ARTICLE OPEN ACCESS CLASS OF EVIDENCE

Galcanezumab in chronic migraineThe randomized double-blind placebo-controlled REGAIN study

Holland C Detke PhD Peter J Goadsby MD PhD Shufang Wang PhD Deborah I Friedman MD MPH

Katherine J Selzler PhD and Sheena K Aurora MD

Neurologyreg 201891e2211-e2221 doi101212WNL0000000000006640

Correspondence

Dr Detke

detkehclillycom

AbstractObjectiveTo evaluate the efficacy and safety of galcanezumab a humanized monoclonal antibody thatselectively binds to calcitonin gene-related peptide in the preventive treatment of chronicmigraine

MethodsA phase 3 randomized double-blind placebo-controlled study of LY2951742 in patients withchronic migraine (Evaluation of Galcanezumab in the Prevention of Chronic Migraine[REGAIN]) was a phase 3 study with a 3-month double-blind placebo-controlled treatmentphase and a 9-month open-label extension Eligible patients 18 to 65 years of age with chronicmigraine were randomized 211 to monthly subcutaneous injections of placebo (n = 558)galcanezumab 120 mg (with a 240-mg loading dose n = 278) or galcanezumab 240 mg (n =277) The primary endpoint was the overall mean change from baseline in the number ofmonthly migraine headache days (MHDs) during the 3-month double-blind treatment phase

ResultsMean number of monthly MHDs at baseline was 194 for the total sample Both galcanezumabdose groups demonstrated greater overall mean reduction in the number of monthly MHDscompared to placebo (placebo minus27 galcanezumab 120 mg minus48 galcanezumab 240 mg minus46)(p lt 0001 for each dose compared to placebo) There were no clinically meaningful differencesbetween galcanezumab doses and placebo on any safety or tolerability outcome except fora higher incidence of treatment-emergent injection-site reaction (p lt 001) injection-siteerythema (p lt 0001) injection-site pruritus (p lt 001) and sinusitis (p lt 005) in thegalcanezumab 240-mg group relative to placebo

ConclusionsBoth doses of galcanezumab were superior to placebo in reducing the number of monthlyMHDs Galcanezumab appears efficacious safe and well tolerated for the preventive treatmentof chronic migraine

ClinicalTrialsgov identifierNCT02614261

Classification of evidenceThis interventional study provides Class I evidence that galcanezumab is superior to placebo inthe reduction of the number of monthly MHDs

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Page 1083

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Class of EvidenceCriteria for ratingtherapeutic and diagnosticstudies

NPuborgcoe

From Eli Lilly and Company Indianapolis IN (HCD SW KJS SKA) Department of Neurology (PJG) NIHRndashWellcome Trust Kingrsquos Clinical Research Facility Kingrsquos College LondonUK University of California (PJG) San Francisco and Departments of Neurology and Neurotherapeutics and Ophthalmology University of Texas Southwestern Medical CenterDallas

Go to NeurologyorgN for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article

The Article Processing Charge was funded by Eli Lilly and Company

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2018 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology e2211

Chronic migraine (CM) is a neurologic disease characterizedby at least 15 headache days per month of which at least 8 aremigraine1 Although less prevalent than episodic migraineCM is associated with substantially greater headache-relateddisability comorbid medical and psychiatric conditions andhealth care resource use and poorer quality of life2 Individualswith CM are at particularly high risk for headache associatedwith acute medication overuse which may exacerbate thedisease3 Therefore it is of critical importance to developeffective and well-tolerated migraine preventive treatments toreduce disability and to prevent disease progression

Calcitonin gene-related peptide (CGRP) is a promising targetfor migraine prevention4 Three previous monoclonal anti-bodies to CGRP or one of its receptors have been studied aspreventive therapy for CM Eptinezumab5 fremanezumab6

and erenumab7 have shown efficacy in either phase 2 or phase3 clinical trials in patients with CM Galcanezumab is a hu-manized monoclonal antibody that selectively binds to andblocks the physiologic activity of CGRP8 Patients with episodicmigraine treated with galcanezumab had a significantly greatermean reduction in the number of monthly migraine headachedays (MHDs) and low rates of treatment discontinuationcompared with those treated with placebo9ndash12 The presentreport includes results from the 3-month double-blind periodof a phase 3 clinical trial of galcanezumab in patients with CM

MethodsStandard protocol approvals registrationsand patient consentsWe conducted the study at 116 headache and clinical researchcenters in 12 countries Argentina Canada Czech RepublicGermany Israel Italy Mexico the Netherlands Spain Tai-wan the United Kingdom and the United States (dataavailable from Dryad appendix e-1 doiorg105061dryad8655q79) The study protocol was reviewed and approved bythe appropriate institutional review board for each site andwas conducted according to Good Clinical Practice and theDeclaration of Helsinki guidelines Before undergoing any studyprocedures patients provided written informed consent Thefirst patient was enrolled in January 2016 and the last patientcompleted the double-blind portion of the study inMarch 2017The study is registered at ClinicalTrialsgov (NCT02614261)

Study designThe study comprised 5 study periods (1) a 3- to 45-dayscreening period (2) a 1-month prospective baseline period

to determine patient eligibility on the basis of daily entriesinto an electronic patient-reported outcomes (ePRO) diary(3) a 3-month randomized double-blind placebo-controlledtreatment period (4) a 9-month open-label extension and(5) a 4-month posttreatment period to observe the washoutof the study drug Here we report results through the double-blind treatment period (study period 3) Results from the open-label and posttreatment periods will be reported separately

Patient selectionPatients were men and women 18 to 65 years of age atscreening with a diagnosis of CM as defined by the In-ternational Classification of Headache Disorders 3rd editionbeta version (ICHD-3 beta) guidelines1 and migraine onsetbefore 50 years of age Patients had to have at least 15headache days per month of which at least 8 were migrainefor gt3 months before screening and as assessed by the ePROdiary during the 1-month prospective baseline periodPatients also needed at least 1 headache-free day per monthwithin 3 months before screening and during baselinePatients had to be at least 80 compliant with ePRO dailydiary entries and were blinded to diary eligibility criteria

We excluded patients who had persistent daily headachecluster headache head or neck trauma within the past 6months possible posttraumatic headache or primary head-ache other than CM Patients could not have previously failedto respond to adequate trials of migraine preventives withLevel A or Level B evidence from gt3 different medicationclasses (based on the list of such preventives found in theAmerican Academy of Neurologyrsquos evidence-based guide-lines13 or onabotulinumtoxinA or B) Patients could not taketherapeutic antibodies during or within 1 year before thestudy and could not have serious or unstable medical orpsychiatric conditions history of stroke or history of sub-stance abuse or dependence in the past year or be at risk foracute cardiovascular events based on history or ECG findings

Patients could take acute headache medication as neededthroughout the trial but could take opioid- or barbiturate-containingmedications nomore than 3 days per month couldnot take oral corticosteroids and could receive no more than1 steroid injection during the study and only if in an emer-gency setting Patients had to wash out all migraine preventivemedications except topiramate or propranolol patients couldremain on either topiramate or propranolol if on a stable dosein the 2 months before starting the prospective baseline pe-riod and remaining on that dose throughout the baseline anddouble-blind periods Patients staying on topiramate or

GlossaryADA= anti-drug antibodiesAE= adverse eventCM= chronicmigraineCGRP= calcitonin gene-related peptide ePRO= electronicpatient-reported outcomes ICHD = International Classification of Headache Disorders 3rd edition beta versionMHD = migraineheadache dayMIDAS = Migraine Disability AssessmentMSQ = Migraine-Specific Quality of Life Questionnaire PGI-S = PatientGlobal Impression of Severity of Illness REGAIN = Evaluation of Galcanezumab in the Prevention of Chronic Migraine

e2212 Neurology | Volume 91 Number 24 | December 11 2018 NeurologyorgN

propranolol were known as the concurrent migraine pre-ventive cohort Otherwise patients discontinued all migrainepreventives at least 30 days before entering the baseline pe-riod (or at least 4 months prior for botulinum toxin)

Randomization and maskingEligible patients were randomized 211 to receive monthlysubcutaneous injections of placebo galcanezumab 120 mg(with a 240-mg loading dose) or galcanezumab 240 mg forthe 3-month double-blind period Assignment to treatmentwas via computer-generated random sequence with an in-teractive web-response system Randomization was stratifiedby country acute headache medication overuse (yesno) asdetermined during prospective baseline and presence ofconcurrent migraine preventive (yesno)

To preserve blinding patients in all treatment groups receivedtwo 1-mL injections at each monthly dosing visit (2 placeboinjections 1 placebo and 1 galcanezumab 120-mg injection or2 galcanezumab 120-mg injections) in blinded prefilled syringesPatients in the galcanezumab 120-mg group received 240 mg attheir first dosing visit followed by 120 mg at the subsequentmonths All patients had to remain in the office for a 30-minutepostinjection observation period after the first dose

Study objectives and measuresThe primary objective tested the hypothesis that at least 1dose of galcanezumab (120 or 240 mgmo) was superior toplacebo in the prevention of migraine in patients with CM asmeasured by the overall mean change from baseline in thenumber of monthly MHDs during the 3-month double-blindtreatment period An MHD was a calendar day with a head-ache lasting ge30 minutes with features meeting ICHD-3 betacriteria for migraine or probable migraine A headache alsoqualified as a migraine if the patient believed it was a migraineat onset and was relieved by a triptan or ergot A headache daywas a calendar day with any headache lasting ge30 minutes(including migraine probable migraine and nonmigraineheadache)

Key secondary objectives compared galcanezumab with pla-cebo on response rates (proportion of patients with ge50ge75 and 100 reduction from baseline in monthly MHDsacross months 1ndash3) mean change in functioning at month 3measured by the Migraine-Specific Quality of Life Question-naire (MSQ) Role Function-Restrictive score14 overall meanreduction in monthly MHDs with acute headache medicationuse across months 1 to 3 and mean change in Patient GlobalImpression of Severity of Illness (PGI-S)15 at month 3 Othersecondary objectives included comparison of galcanezumabwith placebo on additional headache parameters (eg monthlyheadache days headache hours and migraine headache hours)across months 1 to 3 and the Migraine Disability Assessment(MIDAS) total score at month 31617

Patients reported all headache information in the ePRO diaryincluding duration severity and features as well as drug name

and dose of acute headache medications taken that calendarday Patients completed self-report scales at office visits in-cluding the MSQ (monthly) PGI-S (monthly) and MIDAS(every 3 months) The MSQ version 21 assesses the effect ofmigraine on daily functioning in 3 domains over a 4-weekrecall period Role Function-Restrictive (7 items) RoleFunction-Preventive (4 items) and Emotional Function (3items)18 The MSQ items are rated on a scale of 1 to 6 withdomain scores converted to a scale of 0 to 100 such that higherscores represent better functioning The PGI-S scale is a sin-gle-item instrument asking patients to rate the severity of theiroverall migraine illness on a scale of 1 (normal not at all ill) to7 (extremely ill) The MIDAS is a 5-item patient-rated in-strument assessing number of days negatively affected bymigraine during the 3-month recall period with scores ge21representing severe disability

Double-blind safety assessments included adverse events(AEs) (all visits) vital signs (monthly) and weight laboratorymeasures ECGs (baseline and month 3) and treatment-emergent anti-drug antibodies (ADA all visits) Suicidalitywas assessed monthly by the Columbia-Suicide SeverityScale19 a required assessment for all investigational neuro-logic treatments

Statistical analysisThe target sample size was 1140 based on the assumption ofa 15 discontinuation rate and an effect size of 030 in the lastmonth of the 3-month treatment phase to provide asymp95power that at least 1 galcanezumab group would separatefrom placebo at a 1-sided 0025 significance level

We conducted analyses on all randomized patients re-ceiving at least 1 dose of study medication We conductedefficacy analyses on an intent-to-treat basis with patientsanalyzed according to assigned treatment group We con-ducted safety analyses according to patientsrsquo modal doserather than the assigned dose Five patients assigned to120-mg galcanezumab had a modal dose of 240 mg becausethey discontinued after the loading dose and before the firstmaintenance dose

We performed analyses of continuous repeated efficacymeasures using a restricted maximum likelihood-basedmixed-models repeated-measures technique with prespecified modelterms of treatment country acute headache medicationoveruse concurrent preventive use month treatment timesmonth baseline and baseline times month Overall mean changefrom baseline (ie the average change across months 1ndash3) isestimated from the model For continuous safety and efficacyanalyses with objectives evaluated at month 3 (PGI-S andMIDAS) we used an analysis of covariance model to analyzechange from baseline to last-observation-carried-forwardendpoint Response rates represent the mean percentage ofresponders from the categorical pseudondashlikelihood-basedrepeated-measures analysis assessing overall response rateacross months 1 2 and 3 We used the Fisher exact test to

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analyze demographic and baseline illness characteristics Forcategorical safety analyses we used the Cochran-Mantel-Haenszel test for between-group comparisons adjusting forbaseline medication overuse and concurrent preventivemedication use

We adjusted for multiplicity in the primary and prespecifiedkey secondary analyses using a superchain procedure tocontrol for type I error20 Hypothesis testing occurred se-quentially through parallel dose branches with the possibilityto recycle available α as depicted in figure 1 which includesnotational conventions consistent with that of previouslydescribed methods20ndash23We calculated multiplicity-adjusted αthresholds for each hypothesis in each step of the pro-cedure using the appropriate multiplicity adjustmenttechnique (the Dunnett test24 the Hochberg procedure25

or the Bonferroni-Holm procedure26) We then comparedthe unadjusted p value for each hypothesis against itsmultiplicity-adjusted α level We considered endpoints withan unadjusted p value higher than the adjusted α level to benot statistically significant after multiplicity adjustmentOnce we failed to reject the null hypothesis for an endpointin the sequence (including any retesting with any availablerecycled α) we stopped the procedure and did not test anyfurther endpoints in the sequence for that dose branch Weautomatically considered any untested endpoints in thesequence as not statistically significant after multiplicityadjustment

We performed all statistical analyses using SAS EnterpriseGuide 71 (SAS Institute Cary NC)

Data availabilityLilly makes patient-level data available from Lilly-sponsoredstudies on marketed drugs for approved uses after acceptancefor publication Lilly is one of several companies that providethis access through the website clinicalstudydatarequestcomQualified researchers can submit research proposals and re-quest anonymized data to test new hypotheses Lillyrsquos data-sharing policies are provided on the clinicalstudydatarequestcom site under the Study Sponsors page

Classification of evidenceThis interventional study provides Class I evidence for theprimary research question namely that both dose regimens ofgalcanezumab (120 mgmo with a 240-mg loading dose and240 mgmo) are superior to placebo in the reduction of thenumber of monthly MHDs

ResultsPatient dispositionOf 1903 patients screened we randomized 1117 (figure 2)Four did not receive the study drug leaving 1113 in theintent-to-treat population More than 90 of the patients ineach treatment group completed the double-blind treatmentperiod (figure 2)

Patient demographics andbaseline characteristicsDemographic and baseline characteristics were generallysimilar across treatment groups (table 1) The galcanezumab240-mg group had a higher percentage of patients who had

Figure 1 Multiple testing procedure

Arrows indicate direction and weighting of αpropagation The procedure initially teststhe parallel branches (dose sequences) si-multaneously and then recycles available αbetween the branches to retest endpointfamilies containing nonrejected null hypoth-eses Notation is consistent with previouslyreported methods20ndash23 Acute meds = MHDwith the use of acute (abortive) treatmentMHD = migraine headache days (meanchange from baseline) MSQ = Migraine-Spe-cific Quality of Life Questionnaire Role Func-tion-Restrictivedomain PGI-S= PatientGlobalImpression of Severity RR = response rate

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prior treatment failure of ge2migraine preventives in the past 5years (35) compared with the galcanezumab 120-mg group(24) There were also a few statistical differences fromplacebo in the galcanezumab 240-mg group but they were notclinically meaningful Only 15 of patients overall remainedon a concurrent preventive (topiramate or propranolol)during the study

Efficacy outcomesOn the primary endpoint both doses of galcanezumab weresuperior to placebo in the overall mean reduction in thenumber of monthly MHDs from baseline (table 2) Monthlyreductions in MHDs were statistically different from placebofor both galcanezumab doses starting with month 1 (figure 3)Over the 3 months of treatment the mean percentages ofpatients with ge50 and ge75 reduction from baseline inMHDs were higher for both galcanezumab doses than forplacebo (ge50 response rate both doses p lt 0001 ge75response rate 120 mg p lt 005 240 mg p lt 0001 figure 4)After adjustment for multiplicity galcanezumab 240 mgdemonstrated statistical improvement vs placebo on theprimary and all key secondary endpoints except for 100response rate while galcanezumab 120 mg had statisticalimprovement vs placebo on the primary endpoint and thege50 response rate (table 2) Results for other (nonkey)

secondary measures are presented in table 2 There wereno statistical differences between doses on any efficacymeasure

SafetyThere were no deaths in this study Treatment-emergent AEswere reported by 50 58 and 57 of patients in the pla-cebo galcanezumab 120-mg and galcanezumab 240-mggroups respectively (table 3) Most treatment-emergentAEs were mild or moderate in severity The most commontreatment-emergent AE was injection-site pain but this didnot differ significantly between groups (4 placebo 6 gal-canezumab 120 mg 7 galcanezumab 240 mg) Injection-sitereaction injection-site erythema injection-site pruritus andsinusitis occurred more frequently in the galcanezumab 240-mg group relative to placebo with injection-site pruritus andinjection-site erythema also occurring more frequently withthe 240-mg than the 120-mg galcanezumab dose Six placebo-treated patients discontinued as a result of AEs that includedabdominal pain alopecia headache migraine and myocardialinfarction Five galcanezumab-treated patients discontinuedbecause of an AE that included increased weight in the 120-mg group and depression increased hepatic enzymesinjection-site pain and acute pancreatitis in the 240-mggroup

Figure 2 Patient cohort diagram of the double-blind phase of the REGAIN study

REGAIN = Evaluation of Galcanezumab in the Prevention of Chronic Migraine

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There were 10 serious AEs during the study with 4 reportedin the placebo group (alcoholic pancreatitis epistaxis gastri-tis and myocardial infarction) 1 in the galcanezumab 120-mggroup (colon cancer) and 5 in the galcanezumab 240-mggroup (hypokalemia and nephrolithiasis in 1 patient acutepancreatitis pulmonary embolism and renal colic)

We observed no clinically meaningful differences betweengalcanezumab and placebo in laboratory values vital signsweight or quantitative or qualitative ECGs Two patients inthe study had a treatment-emergent abnormal hepatic en-zyme 1 in the placebo group (1 of 558 or 02) and 1 in thegalcanezumab 240-mg dose group (1 of 282 or 04)

Treatment-emergent suicidal ideation assessed by the Co-lumbia-Suicide Severity Scale was reported for 4 (1)patients on placebo 3 (1) patients in the galcanezumab 120-mg group and 2 (1) patients in the galcanezumab 240-mggroup with no suicidal behavior

Anti-drug antibodiesDuring the double-blind treatment phase treatment-emergent ADA occurred in 22 patients across the groups(15 27 and 26 of the placebo galcanezumab 120-mgand galcanezumab 240-mg groups respectively) Of these22 patients 13 had neutralizing ADA present (06 23 and15 of the placebo galcanezumab 120-mg and galcanezumab

Table 1 Patient demographics and baseline disease characteristics

Placebo (n = 558)

Galcanezumab

120 mg (n = 278) 240 mg (n = 277)

Age y 416 (121) 397 (119)a 411 (124)

Female n () 483 (87) 237 (85) 226 (82)

Race n ()

White 432 (77) 223 (80) 224 (81)

Black 39 (7) 16 (6) 17 (6)

Asian 26 (5) 13 (5) 14 (5)

Other 61 (11) 26 (9) 21 (8)

Body mass index kgm2 269 (56) 264 (55) 267 (52)

Migraine illness duration y 219 (129) 204 (127) 201 (127)a

MHDmo 196 (46) 194 (43) 192 (46)

MHDmo with acute medication use 155 (66) 151 (63) 145 (63)a

Headache dmo 215 (41) 212 (40) 214 (41)

Migraine headache hmo 1367 (910) 1360 (795) 1347 (866)

Headache hmo 1451 (951) 1447 (854) 1459 (934)

Patient-reported aura n () 310 (56) 153 (55) 141 (51)

Prior preventive treatment in past 5 y n () 435 (78) 211 (76) 220 (79)

Failed ge2 preventives in past 5 y n () 163 (29) 68 (24) 97 (35)b

Acute headache medication overuse n () 353 (63) 178 (64) 177 (64)

Concurrent preventive treatment n () 82 (15) 37 (13) 43 (16)

MIDAS total score 687 (574) 625 (495) 692 (641)

MSQ RF-R score 384 (172) 393 (173) 389 (173)

MSQ RF-P score 550 (208) 555 (220) 571 (205)

MSQ EF score 442 (260) 453 (258) 457 (274)

PGI-S score 49 (12) 48 (12) 49 (13)

Abbreviations EF = Emotional Function MHD = migraine headache days MIDAS = Migraine Disability Assessment MSQ = Migraine-Specific Quality of LifeQuestionnaire version 21 PGI-S = Patient Global Impression-Severity of Illness RF-P = Role Function-Preventive RF-R = Role Function-RestrictiveData are mean (SD) unless otherwise indicateda p le 005 vs placebob p le 001 vs galcanezumab 120 mg

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Table 2 Primary and secondary endpoints (time frame is across months 1 through 3 unless otherwise specified)

Placebo (n = 538)

Galcanezumab

120 mg (n = 273) 240 mg (n = 274)

Primary endpoint

Monthly MHDs minus27 (04) minus48 (04) minus46 (04)

Difference (95 CI) minus21 (minus29 to minus13) minus19 (minus27 to minus11)

p Value vs placeboa lt0001 (S) lt0001 (S)

Key secondary endpoints

ge50 response 154 (16) 276 (27) 275 (26)

Odds ratio (95 CI) 21 (16 to 28) 21 (16 to 28)

p Value vs placeboa lt0001 (S) lt0001 (S)

ge75 response 45 (09) 70 (14) 88 (17)

Odds ratio (95 CI) 16 (10 to 25) 20 (14 to 31)

p Value vs placeboa 0031 (NS) lt0001 (S)

100 response 05 (03) 07 (04) 13 (06)

Odds ratio (95 CI) 14 (04 to 44) 26 (10 to 70)

p Value vs placeboa 0597 (NS)b 0058 (NS)

Monthly MHDs with acute medication use minus22 (03) minus47 (04) minus43 (04)

Difference (95 CI) minus25 (minus33 to minus18) minus20 (minus28 to minus13)

p Value vs placeboa lt0001 (NS)b lt0001 (S)

MSQ RF-R scorec 168 (12) 218 (14) 231 (16)

Difference (95 CI) 51 (21 to 80) 63 (30 to 96)

p Value vs placeboa lt0001 (NS)b lt0001 (S)

PGI-S scorec minus06 (01) minus08 (01) minus09 (01)

Difference (95 CI) minus01 (minus03 to 01) minus03 (minus05 to minus01)

p Value vs placeboa 0181 (NS)b 0006 (S)

Other secondary endpoints

Monthly headache days minus30 (04) minus48 (04) minus46 (04)

Difference (95 CI) minus18 (minus27 to minus10) minus16 (minus24 to minus08)

p Value vs placeboa lt0001 lt0001

Monthly headache hours minus134 (39) minus362 (47) minus315 (47)

Difference (95 CI) minus227 (minus317 to minus137) minus181 (minus271 to minus91)

p Value vs placeboa lt0001 lt0001

Monthly migraine headache hours minus141 (38) minus362 (46) minus321 (46)

Difference (95 CI) minus221 (minus309 to minus133) minus180 (minus268 to minus93)

p Value vs placeboa lt0001 lt0001

MSQ RF-P scorec 110 (12) 180 (14) 161 (14)

Difference (95 CI) 70 (42 to 98) 51 (23 to 79)

p Value vs placeboa lt0001 lt0001

Continued

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240-mg groups respectively) with a statistical difference be-tween galcanezumab 120 mg and placebo (p lt 005) Maxi-mum ADA titers among these patients ranged from 120 to 1160 There was no discernible effect of ADA on treatmentefficacy or tolerability

DiscussionThis 3-month phase 3 study met its primary objective in thatboth doses of galcanezumab were superior to placebo in theoverall mean reduction of monthly MHDs in CM There wasno previous phase 2 study of galcanezumab in patients withCM Patients in this study had an average of 193 MHDs permonth and an average MIDAS score of 658 indicating very

severe27 disability Monthly MHDs decreased by asymp5 witha difference from placebo of 2MHDs representing a clinicallymeaningful positive change28 Despite the high MHD fre-quency and relatively short duration of the study the per-centage of patients with ge50 reduction in the number ofmonthly MHDs was gt25 in both galcanezumab dosegroups and almost twice as many galcanezumab-treatedpatients had ge75 reduction compared with placebo Themean increase in functioning by 23 points on the 100-pointMSQRole Function-Restrictive domain for the galcanezumab240-mg group also represents a clinically important changethese patients with CM improved to a level of functioningmore consistent with that of episodic migraine Efficacyresults appeared generally consistent with those from other

Table 2 Primary and secondary endpoints (time frame is across months 1 through 3 unless otherwise specified) (continued)

Placebo (n = 538)

Galcanezumab

120 mg (n = 273) 240 mg (n = 274)

MSQ EF scorec 141 (16) 210 (19) 207 (19)

Difference (95 CI) 70 (32 to 108) 66 (28 to 104)

p Value vs placeboa lt0001 lt0001

MIDAS total scorec minus115 (34) minus203 (41) minus170 (41)

Difference (95 CI) minus87 (minus164 to minus11) minus55 (minus131 to 21)

p Value vs placeboa 0025 0157

Abbreviations CI = confidence interval EF = Emotional Function MHD = migraine headache day MIDAS = Migraine Disability Assessment MSQ = Migraine-Specific Quality of Life version 21 NS = not significant after multiplicity adjustment RF-P = Role Function-Preventive RF-R = Role Function-Restrictive PGI-S =Patient Global Impression of Severity of Illness S = significant after multiplicity adjustmentData are least-squares mean change from baseline (SE) or estimated percentage (SE) unless otherwise stateda p Value indicates nominal significance without multiplicity adjustment S or NS indicates significant or not significant after multiplicity adjustmentb Item not tested after all α expended on previous items in multiplicity adjustment testing sequence (figure 1) Therefore item is considered not statisticallysignificant regardless of p valuec Time frame is at month 3

Figure 3 Reduction in MHDs at each month

Reduction in migraine headache days (MHDs) at eachmonth was statistically greater in both galcanezumabdose groups compared with placebo Differences be-tween galcanezumab doses were not significant LS =least squares SE = standard error p lt 0001 vsplacebo p lt 001 vs placebo

e2218 Neurology | Volume 91 Number 24 | December 11 2018 NeurologyorgN

large randomized double-blind trials evaluating a pre-ventive treatment in a CM population such as those forCGRP pathway blockers5ndash7 onabotulinumtoxinA2930 andtopiramate3132

In addition to efficacy the safety and tolerability profiles areessential components in evaluating the overall therapeuticbenefit of a treatment investigated in a clinical trial28 The highrates of study completion (95) and low rates of discontin-uation due to AEs (1) for the galcanezumab-treated patientssuggest that galcanezumab was well tolerated consistent withfindings in the episodic migraine studies111233 Incidences ofindividual treatment-emergent AEs were low with the mostcommon being injection-site pain (6ndash7 across galcane-zumab doses) Incidences of injection-site related treatment-emergent AEs such as injection-site reaction injection-siteerythema and injection-site pruritus were also low butreported in a greater proportion of patients receiving galca-nezumab 240 mg compared with placebo Most injection-sitereactions were mild to moderate in severity and resolvedwithin a few days with no serious events In addition therewere no clinically meaningful differences from placebo withrespect to changes in laboratory parameters vital signs orECGs

Comparison of the 2 galcanezumab doses yielded few differ-ences Although the galcanezumab 240-mg dose met statisticalsignificance onmore key secondary endpoints after multiplicityadjustment than did the 120-mg dose there were no statisticaldifferences between the 2 doses on any of the efficacymeasuresTogether the data suggest that the galcanezumab 120-mg doseperformed as well as the galcanezumab 240-mg dose with re-spect to reductions in monthly MHDs other migraine andheadache parameters and improvements in functioning and

quality of life With respect to safety and tolerability the inci-dences of injection-site erythema and injection-site prurituswere higher in the galcanezumab 240-mg group than the120-mg group Otherwise the 2 doses appeared quite similar

Some limitations should be noted Restrictions in the inclusioncriteria may limit the generalizability of the results Patientswith serious and unstable medical conditions were excluded aswere patients who had demonstrated significant treatment-resistance to multiple previous migraine preventive medi-cations In addition the 3-month duration of the study whilesufficient to demonstrate efficacy may not be long enough todemonstrate the ultimate effects of the treatment here analysisof the 9-month open-label extension may help Neverthelessfurther study is needed to evaluate both the benefits and risks oflong-term use of galcanezumab in the CM patient population

This phase 3 trial of galcanezumab for prevention of CMdemonstrated that both doses of galcanezumab were effica-cious safe and well tolerated after treatment for up to 3months These findings contribute further support that theCGRP pathway inhibition is a biologically specific disease-targeted approach to the prevention of migraine that offers animportant advance in the management of a common anddisabling neurologic disease

Author contributionsDr Detke contributed to the study design interpretation ofdata and creatingrevising the content Dr Goadsby con-tributed to the interpretation of data and revised the manu-script for content Dr Wang contributed to the analyses ofdata and study design and revised the manuscript for contentDr Friedman Dr Selzler and Dr Aurora revised the manu-script for content

Figure 4 Mean percentages of patients with ge50 ge75 or 100 response across months 1 through 3

Response refers to percent reduction from baseline inmonthly migraine headache days Differences be-tween galcanezumab doses were not significant SE =standard error p lt 0001 (statistically significant vsplacebo after multiplicity adjustment) p lt 005 (notstatistically significant after multiplicity adjustment)

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AcknowledgmentThe authors thank all of the study participants siteinvestigators and personnel involved in the Evaluation ofGalcanezumab in the Prevention of Chronic Migraine(REGAIN) study They also thank Vladimir SkljarevskiMD Brian Millen PhD and Jyun Yan Yang MD for theircontributions during the study and Jonna Ahl PhD forassistance in drafting the manuscript

Study fundingStudy was funded by Eli Lilly and Company This work hasbeen reported previously at the American Headache Societyand International Headache Society meetings in 2017

DisclosureH Detke is a full-time employee and minor shareholder of EliLilly and Company P Goadsby reports grants from Eli Lillyand Company personal fees from Alder BioPharmaceuticalsDr Reddyrsquos Laboratories Electrocore LLC Novartis Pfizer

Inc Scion Teva Pharmaceuticals medicolegal work JournalWatch Up-to-Date Oxford University Press MassachusettsMedical Society and Wolters Kluwer grants and personalfees from Allergan Amgen and eNeura Inc and other fromTrigemina Inc In addition Dr Goadsby has a patent formagnetic stimulation for headache licensed to eNeura withoutfee S Wang is a full-time employee and minor shareholder ofEli Lilly and Company D Friedman reports speaker fees fromAllergan advisory board and speaker fees from Supernus andAmgen advisory board consultant and speaker fees fromAvanir advisory board fees from Alder BioPharmaceuticalsand Biohaven Pharmaceuticals consultant and advisory boardfees from electroCore advisory board and grant support fromTeva and Zosano grant support and consultant fees from EliLilly and Company and grant support from Merck Auto-nomic Technologies Inc and Axon Optics D Friedman hasbeen a consultant for Promius serves on editorial board forNeurology Reviews and is a contributing author to MedLinkNeurology K Selzler and S Aurora are full-time employees

Table 3 Treatment-emergent AEs that occurred in ge2 of galcanezumab-treated patients treated with either dose ofgalcanezumab and greater than placebo

AE Placebo (n = 558) n ()

Galcanezumab n ()

120 mg (n = 273) 240 mg (n = 282)

Patients with ge1 events 279 (50) 159 (58)a 160 (57)

Injection-site pain 24 (4) 17 (6) 20 (7)

Nasopharyngitis 26 (5) 17 (6) 9 (3)

Upper respiratory tract infection 13 (2) 9 (3) 9 (3)

Injection-site reaction 10 (2) 8 (3) 15 (5)b

Injection-site erythema 5 (1) 4 (1) 13 (5)cd

Fatigue 10 (2) 6 (2) 6 (2)

Back pain 14 (3) 9 (3) 2 (1)d

Urinary tract infection 7 (1) 6 (2) 4 (1)

Abdominal pain 9 (2) 6 (2) 4 (1)

Diarrhea 9 (2) 3 (1) 6 (2)

Injection-site pruritus 1 (0) 0 (0) 7 (2)bd

Migraine 5 (1) 5 (2) 4 (1)

Influenza-like illness 3 (1) 5 (2) 4 (1)

Neck pain 8 (1) 7 (3) 0 (0)ad

Oropharyngeal pain 3 (1) 2 (1) 5 (2)

Sinusitis 5 (1) 4 (1) 8 (3)a

Arthralgia 5 (1) 1 (0) 5 (2)

Pyrexia 2 (0) 5 (2)a 1 (0)

Abbreviation AE = adverse eventa p lt 005 vs placebob p lt 001 vs placeboc p lt 0001 vs placebod p lt 005 vs galcanezumab 120 mg

e2220 Neurology | Volume 91 Number 24 | December 11 2018 NeurologyorgN

and minor shareholders of Eli Lilly and Company Go toNeurologyorgN for full disclosures

Publication historyReceived by Neurology February 28 2018 Accepted in final formAugust 9 2018

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9 Dodick DW Goadsby PJ Spierings ELH Scherer JC Sweeney SP Grayzel DS Safetyand efficacy of LY2951742 a monoclonal antibody to calcitonin gene-relatedpeptide for the prevention of migraine a phase 2 randomised double-blindplacebo-controlled study Lancet Neurol 201413885ndash892

10 Skljarevski V Oakes TM Zhang Q et al Galcanezumab for episodic migraine pre-vention a randomized phase 2b placebo-controlled dose-ranging clinical trial JAMANeurol 201875187ndash193

11 Stauffer VL Dodick DW Zhang Q Carter JN Ailani J Conley RR Evaluation ofgalcanezumab for the prevention of episodic migraine the EVOLVE-1 randomizedclinical trial JAMA Neurol 2018751080ndash1088

12 Skljarevski VMatharuMMillen BAOssipovMH Kim BK Yang JY Efficacy and safetyof galcanezumab for the prevention of episodicmigraine results of the EVOLVE-2 phase3 randomized controlled clinical trial Cephalalgia 2018381442ndash1454

13 Silberstein SD Holland S Freitag F Dodick DW Argoff C Ashman E Evidence-based guideline update pharmacologic treatment for episodic migraine prevention inadults Neurology 2012781337ndash1345

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NeurologyorgN Neurology | Volume 91 Number 24 | December 11 2018 e2221

DOI 101212WNL0000000000006640201891e2211-e2221 Published Online before print November 16 2018Neurology

Holland C Detke Peter J Goadsby Shufang Wang et al REGAIN study

Galcanezumab in chronic migraine The randomized double-blind placebo-controlled

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