Clinical trial NCT04442295: An Open-Label Study to Investigate the Safety of Single and Multiple Ascending Doses in Children and Adolescents With Dravet Syndrome
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Dravet Syndrome
Keywords: Pediatric epilepsy
Epileptic Encephalopathies
Refractory Myoclonic Epilepsy
Severe Myoclonic Epilepsy in Infancy
Lead sponsor: Stoke Therapeutics, Inc
Sponsor class: INDUSTRY
First posted: 2020-06-22
Enrollment: 62
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Safety and Tolerability of single and multiple doses of STK-001 with respect to:
timeFrame: Screening (Day -28) until 6 months after single and multiple drug dosing
measure: Pharmacokinetic (PK) Parameters
timeFrame: Day 1 (Dosing) until 6 months after single and multiple drug dosing
measure: Exposure of STK-001 in Cerebrospinal Fluid (CSF)
timeFrame: Day 1 (Dosing) until 6 months after single and multiple drug dosing
Secondary outcomes:
measure: Measurement of seizure frequency
timeFrame: Screening (Day -28) until 6 months after single and multiple drug dosing
measure: Change in Caregiver Global Impression of Change Scale
timeFrame: Baseline (Day -1) until 6 months after single and multiple drug dosing
measure: Change in Clinician-assessed Global Impression of Change Scale
timeFrame: Baseline (Day -1) until 6 months after single and multiple drug dosing
measure: Measurement of Quality of Life
timeFrame: Baseline (Day -1) until 6 months after single and multiple drug dosing
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Benioff Children's Hospital
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Miami
country: United States
facility: Nicklaus Children's Hospital
state: Florida
city: Orlando
country: United States
facility: AdventHealth Orlando
state: Florida
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics; Pediatric Specialty Clinic
state: Iowa
city: Boston
country: United States
facility: Massachusetts General Hospital - Pediatric Epilepsy Program
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan - Mott Children's Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: NYU Comprehensive Epilepsy Center
state: New York
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: Le Bonheur Children's Hospital
state: Tennessee
city: Fort Worth
country: United States
facility: Cook Children's Health Care System
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Tacoma
country: United States
facility: Multicare Institute for Research and Innovation
state: Washington
Study officials:
affiliation: Medical Director
name: Ann Dandurand, MD
role: STUDY_DIRECTOR
References: