Study DesignStudy DesignOverview and lessons Overview and lessons

learnedlearnedAlan Percy, MDAlan Percy, MD JUNE 23, 2008JUNE 23, 2008

RETT SYNDROME CLINICAL RETT SYNDROME CLINICAL TRIALS MINI-SYMPOSIUMTRIALS MINI-SYMPOSIUM

Types of TrialsTypes of Trials

Specific featuresSpecific features anxiety, breathing, stereotypiesanxiety, breathing, stereotypies

Specific systemsSpecific systems neuroendocrine, neurotransmitters, neuroendocrine, neurotransmitters,

cognition, communicationcognition, communication Direct targeting of Direct targeting of MECP2MECP2

Read-through agents, modulate XCI, Read-through agents, modulate XCI, gene replacementgene replacement

Study DesignStudy Design

Open labelOpen label

Double-blind, placebo controlledDouble-blind, placebo controlled

Double-blind, placebo controlled Double-blind, placebo controlled crossovercrossover

N of one N of one

Stratification StrategiesStratification Strategies

AgeAge

Mutation – caution on exclusivityMutation – caution on exclusivity

Clinical severity indexClinical severity index

Combined strategyCombined strategy

Lessons LearnedLessons Learned Overall: Lack of quantitative Overall: Lack of quantitative

behavioral outcome measurebehavioral outcome measure Before Before MECP2MECP2

naltrexone trial: failed to consider age in naltrexone trial: failed to consider age in randomization scheme resulting in randomization scheme resulting in imbalance by age between treatment imbalance by age between treatment groupsgroups

Post-Post-MECP2MECP2 folate-betaine trial: age stratified (folate-betaine trial: age stratified ( and and

5); failed to balance mutations 5); failed to balance mutations between drug and placebo groupsbetween drug and placebo groups

Outcome MeasuresOutcome Measures

Common dataset formatsCommon dataset formats

Common clinical severity indexCommon clinical severity index

Objective measure develomentObjective measure develoment behaviorbehavior cognitioncognition communicationcommunication

Scope of TrialScope of Trial

Single institutionSingle institution

Inter-institutionalInter-institutional

Intercontinental (transgalactic)Intercontinental (transgalactic)

Existing ResourcesExisting Resources Patient advocacy groupsPatient advocacy groups

InterRett, RettBase, and RettSearchInterRett, RettBase, and RettSearch

North American databaseNorth American database

Rare Disease databaseRare Disease database

European databasesEuropean databases

North American North American DatabaseDatabase

Total enrolledTotal enrolled 19281928

TestedTested 1165 (60%)1165 (60%)

Not testedNot tested 763 (40%)763 (40%)

MECP2MECP2 Not known Not known 869 (45%) 869 (45%)

Tested, KnownTested, Known 1059 (91%)1059 (91%)

Tested, Not knownTested, Not known 106 (9%)106 (9%)

Tested, MutationTested, Mutation 914 (86%)914 (86%)

Tested, No mutationTested, No mutation 145 (14%)145 (14%)

North American North American DatabaseDatabase

GroupGroup TotaTotall

MutatioMutation n

No No mutatiomutatio

nn

UnknowUnknownn

TypicalTypical 16481648 791 791 (91%)(91%)

79 (9%)79 (9%) 778778

Atypical Atypical 259259 94 (58%)94 (58%) 68 (42%)68 (42%) 9797

Not RSNot RS 2121 21 21 (100%)(100%)

00 00

DTCC DatabaseDTCC DatabaseMutationMutation DTCC (%)DTCC (%) North Am (%)North Am (%)T158MT158M 11.311.3 11.911.9

R255XR255X 10.610.6 9.09.0

R168XR168X 8.98.9 9.49.4

R306CR306C 7.97.9 6.86.8

R294XR294X 6.36.3 6.26.2

R270XR270X 5.75.7 7.27.2

R133CR133C 5.05.0 6.46.4

R106WR106W 3.43.4 4.44.4

C-terminal delC-terminal del 9.19.1 8.88.8

Large deletionLarge deletion 8.28.2 6.46.4