1. Study Design Overview and lessons learned Alan Percy, MD JUNE 23, 2008 RETT SYNDROME CLINICAL TRIALS MINI-SYMPOSIUM

2. Types of Trials Specific features Specific features anxiety, breathing, stereotypies anxiety, breathing, stereotypies Specific systems Specific systems neuroendocrine, neurotransmitters, cognition, communication neuroendocrine, neurotransmitters, cognition, communication Direct targeting of MECP2 Direct targeting of MECP2 Read-through agents, modulate XCI, gene replacement Read-through agents, modulate XCI, gene replacement

3. Study Design Open label Open label Double-blind, placebo controlled Double-blind, placebo controlled Double-blind, placebo controlled crossover Double-blind, placebo controlled crossover N of one N of one

4. Stratification Strategies Age Age Mutation – caution on exclusivity Mutation – caution on exclusivity Clinical severity index Clinical severity index Combined strategy Combined strategy

8. Lessons Learned Overall: Lack of quantitative behavioral outcome measure Overall: Lack of quantitative behavioral outcome measure Before MECP2 Before MECP2 naltrexone trial: failed to consider age in randomization scheme resulting in imbalance by age between treatment groups naltrexone trial: failed to consider age in randomization scheme resulting in imbalance by age between treatment groups Post-MECP2 Post-MECP2 folate-betaine trial: age stratified (  and  5); failed to balance mutations between drug and placebo groups folate-betaine trial: age stratified (  and  5); failed to balance mutations between drug and placebo groups

9. Outcome Measures Common dataset formats Common dataset formats Common clinical severity index Common clinical severity index Objective measure develoment Objective measure develoment behavior behavior cognition cognition communication communication

10. Scope of Trial Single institution Single institution Inter-institutional Inter-institutional Intercontinental (transgalactic) Intercontinental (transgalactic)

11. Existing Resources Patient advocacy groups Patient advocacy groups InterRett, RettBase, and RettSearch InterRett, RettBase, and RettSearch North American database North American database Rare Disease database Rare Disease database European databases European databases

12. North American Database Total enrolled 1928 Tested Tested 1165 (60%) Not tested Not tested 763 (40%) MECP2 Not known 869 (45%) Tested, Known Tested, Known 1059 (91%) Tested, Not known Tested, Not known 106 (9%) Tested, Mutation 914 (86%) Tested, No mutation 145 (14%)

13. North American Database GroupTotalMutation No mutation Unknown Typical1648 791 (91%) 79 (9%) 778 Atypical259 94 (58%) 68 (42%) 97 Not RS 21 21 (100%) 00

14. DTCC Database Mutation DTCC (%) North Am (%) T158M11.311.9 R255X10.69.0 R168X8.99.4 R306C7.96.8 R294X6.36.2 R270X5.77.2 R133C5.06.4 R106W3.44.4 C-terminal del 9.18.8 Large deletion 8.26.4

15. Figure 1 RETT SYNDROME – SURVIVAL BY DATE OF BIRTH