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

Phase 1

Completed

• Conditions: Dravet Syndrome
• Interventions: Drug: STK-001 - Multiple Ascending Doses; Drug: STK-001 - Single Ascending Doses

• Registration Number: NCT04442295
• Lead Sponsor: Stoke Therapeutics, Inc

Brief Summary

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

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.

Study Timeline

• Study Start: 2020-06-03
• Study First Submitted: 2020-06-08
• Study First Submitted QC: 2020-06-19
• Study First Posted: 2020-06-22
• Primary Completion: 2023-12-13
• Study Completion: 2024-04-03
• Status Verified: 2024-10
• Disposition First Submitted: 2024-10-22
• Last Update Submitted: 2024-10-22
• Disposition First Posted: 2024-10-23
• Last Update Posted: 2024-10-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 62

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Multiple Ascending Doses	STK-001 - Multiple Ascending Doses	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.
Single Ascending Doses	STK-001 - Single Ascending Doses	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.

Primary Outcome Measures

Name	Time	Method
Safety and Tolerability of single and multiple doses of STK-001 with respect to:	Screening (Day -28) until 6 months after single and multiple drug dosing	1. Incidence of adverse events; 2. incidence of abnormal vital signs; 3. Abnormal physical examination findings; 4. Abnormal 12-lead electrocardiogram (ECG); 5. Abnormal laboratory parameters
Pharmacokinetic (PK) Parameters	Day 1 (Dosing) until 6 months after single and multiple drug dosing	Analysis of plasma concentrations of STK-001
Exposure of STK-001 in Cerebrospinal Fluid (CSF)	Day 1 (Dosing) until 6 months after single and multiple drug dosing	Measurement of STK-001 concentrations

Secondary Outcome Measures

Name	Time	Method
Measurement of seizure frequency	Screening (Day -28) until 6 months after single and multiple drug dosing	Measured by paper diary
Change in Caregiver Global Impression of Change Scale	Baseline (Day -1) until 6 months after single and multiple drug dosing	Change from baseline in overall clinical status as measured by the Clinical Global Impression of Change (CGIC).; Values of scales: 1. Very much improved; 2. Much improved; 3. Minimally improved; 4. No change; 5. Minimally worse; 6. Much worse; 7. Very much worse
Change in Clinician-assessed Global Impression of Change Scale	Baseline (Day -1) until 6 months after single and multiple drug dosing	Change from baseline in overall clinical status as measured by the Caregiver Global Impression of Change (CaGIC); Values of scales: 1. Very much improved; 2. Much improved; 3. Minimally improved; 4. No change; 5. Minimally worse; 6. Much worse; 7. Very much worse
Measurement of Quality of Life	Baseline (Day -1) until 6 months after single and multiple drug dosing	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.

Trial Locations

Locations (18)

UCSF Benioff Children's Hospital; 🇺🇸 San Francisco, California, United States

Primary Children's Hospital; 🇺🇸 Salt Lake City, Utah, United States

Seattle Children's Hospital; 🇺🇸 Seattle, Washington, United States

Nicklaus Children's Hospital; 🇺🇸 Miami, Florida, United States

Oregon Health & Science University; 🇺🇸 Portland, Oregon, United States

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States

University of Iowa Hospitals and Clinics; Pediatric Specialty Clinic; 🇺🇸 Iowa City, Iowa, United States

AdventHealth Orlando; 🇺🇸 Orlando, Florida, United States

NYU Comprehensive Epilepsy Center; 🇺🇸 New York, New York, United States

University of Michigan - Mott Children's Hospital; 🇺🇸 Ann Arbor, Michigan, United States

Le Bonheur Children's Hospital; 🇺🇸 Memphis, Tennessee, United States

Multicare Institute for Research and Innovation; 🇺🇸 Tacoma, Washington, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Ann & Robert H. Lurie Children's Hospital of Chicago; 🇺🇸 Chicago, Illinois, United States

Children's National Medical Center; 🇺🇸 Washington, District of Columbia, United States

Massachusetts General Hospital - Pediatric Epilepsy Program; 🇺🇸 Boston, Massachusetts, United States

Cook Children's Health Care System; 🇺🇸 Fort Worth, Texas, United States