A Clinical Study to Evaluate the Safety and Efficacy of ETX101 in Infants and Children With SCN1A-Positive Dravet Syndrome

Study Overview
=================
Brief Summary
-----------------
ENDEAVOR is a Phase 1/2, 2-part, multicenter study to evaluate the safety and efficacy of ETX101 in participants with SCN1A-positive Dravet syndrome aged 6 to 36 months. Part 1 follows an open-label, dose-escalation design, and Part 2 is a randomized, double-blind, sham delayed-treatment control, dose-selection study.

Official Title
-----------------
ENDEAVOR: A Clinical Study to Evaluate the Safety and Efficacy of ETX101, an AAV9-Delivered Gene Therapy in Infants and Children With SCN1A-Positive Dravet Syndrome

Conditions
-----------------
Dravet Syndrome

Intervention / Treatment
-----------------
* Drug: ETX101


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant must have a predicted loss of function pathogenic or likely pathogenic SCN1A variant. Participant must have experienced their first convulsive seizure between the ages of 3 and 15 months. Participant must have a clinical diagnosis of Dravet syndrome or the treating clinician must have a high clinical suspicion of a diagnosis of Dravet syndrome. Participant is receiving at least one prophylactic antiseizure medication. Exclusion Criteria: Participant has another genetic mutation or clinical comorbidity which could potentially confound the typical Dravet phenotype. Participant has a known central nervous system structural and/or vascular abnormality (indicated by an MRI or CT scan of the brain). Participant has an abnormality that may interfere with CSF distribution and/or has an existing ventriculoperitoneal shunt. Participant is currently taking or has taken antiseizure medications (ASMs) at a therapeutic dose that are contraindicated in Dravet syndrome, including sodium channel blockers. Participant has experienced seizure freedom for a period of 4 consecutive weeks within the 90-day period prior to informed consent. Participant has previously received gene or cell therapy. Participant is currently enrolled in a clinical trial or receiving an investigational therapy, including under an expanded access and/or compassionate use program. Participant has clinically significant underlying liver disease.

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 36 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1<br>Part 1 will follow an open-label, rule-based, dose-escalation design and will initially evaluate 2 dose levels of ETX101 in participants. | Drug: ETX101<br>* ETX101 is a non-replicating, recombinant adeno-associated viral vector serotype 9 (rAAV9) comprising a GABAergic regulatory element (reGABA) and an engineered transcription factor that increases transcription of the SCN1A gene (eTFSCN1A). ETX101 is intended as a one-time intracerebroventricular (ICV) administration.<br>|
| Sham Comparator: Part 2<br>Part 2 is a dose-selection study, which will follow a double-blind (up through Week 16), randomized, sham delayed-treatment control design There will be up to 3 cohorts in Part 2. Participants will be randomized 1:1:1 to study treatment (ie, Dose Level 1 or Dose Level 2) or sham procedure with delayed treatment. At the conclusion of Part 1, if the recommendation is made to proceed with a single dose level of ETX101 in Part 2, participants will be randomized 1:1 to study treatment or sham procedure with delayed treatment. | Drug: ETX101<br>* ETX101 is a non-replicating, recombinant adeno-associated viral vector serotype 9 (rAAV9) comprising a GABAergic regulatory element (reGABA) and an engineered transcription factor that increases transcription of the SCN1A gene (eTFSCN1A). ETX101 is intended as a one-time intracerebroventricular (ICV) administration.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportions of participants experiencing any treatment-emergent adverse events (AEs), serious adverse events (SAEs), related AEs, AEs with severity Grade ≥ 3, AEs resulting in study discontinuation, and AEs with a fatal outcome. |  | Day 1 through Week 52 | 
| Percent change in monthly countable seizure frequency (MCSF) period, with countable seizures defined as generalized tonic-clonic/clonic, focal motor with clearly observable clinical signs, tonic, or atonic seizures. |  | Between the 8-week baseline period (prior to Day 1) and the First Assessment Period (which is the 12-week between Week 5 and Week 16) | 
| Proportion of participants free from episodes of prolonged seizures and/or status epilepticus. |  | Day 1 through Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with ≥ 90% reduction in monthly countable seizure frequency (MCSF). |  | Between the 8-week baseline period (prior to Day 1) and the First Assessment Period (which is the 12-week period between Week 5 and Week 16). | 
| Absolute change in the raw score of the Bayley-III receptive language sub-domain. Domain raw scores range from 0 to 49 and higher scores correspond to better outcomes compared to a normal population. |  | Baseline through Week 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Dravet, SCN1A, DEE, developmental and epileptic encephalopathy, Dravet Syndrome, SCN1A-positive, SCN1A+