study design overview and lessons learned alan percy, md june 23, 2008 rett syndrome clinical trials...
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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