An Open-Label Study to Investigate the Safety of Single and Multiple Ascending Doses in Children and Adolescents With Dravet Syndrome

Study Overview
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Brief Summary
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Stoke Therapeutics is evaluating the safety and tolerability of single and multiple ascending doses of STK-001 in patients with Dravet syndrome. Change in seizure frequency, overall clinical status, and quality of life will be measured as secondary endpoints in this open-label study.

Detailed Description
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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
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An Open-Label Study to Investigate the Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Antisense Oligonucleotide STK-001 in Children and Adolescents With Dravet Syndrome

Conditions
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Dravet Syndrome

Intervention / Treatment
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* Drug: STK-001 - Single Ascending Doses
* Drug: STK-001 - Multiple Ascending Doses


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Dravet Syndrome (DS) with onset of recurrent focal motor or hemiconvulsive or generalized tonic-clonic seizures prior to 12 months of age, which are often prolonged and triggered by hyperthermia. No history of causal MRI lesion No other known etiology Normal development at seizure onset. Documented pathogenic, likely pathogenic variant, or variant of uncertain significance in the SCN1A gene associated with DS. Use of at least 2 prior treatments for epilepsy that either had lack of adequate seizure control (requiring an additional AED) or had to be discontinued due to an AE(s). Currently taking at least one AED at a dose which has been stable for at least 4 weeks prior to Screening. Stable epilepsy medications or interventions for epilepsy (including ketogenic diet or vagal nerve stimulator) for at least 4 weeks prior to Screening. Exclusion Criteria: Known pathogenic mutation in another gene that causes epilepsy Currently treated with an AED acting primarily as a sodium channel blocker, as maintenance treatment, 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 4 weeks prior to Screening or prior to dosing on Day 1, other than epilepsy. History of brain or spinal cord disease (other than epilepsy or DS), or history of bacterial meningitis or brain malformation Spinal deformity or other condition that may alter the free flow of cerebrospinal fluid (CSF) or has an implanted CSF drainage shunt. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, may influence the results of the study, or may affect the patient's ability to participate in the study.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Ascending Doses<br>Enrollment of patients in two age groups. A Sentinel group of 2 patients aged 13 to 18 years of age, inclusive, and an expanded group of 2 patients 2 to 12 years of age to receive single doses. There will be an option to dose up to 6 additional patients at each dose level and an option to expand the maximum tolerated dose level with 5 additional patients. | Drug: STK-001 - Single Ascending Doses<br>* Experimental : Single Ascending Doses - STK-001 drug product is an antisense oligonucleotide administered as an intrathecal injection. Four dose levels will be evaluated ( 10mg, 20mg,30mg, 45mg and 70mg ).<br>|
| Experimental: Multiple Ascending Doses<br>Enrollment of patients in two age groups. A Sentinel group of 2 patients aged 13 to 18 years of age, inclusive, and an expanded group of 2 patients 2 to 12 years of age to receive multiple doses. There will be an option to dose up to 6 additional patients at each dose level and an option to expand the maximum tolerated dose level with 10 additional patients. | Drug: STK-001 - Multiple Ascending Doses<br>* Experimental : Multiple Ascending Doses - STK-001 drug product is an antisense oligonucleotide administered as an intrathecal injection. Three dose levels will be evaluated ( 20mg,30mg and 45mg ).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of single and multiple doses of STK-001 with respect to: | Incidence of adverse events incidence of abnormal vital signs Abnormal physical examination findings Abnormal 12-lead electrocardiogram (ECG) Abnormal laboratory parameters | Screening (Day -28) until 6 months after single and multiple drug dosing | 
| Pharmacokinetic (PK) Parameters | Analysis of plasma concentrations of STK-001 | Day 1 (Dosing) until 6 months after single and multiple drug dosing | 
| Exposure of STK-001 in Cerebrospinal Fluid (CSF) | Measurement of STK-001 concentrations | Day 1 (Dosing) until 6 months after single and multiple drug dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of seizure frequency | Measured by paper diary | Screening (Day -28) until 6 months after single and multiple drug dosing | 
| Change in Caregiver Global Impression of Change Scale | Change from baseline in overall clinical status as measured by the Clinical Global Impression of Change (CGIC). Values of scales: Very much improved Much improved Minimally improved No change Minimally worse Much worse Very much worse | Baseline (Day -1) until 6 months after single and multiple drug dosing | 
| Change in Clinician-assessed Global Impression of Change Scale | Change from baseline in overall clinical status as measured by the Caregiver Global Impression of Change (CaGIC) Values of scales: Very much improved Much improved Minimally improved No change Minimally worse Much worse Very much worse | Baseline (Day -1) until 6 months after single and multiple drug dosing | 
| Measurement of Quality of Life | Change in quality of life as measured by the EuroQoL-five dimensions, youth version (EQ-5D-Y) instrument. The scale is scored from 0-100. The reference to a high score indicates a better outcome of quality of life. | Baseline (Day -1) until 6 months after single and multiple drug dosing | 

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