An Open-Label Extension Study of STK-001 for Patients With Dravet Syndrome

Study Overview
=================
Brief Summary
-----------------
Stoke Therapeutics is evaluating the long-term safety & tolerability of repeated doses of STK-001 in patients with Dravet syndrome who previously participated in studies of STK-001. Change in seizure frequency and overall clinical status, and quality of life will be measured as secondary endpoints in this open-label study.

Detailed Description
-----------------
This study is a multi-center, open-label, multiple-dose, safety extension study for patients who have completed another study of STK-001 and meet study eligibility criteria. STK-001 is an investigational new medicine for the treatment of Dravet syndrome. STK-001 is an antisense oligonucleotide (ASO) that is intended to increase the level of productive SCN1A messenger RNA (mRNA) and consequently increase the expression of the sodium channel Nav1.1 protein. This RNA-based approach is not gene therapy, but rather RNA modulation, as it does not manipulate nor insert genetic deoxyribonucleic acid (DNA). STK-001 is designed to upregulate Nav1.1 protein expression from the nonmutant (wild-type) copy of the SCN1A gene to restore physiological Nav1.1 levels. Nav1.1 levels are reduced in people with Dravet syndrome. Stoke has generated preclinical data demonstrating proof-of-mechanism for STK-001.

Official Title
-----------------
An Open-Label Extension Study for Patients With Dravet Syndrome Who Previously Participated in Studies of STK-001

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

Intervention / Treatment
-----------------
* Drug: STK-001


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Completed dosing with STK-001 and the End of Study Visit in Study STK-001-DS-101, with an acceptable safety profile per Investigator judgment. Had satisfactory compliance with study visits and procedures in Study STK-001-DS-101 per Investigator and Sponsor judgment. Completed Study STK-001-DS-101 within 4 weeks of the start of their participation in Study STK-001-DS-501 unless approved by sponsor. Exclusion Criteria: Met any withdrawal criteria from Study STK-001-DS-101. Currently treated with an antiepileptic drug (AED) acting primarily as a sodium channel blocker, as maintenance therapy, including phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide, or rufinamide. Clinically significant unstable medical conditions other than epilepsy. Clinically relevant symptoms or a clinically significant illness (in the judgment of the Investigator) at Screening or prior to dosing on Day 1, other than epilepsy. Spinal deformity or other condition that may alter the free flow of CSF or has an implanted CSF drainage shunt. Treated (or is being treated) with an investigational product (other than STK-001) since participating in Study STK-001-DS-101. Participating in an observational study, they are excluded unless approved by the Sponsor.

Ages Eligible for Study
-----------------
Minimum Age: 30 Months

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

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

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

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: STK-001 multiple dose levels<br>Enrollment of patients after completion of study STK-001-DS-101 if eligible for additional dosing in this extension study. Patients will receive IT administration of study drug STK-001 at the dose level they received while participating in Study STK-001-DS-101, or at a dose level recommended by the Safety Monitoring Committee (SMC).The highest dose administered in this study may not exceed that which has already been evaluated in an STK-001 Phase 1/2 study, and doses above 30 mg/dose in this study require approval from the Food and Drug Administration (FDA). Patients will initially receive 3 doses, one every approximately 4 months (16 weeks). Patients who are tolerating treatment may continue treatment with doses approximately every 4 months, with an End of Study/Follow-up Visit 24 weeks after the last dose of study drug. Patients who do not continue treatment after the third dose will have a Follow-up Visit (V5) at Week 48 and an End of Study Visit at Week 56. | Drug: STK-001<br>* STK-001 drug product is an antisense oligonucleotide administered as an intrathecal injection.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of multiple doses of STK-001 | Safety variables for analysis include the incidence, type, severity, and seriousness of AEs, and changes in vital signs, ECG, laboratory, immunogenicity, physical examination, and Gillette FAQ parameters. | Screening (Day -1) until 6 months after multiple drug dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) Parameters | Analysis of plasma concentrations of STK-001 | Dosing (Day 1) until 6 months after multiple drug dosing | 
| Exposure of STK-001 in Cerebrospinal Fluid (CSF) | Measurement of STK-001 concentrations | Dosing (Day 1) until Week 32 (last study drug dosing day) | 
| Measurement of Seizure Frequency | Measurement of Seizure Frequency (by paper diary) | Screening (Day -1) until 6 months after multiple drug dosing | 
| Change in overall clinical status | Change in overall clinical status as measured by the Clinical Global Impression of Change (CGIC) and the Caregiver Global Impression of Change (CaGIC) | Screening (Day -1) until 6 months after multiple drug dosing | 
| Change in Quality of Life | Change in quality of life as measured by the EuroQoL-five dimensions, youth version (EQ-5D-Y) instrument | Screening (Day -1) until 6 months after multiple drug dosing | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pediatric epilepsy, Epileptic Encephalopathies, Refractory Myoclonic Epilepsy, Severe Myoclonic Epilepsy in Infancy