?Inthisstudy,wearetryingtocomparetwomedications,levetiracetamandtopiramate,toa

placebomedication,tofigureoutifthesemedicationscanhelptopreventmigraineheadaches.Aplaceboisamatchingpillthathasnoactivedrugsinit.Whenwearetryingtostudyifadrugworksornot,wehavetocompareittoplacebo.

Ifyoujointhisstudy,youwillfilloutaheadachediaryeveryday.Afteronemonth,ifyoustillhaveenoughheadachesandstillwanttobeinthestudy,youwillstarttreatment.Youwillhaveanequalchanceofgettingtreatedwitheitherlevetiracetam,topiramateorplacebo.Thepharmacistwilluseacomputertofigureoutwhichtreatmentyouwillget.Youwillnotknowwhichtreatmentyouaregetting.Thestudydoctorandcoordinatorwillalsonotknowwhichtreatmentyouareon.Youwilltakethetreatmenteverydayfor24weeks.Afterthat,wewillslowlytakeyouoffthetreatmentover4weeks,andthenfollowyouforanother4weekstoseehowyouaredoing.

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Youwillhavemonthlycallsfromthestudyresearchcoordinatorandmonthlyvisitswiththestudydoctorintheclinic.Ateachvisit,youwillseethestudydoctor.Yourweightwillbetakenandyouwilltellthedoctorhowyouarefeelingwithyourheadachesandanyproblemsyouarehaving.Ifneeded,youwillhaveaphysicalexam.Thestudydoctorwillalsolookatyourheadachediarytoseehowthingsaregoing.Ateachmonthlytelephonecall,thestudycoordinatorwillcontactyoutoaskyouhowthingsaregoingwiththemedicationandyourheadaches.

4.ThegoodandthebadthingsaboutdoingthisstudyIfyoudecidetobeinthisstudy,goodthingsmighthappen.Themedicationthatyougetmight

helptopreventyourmigrainesandmakeyoubetterabletofunctioninschool,athomeandinactivities.Youwillgetthismedicationfor24weeksatnocost.Theinformationthatwegetfromthisstudymighthelpkidswithmigrainesinthefuture.

Ifyoudecidetobeinthisstudy,somebadthingscouldhappen.Themedicationcouldgiveyou

sideeffects.Someofthepossiblesideeffectswithlevetiracetamandtopiramateareweightloss,decreasedappetite,changesinbehaviororconcentrationandaverysmallincreaseinthechanceofgettingkidneystones.Theplacebomedicationwillnothaveactivedrugsinit.Somepeoplefeelbetterwithplacebo,andsomepeoplealsohavesideeffectsfromplacebo.

5.WillanyoneknowthatIdidthisstudy?Wewillnotshareanyinformationaboutyouwithanyoneoutsideofthestudy.Wewillnottell

anyoneoutsideofthisstudythatyouparticipated.6.DoIhavetodothis?Youdonothavetobeinthisstudy.Itisokaytosayno.Youcantellyourparentsorthestudy

doctorthatyoudonotwanttobeinthisstudyatanytime.Thatwillbeokay.ItwillnotaffectanycarethatyoureceiveorwillreceiveatCHEO.

Ifyoudecidetobeinthestudy,youcanchangeyourmindatanytimelater.Youcanstillsayno

andthatwillbeokay.7.WhocanItalktoaboutthestudy?Theresearchcoordinatorcanansweryourquestionsaboutthestudyatanytime.Youcanalso

talktoyourmom,yourdadorwhoeverlooksafteryou.8.Confidentiality

CHEOinternalmonitoringresearchstaffmayreviewtheresearchfilesforqualityimprovementpurposes.Yourcontactinformationwillbestoredinasafe,encryptedsoftwaresothatthestudycoordinatorcancontactyou.Therestofthestudydocumentswillnotcontainanyinformationthatcanbelinkedtoyouspecifically,likeyournameordateofbirth.Therestofthedocumentswillonlycontainyourstudyidentificationnumber.

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ASSENTFORMDoyouwanttobeinthisstudy?Pleasecheckonebox: �Yes,Iwanttobeinthestudy. �No,Idonotwanttobeinthestudy._______________________________________NameofChild(Print) _______________________________________ _____________________________SignatureofChild Date: mm/dd/yyyy _______________________________________NameofParentorLegalGuardian(Print)Iattestthattheparticipanthadenoughtimetoconsiderthisinformation,hadanopportunityto

askquestionsandvoluntarilyagreedtobeinthestudy_________________________________________________NameofPersonExplainingAssent(Print) __________________________________________ _____________________________SignaturePersonExplainingAssent Date:mm/dd/yyyy

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20. AppendixN.BrochuretoExplainStudyProcedurestoParticipants

OPTIMIZINGMIGRAINEPROPHYLAXISINPEDIATRICS(OMPPTrial)

1.Whatisthisstudyabout?Thisstudyistryingtodetermineiflevetiracetamandtopiramateareeffectiveinpreventing

migrainesinkids.2.Whatwillhappeninthisstudy?Ifyouagreetoparticipateinthisstudy,youwillberandomlyassignedtoreceiveeither

topiramate,levetiracetamorplacebofor24weeks.Throughoutthestudy,youwillbeaskedtocompleteaheadachediaryeveryday.Thefirst4

weekswillbeabaselineperiod,whereyoufilloutthediarysothatwecanseehowmanymigrainesyouarehaving.If,afterthe4weeks,youarestillhavingenoughmigrainesandstillwanttoparticipate,thenyouwillbeassignedtooneofthestudymedications.Afterthis,the24weeksoftreatmentwillstart.Youwillthenbeslowlytakenoffthemedicationforaperiodof4weeks,andfollowedforanother4weeks.Duringthestudy,youwillbemonitoredwithstudyvisitsandtelephonefollow-ups.

3.HowmanystudyvisitswillIhave?Everymonth,youwillcomeintothehospitaltohaveavisitwiththestudydoctor.Duringthese

visits,youwillhaveyourweighttaken,aphysicalexamifneeded,andthestudydoctorwillgooverhowthingsaregoingwithyourheadachesandthemedication.Itisveryimportantthatyoufilloutyourheadachediaryeverydayandbringittoyourvisits,becausethisishowthestudydoctorwillknowifyourmigrainesaregettingbetterornot.

4.Howmanytelephonefollow-upswillIhave?Everymonth,thestudycoordinatorwillcallyoutocheckin.Thestudycoordinatorwillgoover

howthingsarewithyourheadachesandwhetheryouareexperiencinganysideeffectsfromthemedication.Itisveryimportantthatyoufillouryourheadachediaryeveryday,becauseitwillhelpyoutogivethestudycoordinatoraccurateinformationanditwillhelpyoutokeeptrackofhowyouaredoing.

5.WhatelsewillIhavetodoforthisstudy?Asisdescribedabove,youwillhavetofilloutaheadachediaryeveryday.Thisdiarywillonly

takeacoupleofminutestofillout.Thediaryiseasytofillout:ithasafewquestionsthatrequireonlycheckboxanswers,andonequestionwhereyourecordhowmanyrescuemedicationsyoutookforyourheadache(s)thatdaywithanumber.Wewillalsogiveyouaquestionnairetoseehowyourmigrainesareaffectingyourlife.Youwilltakethissurveythreetimes:onceatbaseline,onceattheendoftreatmentandonceattheendoffollow-up.Thissurveyonlytakesafewminutestocomplete.

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Asisdescribedabove,youwillbeaskedtoattendmonthlyhospitalvisitswiththestudydoctorandtotakemonthlytelephonecallsfromthestudycoordinator.

6.Whenwillmyinvolvementinthestudybeover?Afterthestudyfollow-upperiodisover,youwillnolongerbeinvolvedwiththisstudy.Your

studydoctorwillensurethatyouhavefollow-upforyourmigraineswitheitherachildneurologistatthehospitaloryourfamilydoctor.

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21. AppendixO.PASSReport1–SuperiorityHypothesisSampleSizeCalculation

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Group Sequential - Means Numeric Results for Two-Sided Hypothesis Test of Means Target Actual Power Power N1 N2 N Mean1 Mean2 S1 S2 Alpha 0.80 0.80197 71 71 142 2.60 1.41 2.5 2.5 0.050 References Chow, S.C.; Shao, J.; Wang, H. 2003. Sample Size Calculations in Clinical Research. Marcel Dekker. New York. Lan, K.K.G. and DeMets, D.L. 1983. 'Discrete sequential boundaries for clinical trials.' Biometrika, 70, pages 659-663. O'Brien, P.C. and Fleming, T.R. 1979. 'A multiple testing procedure for clinical trials.' Biometrics, 35, pages 549-556. Pocock, S.J. 1977. 'Group sequential methods in the design and analysis of clinical trials.' Biometrika, 64, pages 191-199. Reboussin, D.M., DeMets, D.L., Kim, K, and Lan, K.K.G. 1992. 'Programs for computing group sequential boundaries using the Lan-DeMets Method.' Technical Report 60, Department of Biostatistics, University of Wisconsin-Madison. Report Definitions Target Power is the desired power value (or values) entered in the procedure. Power is the probability of rejecting a false null hypothesis. Actual Power is the power obtained in this scenario. Because N1 and N2 are discrete, this value is often (slightly) larger than the target power. N1 and N2 are the number of items sampled from each population. N is the total sample size, N1 + N2. Mean1 is the mean of populations 1 and 2 under the null hypothesis of equality. Mean2 is the mean of population 2 under the alternative hypothesis. S1 and S2 are the population standard deviations of groups 1 and 2. Alpha is the probability of rejecting a true null hypothesis. Summary Statements Sample sizes of 71 and 71 achieve 80% power to detect a difference of 1.19 between the group means with standard deviations of 2.5 and 2.5 at a significance level (alpha) of 0.050 using a two-sided z-test. These results assume that 4 sequential tests are made using the O'Brien-Fleming spending function to determine the test boundaries. Details when Spending = O'Brien-Fleming, N1 = 71, N2 =71, S1 = 2.5, S2 = 2.5, Diff = 1.19 Lower Upper Nominal Inc Total Inc Total Look Time Bndry Bndry Alpha Alpha Alpha Power Power 1 0.50 -4.33263 4.33263 0.000 0.000 0.000 0.00178 0.002 2 1.00 -2.96311 2.96311 0.003 0.003 0.003 0.16739 0.169 3 1.50 -2.35902 2.35902 0.018 0.016 0.019 0.37325 0.542 4 2.00 -2.01406 2.01406 0.044 0.031 0.050 0.25955 0.802 Drift 2.83610

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Group Sequential - Means Chart Section

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22. AppendixP.PASSReport2–Non-InferiorityHypothesisSampleSizeCalculation

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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Scenario 1 Numeric Results for Group Sequential Test of Non-Inferiority Higher Means are Better Hypotheses: H0: Mean1 - Mean2 = NIM; H1: Mean1 - Mean2 < NIM Test Statistic: T-Test Alpha-Spending Function: O'Brien-Fleming Analog Beta-Spending Function: None Futility Boundary Type: None Number of Looks: 4 Simulations: 2000 Pool Size: 10000 Numeric Summary for Scenario 1 ------------------ Power ------------------- -------------------------- Alpha ---------------------------- Value 95% LCL 95% UCL Target Actual 95% LCL 95% UCL Beta 0.811 0.794 0.828 0.050 0.050 0.040 0.060 0.189 ----- Average Sample Size ---- -- Given H0 -- -- Given H1 -- Non-Inf. Std N1 N2 Grp1 Grp2 Grp1 Grp2 Margin Mean1 Mean2 Dev 79 79 78 78 62 62 1.0000 2.6000 2.6000 2.5000 References Jennison, C.; Turnbull, B.W. 2000. Group Sequential Methods with Applications to Clinical Trials. Chapman & Hall. Boca Raton, FL. Devroye, Luc. 1986. Non-Uniform Random Variate Generation. Springer-Verlag. New York. Matsumoto, M. and Nishimura,T. 1998. 'Mersenne twister: A 623-dimensionally equidistributed uniform pseudorandom number generator.' ACM Trans. On Modeling and Computer Simulations. Zar, Jerrold H. 1984. Biostatistical Analysis (Second Edition). Prentice-Hall. Englewood Cliffs, New Jersey.

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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Report Definitions Power is the probability of rejecting a false null hypothesis at one of the looks. It is the total proportion of alternative hypothesis simulations that are outside the significance boundaries. Power 95% LCL and UCL are the lower and upper confidence limits for the power estimate. The width of the interval is based on the number of simulations. Target Alpha is the user-specified probability of rejecting a true null hypothesis. It is the total alpha spent. Actual Alpha is the alpha level that was actually achieved by the experiment. It is the total proportion of the null hypothesis simulations that are outside the significance boundaries. Alpha 95% LCL and UCL are the lower and upper confidence limits for the actual alpha estimate. The width of the interval is based on the number of simulations. Beta is the probability of accepting a false null hypothesis. It is the total proportion of alternative hypothesis simulations that do not cross the significance boundaries. N1 and N2 are the sample sizes of each group if the study reaches the final look. Average Sample Size Given H0 Grp1 and Grp2 are the average or expected sample sizes of each group if H0 is true. These are based on the proportion of null hypothesis simulations that cross the significance or futility boundaries at each look. Average Sample Size Given H1 Grp1 and Grp2 are the average or expected sample sizes of each group if H1 is true. These are based on the proportion of alternative hypothesis simulations that cross the significance or futility boundaries at each look. Non-inferiority margin is the distance from the control mean that is still considered non-inferior. Mean1, Mean2, and Std Dev are the parameters that were set by the user to define the null and alternative simulation distributions. Summary Statements Group sequential trials with group sample sizes of 79 and 79 at the final look achieve 81% power to detect a difference of 1.0000 at the 0.050 significance level (alpha) using a one-sided T-Test. Accumulated Information Details for Scenario 1 Accumulated Information -------- Accumulated Sample Size -------- Look Percent Group 1 Group 2 Total 1 25.0 20 20 40 2 50.0 40 40 80 3 75.0 60 60 120 4 100.0 79 79 158 Accumulated Information Details Definitions Look is the number of the look. Accumulated Information Percent is the percent of the sample size accumulated up to the corresponding look. Accumulated Sample Size Group 1 is total number of individuals in group 1 at the corresponding look.

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Accumulated Sample Size Group 2 is total number of individuals in group 2 at the corresponding look. Accumulated Sample Size Total is total number of individuals in the study (group 1 + group 2) at the corresponding look.

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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Boundaries for Scenario 1 -- Significance Boundary -- T-Value P-Value Look Scale Scale 1 -3.26419 0.00116 2 -2.61944 0.00529 3 -1.97462 0.02532 4 -1.69088 0.04643 Boundaries Definitions Look is the number of the look. Significance Boundary T-Value Scale is the value such that statistics outside this boundary at the corresponding look indicate termination of the study and rejection of the null hypothesis. They are sometimes called efficacy boundaries. Significance Boundary P-Value Scale is the value such that P-Values outside this boundary at the corresponding look indicate termination of the study and rejection of the null hypothesis. This P-Value corresponds to the T-Value Boundary and is sometimes called the nominal alpha.

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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Boundary Plot

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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Boundary Plot - P-Value

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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Significance Boundaries with 95% Simulation Confidence Intervals for Scenario 1 --------- T-Value Boundary --------- --------- P-Value Boundary --------- Look Value 95% LCL 95% UCL Value 95% LCL 95% UCL 1 -3.26419 0.00116 2 -2.61944 -2.88807 -2.42370 0.00529 0.00251 0.00884 3 -1.97462 -2.07622 -1.86435 0.02532 0.02002 0.03238 4 -1.69088 -1.82038 -1.62086 0.04643 0.03531 0.05353 Significance Boundary Confidence Limit Definitions Look is the number of the look. T-Value Boundary Value is the value such that statistics outside this boundary at the corresponding look indicate termination of the study and rejection of the null hypothesis. They are sometimes called efficacy boundaries. P-Value Boundary Value is the value such that P-Values outside this boundary at the corresponding look indicate termination of the study and rejection of the null hypothesis. This P-Value corresponds to the T-Value Boundary and is sometimes called the nominal alpha. 95% LCL and UCL are the lower and upper confidence limits for the boundary at the given look. The width of the interval is based on the number of simulations.

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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Alpha-Spending and Null Hypothesis Simulation Details for Scenario 1 --------- Target --------- --------- Actual ---------- Proportion Cum. Cum. H1 Sims H1 Sims --- Signif. Boundary--- Spending Spending Cum. Outside Outside T-Value P-Value Function Function Alpha Alpha Signif. Signif. Look Scale Scale Alpha Alpha Spent Spent Boundary Boundary 1 -3.26419 0.00116 0.000 0.000 0.000 0.000 0.036 0.036 2 -2.61944 0.00529 0.005 0.006 0.006 0.006 0.191 0.226 3 -1.97462 0.02532 0.018 0.024 0.018 0.024 0.382 0.608 4 -1.69088 0.04643 0.026 0.050 0.027 0.050 0.204 0.811 Alpha-Spending Details Definitions Look is the number of the look. Significance Boundary T-Value Scale is the value such that statistics outside this boundary at the corresponding look indicate termination of the study and rejection of the null hypothesis. They are sometimes called efficacy boundaries. Significance Boundary P-Value Scale is the value such that P-Values outside this boundary at the corresponding look indicate termination of the study and rejection of the null hypothesis. This P-Value corresponds to the Significance T-Value Boundary and is sometimes called the nominal alpha. Spending Function Alpha is the intended portion of alpha allocated to the particular look based on the alpha-spending function. Cumulative Spending Function Alpha is the intended accumulated alpha allocated to the particular look. It is the sum of the Spending Function Alpha up to the corresponding look. Alpha Spent is the proportion of the null hypothesis simulations resulting in statistics outside the Significance Boundary at this look. Cumulative Alpha Spent is the proportion of the null hypothesis simulations resulting in Significance Boundary termination up to and including this look. It is the sum of the Alpha Spent up to the corresponding look. Proportion H1 Sims Outside Significance Boundary is the proportion of the alternative hypothesis simulations resulting in statistics outside the Significance Boundary at this look. It may be thought of as the incremental power. Cumulative H1 Sims Outside Significance Boundary is the proportion of the alternative hypothesis simulations resulting in Significance Boundary termination up to and including this look. It is the sum of the Proportion H1 Sims Outside Significance Boundary up to the corresponding look.

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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Scenario 1 Numeric Results for Group Sequential Test of Non-Inferiority Higher Means are Better Hypotheses: H0: Mean1 - Mean2 = NIM; H1: Mean1 - Mean2 < NIM Test Statistic: T-Test Alpha-Spending Function: O'Brien-Fleming Analog Beta-Spending Function: None Futility Boundary Type: None Number of Looks: 4 Simulations: 2000 Pool Size: 10000 Numeric Summary of Scenarios Non-Inf. Std Scenario Power N1 N2 Alpha Margin Mean1 Mean2 Dev 1 0.811 79 79 0.050 1.0000 2.6000 2.6000 2.5000 References Jennison, C.; Turnbull, B.W. 2000. Group Sequential Methods with Applications to Clinical Trials. Chapman & Hall. Boca Raton, FL. Devroye, Luc. 1986. Non-Uniform Random Variate Generation. Springer-Verlag. New York. Matsumoto, M. and Nishimura,T. 1998. 'Mersenne twister: A 623-dimensionally equidistributed uniform pseudorandom number generator.' ACM Trans. On Modeling and Computer Simulations. Zar, Jerrold H. 1984. Biostatistical Analysis (Second Edition). Prentice-Hall. Englewood Cliffs, New Jersey. Report Definitions Power is the probability of rejecting a false null hypothesis at one of the looks. It is the total proportion of alternative hypothesis simulations that are outside the significance boundaries. Alpha is the alpha level that was actually achieved by the experiment. It is the total proportion of the null hypothesis simulations that are outside the significance boundaries. N1 and N2 are the sample sizes of each group if the study reaches the final look. Non-inferiority margin is the distance from the control mean that is still considered non-inferior. Mean1, Mean2, and Std Dev are the parameters that were set by the user to define the null and alternative simulation distributions. Power and Alpha Summary ------------------ Power ------------------- -------------------------- Alpha ---------------------------- Scenario Value 95% LCL 95% UCL Target Actual 95% LCL 95% UCL Beta 1 0.811 0.794 0.828 0.050 0.050 0.040 0.060 0.189

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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Report Definitions Power is the probability of rejecting a false null hypothesis at one of the looks. It is the total proportion of alternative hypothesis simulations that are outside the significance boundaries. Power 95% LCL and UCL are the lower and upper confidence limits for the power estimate. The width of the interval is based on the number of simulations. Target Alpha is the user-specified probability of rejecting a true null hypothesis. It is the total alpha spent. Alpha or Actual Alpha is the alpha level that was actually achieved by the experiment. It is the total proportion of the null hypothesis simulations that are outside the significance boundaries. Alpha 95% LCL and UCL are the lower and upper confidence limits for the actual alpha estimate. The width of the interval is based on the number of simulations. Beta is the probability of accepting a false null hypothesis. It is the total proportion of alternative hypothesis simulations that do not cross the significance boundaries. Sample Size Summary ------- Average Sample Size ------- --- Given H0 --- --- Given H1 --- Scenario Power Alpha N1 N2 Grp1 Grp2 Grp1 Grp2 1 0.811 0.050 79 79 78 78 62 62 Report Definitions Power is the probability of rejecting a false null hypothesis at one of the looks. It is the total proportion of alternative hypothesis simulations that are outside the significance boundaries. Alpha is the alpha level that was actually achieved by the experiment. It is the total proportion of the null hypothesis simulations that are outside the significance boundaries. N1 and N2 are the sample sizes of each group if the study reaches the final look. Average Sample Size Given H0 Grp1 and Grp2 are the average or expected sample sizes of each group if H0 is true. These are based on the proportion of null hypothesis simulations that cross the significance or futility boundaries at each look. Average Sample Size Given H1 Grp1 and Grp2 are the average or expected sample sizes of each group if H1 is true. These are based on the proportion of alternative hypothesis simulations that cross the significance or futility boundaries at each look. Run Time: 23.15 seconds.

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