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

Dravet Syndrome Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04442295
• Other study ID #: STK-001-DS-101
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: June 3, 2020
• Est. completion date: April 3, 2024

Study information

• Verified date: April 2024
• Source: Stoke Therapeutics, Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 62
• Est. completion date: April 3, 2024
• Est. primary completion date: December 13, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 18 Years

Eligibility

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.

Related Conditions & MeSH terms

• Dravet Syndrome
• Epilepsies, Myoclonic
• Syndrome

Intervention

Drug:
• STK-001 - Single Ascending Doses
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 ).
• STK-001 - Multiple Ascending Doses
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 ).

Locations

Country	Name	City	State
United States	University of Michigan - Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Massachusetts General Hospital - Pediatric Epilepsy Program	Boston	Massachusetts
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cook Children's Health Care System	Fort Worth	Texas
United States	University of Iowa Hospitals and Clinics; Pediatric Specialty Clinic	Iowa City	Iowa
United States	Le Bonheur Children's Hospital	Memphis	Tennessee
United States	Nicklaus Children's Hospital	Miami	Florida
United States	NYU Comprehensive Epilepsy Center	New York	New York
United States	AdventHealth Orlando	Orlando	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	UCSF Benioff Children's Hospital	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Multicare Institute for Research and Innovation	Tacoma	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Stoke Therapeutics, Inc

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Pharmacokinetic (PK) Parameters	Analysis of plasma concentrations of STK-001	Day 1 (Dosing) until 6 months after single and multiple drug dosing
Primary	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	Measurement of seizure frequency	Measured by paper diary	Screening (Day -28) until 6 months after single and multiple drug dosing
Secondary	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
Secondary	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
Secondary	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