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

Sponsor

Stoke Therapeutics, Inc (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04442295

Collaborator

(none)

Enrollment

Locations

Arms

Anticipated Duration (Months)

4.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Dravet Syndrome	Drug: STK-001 - Single Ascending Doses Drug: STK-001 - Multiple Ascending Doses	Phase 1/Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

78 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jun 3, 2020

Anticipated Primary Completion Date :

Sep 22, 2024

Anticipated Study Completion Date :

May 4, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	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 and 45mg ).
Experimental: 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.	Drug: 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 ).

Arm

Intervention/Treatment

Experimental: 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.

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 and 45mg ).

Experimental: 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.

Drug: 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 ).

Outcome Measures

Primary Outcome Measures

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]
Incidence of adverse events incidence of abnormal vital signs Abnormal physical examination findings Abnormal 12-lead electrocardiogram (ECG) 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

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: Very much improved Much improved Minimally improved No change Minimally worse Much worse 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: Very much improved Much improved Minimally improved No change Minimally worse Much worse 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Benioff Children's Hospital	San Francisco	California	United States	94158
2	Children's Hospital Colorado	Aurora	Colorado	United States	80045
3	Children's National Medical Center	Washington	District of Columbia	United States	20010
4	Nicklaus Children's Hospital	Miami	Florida	United States	33155
5	AdventHealth Orlando	Orlando	Florida	United States	32803
6	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
7	University of Iowa Hospitals and Clinics; Pediatric Specialty Clinic	Iowa City	Iowa	United States	52242
8	Massachusetts General Hospital - Pediatric Epilepsy Program	Boston	Massachusetts	United States	02114
9	University of Michigan - Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
10	Mayo Clinic	Rochester	Minnesota	United States	55905
11	NYU Comprehensive Epilepsy Center	New York	New York	United States	10016
12	Oregon Health & Science University	Portland	Oregon	United States	97239
13	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
14	Le Bonheur Children's Hospital	Memphis	Tennessee	United States	38105
15	Cook Children's Health Care System	Fort Worth	Texas	United States	76104
16	Primary Children's Hospital	Salt Lake City	Utah	United States	84108
17	Seattle Children's Hospital	Seattle	Washington	United States	98105
18	Multicare Institute for Research and Innovation	Tacoma	Washington	United States	98405