Safety and Efficacy of TSHA-102 in Pediatric Females With Rett Syndrome (REVEAL Pediatric Study)

Study Overview
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Brief Summary
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The REVEAL Pediatric Study is a multi-center, Phase 1/2 open-label, dose-escalation and dose-expansion study of TSHA-102, an investigational gene therapy, in pediatric females with Rett Syndrome. The safety, tolerability, and preliminary efficacy of two dose levels will be evaluated. The study duration is up to 6 years.

Official Title
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A Multicenter, Open Label, Randomized, Dose-Escalation and Dose-Expansion Study of the Safety, Tolerability, and Efficacy of a Single Intrathecal Administration of TSHA-102, an AAV9-Delivered Gene Therapy, for the Treatment of Pediatric Females With Rett Syndrome

Conditions
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Rett Syndrome

Intervention / Treatment
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* Genetic: TSHA-102


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has a confirmed diagnosis of classical/typical Rett Syndrome with a documented mutation of the MECP2 gene that results in loss of function. Participant is between ≥5 to ≤8 years of age at the time of consent. Participant must be up to date with all relevant local vaccination requirements, with last vaccination dose received at least 42 days prior to the start of the immunosuppression regimen. Participant's parent/caregiver must be willing to allow participant to receive blood or blood products for the treatment of an AE if medically needed. Exclusion Criteria: Participant has another neurodevelopmental disorder independent of the MECP2 gene loss of function mutation, or any other genetic syndrome with a progressive course. Participant has a history of brain injury that causes neurological problems. Participant had grossly abnormal psychomotor development in the first 6 months of life. Participant has a diagnosis of atypical Rett syndrome. Participant has an MECP2 mutation that does not cause Rett syndrome. Participant requires non-invasive and invasive ventilatory support. Participant has contraindications for IT administration of TSHA-102 or lumbar puncture procedure, other medical conditions, or contraindications to any medications required for IT administration. Participant has acute or chronic hepatitis B or C infections.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 8 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Dose Level 1 | Genetic: TSHA-102<br>* TSHA-102 is a recombinant, non-replicating, self-complementary AAV9 (scAAV9) vector encoding for the miniMECP2 gene. TSHA-102 is a one-time intrathecal (IT) administration.<br>|
| Experimental: Cohort 2<br>Dose Level 2 | Genetic: TSHA-102<br>* TSHA-102 is a recombinant, non-replicating, self-complementary AAV9 (scAAV9) vector encoding for the miniMECP2 gene. TSHA-102 is a one-time intrathecal (IT) administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Safety | The incidence of participants experiencing any treatment-emergent adverse events (AEs) and serious adverse events (SAEs) | Baseline through week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exploratory Efficacy | Change from baseline in participant's status after TSHA-102 administration as assessed by Clinical Global Impressions Improvement (CGI-I). This 7-point scale (1 = very much improved, 7 = very much worse, etc.) is used by the clinician to assess the participant's overall performance status; higher scores indicate increased severity. | Baseline through week 52 | 
| Exploratory Efficacy | Change from baseline in participant's status after TSHA-102 administration as assessed by Revised Motor Behavior Assessment (R-MBA). This 34-item questionnaire with scores of 0-4 will be administered by a cliniciant to indicate frequency of daily activities (behavioral/social, respiratory, motor/physical, etc.) in participants with Rett Syndrome. Higher scores correlate with greater clinical severity of disease. | Baseline through week 52 | 
| Exploratory Efficacy | Change from baseline in participant's status after TSHA-102 administration as assessed by Rett Syndrome Behavior Questionnaire (RSBQ). The RSBQ is a 45-item questionnaire and is completed by the participant's Caregiver. Scores (0 = not true, 1 = somewhat/sometimes true, or 2 = very true) are applied to subscales including General Mood, Breathing Problems, Fear/Anxiety, Walking/Standing, etc.; higher scores indicate greater severity. | Baseline through week 52 | 
| Exploratory Efficacy | Change from baseline in participant's status after TSHA-102 administration as assessed by Clinical Global Impressions-Severity (CGI-S). This 7-point scale (1 = normal - not I'll all all, 7 = extremely ill, etc.) will be administered by a clinician, based on their experience with patients with the same diagnosis. A higher score indicates greater severity of illness. | Baseline through week 52 | 
| Exploratory Efficacy | Change from baseline in quantitative EEG findings with auditory evoked potential and visual evoked potentials (AEP and VEP). This testing will provide a measure of the electrophysiologic responses of the brain to visual and auditory stimuli. | Baseline through week 52 | 
| Exploratory Efficacy | The percent change from the steroid-free baseline period in monthly countable seizure frequency (MCSF). This testing will provide a measure of participants with seizure freedom following administration of TSHA-102. | Baseline through week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rett Syndrome, Neurodevelopmental Disorder, MECP2