1. Walter E. Kaufmann, M.D. Kennedy Krieger Institute/Johns Hopkins University SCALES AS OUTCOME MEASURES CLINICAL TRIALS IN RETT SYNDROME A Mini-Symposium Chicago, June 22-23, 2008

2. CLINICAL TRIALS IN RETT SYNDROME A Mini-Symposium Chicago, June 22-23, 2008 Severity Scales as Outcome Measures: Ideal Features 1.It measures functionally-relevant (to RTT) changes (e.g., hand function). 2.It detects changes in current severity (as opposed to developmental profiles; e.g., onset of loss of hand function). 3.It follows psychometric properties (i.e., appropriate distribution and reliability in RTT and other groups). 4.It is a truly independent variable (e.g., adaptive communication is co-linear to language skills). 5.It correlates with key biomarker(s). RSBQ meets 1,3,4 criteria

3. Current Severity Scales: Issues 1.Most include developmental parameters. 2.Limited psychometric analysis ( e.g., Kerr & Prescott, 2005 ). 3.Parameters tend to be related (e.g., gait abnormality correlates with scoliosis) or belong to different categories (e.g., breathing and gait abnormalities). 4.Limited information about relationship with standardized measures (e.g., WeeFim). 5.Different scales serve different purposes. CLINICAL TRIALS IN RETT SYNDROME A Mini-Symposium Chicago, June 22-23, 2008

4. Issues: Severity Scale Including Developmental Parameter 6-month trial. 10 subjects per arm. Baseline-end of trial comparison. Scale w/6 items: Two items developmental: no change. Two items: unlikely to change in 6 months. Two items: expected to change in 6 months. Only large effects (return to normal in 100% cohort) are significant CLINICAL TRIALS IN RETT SYNDROME A Mini-Symposium Chicago, June 22-23, 2008

5. Issues: Severity Scale Including Developmental Parameter 6-month trial. 10 subjects per arm. Baseline-end of trial comparison. Scale w/5 items: One item developmental: no change. Two items: unlikely to change in 6 months. Two items: expected to change in 6 months. Intermediate effects (return to normal in 50% cohort or some improvement in 100% cohort) are also significant CLINICAL TRIALS IN RETT SYNDROME A Mini-Symposium Chicago, June 22-23, 2008

6. Issues: Standardized Instrument - VABS Of four scales, three (VABS Communication, VABS Socialization, VABS Daily Living Skills are highly correlated (Rsquared/Rho >0.8). If using VABS in RTT Trial, the main three scales represent only one independent outcome measure CLINICAL TRIALS IN RETT SYNDROME A Mini-Symposium Chicago, June 22-23, 2008

7. Application of Behavioral Measures to Clinical Trials in Rett Syndrome 1.Behavioral parameters may be useful primary measures for monitoring general and selective changes in girls and women with RTT. 2.These evaluations could use standardized general behavioral measures, such as the VABS, or RTT- specific instruments, such as the RSBQ. 3.There is a need for better cognitive measures for RTT, in particular relatively hand-independent tests of nonverbal skills. Advances in the study of nonverbal function in autism and novel tools for behavioral and fMRI research could help. CLINICAL TRIALS IN RETT SYNDROME A Mini-Symposium Chicago, June 22-23, 2008