A Double-blind Study Evaluating the Efficacy, Safety, and Tolerability of Zorevunersen in Patients With Dravet Syndrome

EMPEROR: A Multicenter, Randomized, Double-blind, Sham-controlled, Parallel Group, Phase 3 Study Evaluating the Efficacy, Safety, and Tolerability of Zorevunersen (STK-001) in Patients With Dravet Syndrome

The purpose of the study is to evaluate the efficacy, safety, and tolerability of zorevunersen in Patients with Dravet syndrome.

Study Overview

• Status: Recruiting
• Conditions: Dravet Syndrome
• Intervention / Treatment: Drug: zorevunersen; Other: Sham Comparator

Detailed Description

Zorevunersen is an investigational new medicine for the treatment of Dravet syndrome. It 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).

Zorevunersen 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.

This is a global, multicenter, randomized, double-blind, sham-controlled, parallel group Phase 3 study to assess the efficacy, safety, and tolerability of zorevunersen in patients with Dravet syndrome. The study duration and endpoints are designed to evaluate the potential of zorevunersen for disease modification. The study consists of two parts, Treatment Period 1 and Treatment Period 2. The primary and secondary endpoints will be assessed at the conclusion of Treatment Period 1. These endpoints will be assessed again at the end of Treatment Period 2. The primary endpoint is the change from baseline in major motor seizure frequency. Secondary endpoints include the change in behavior and cognition, clinical status, and health-related quality of life in patients with Dravet syndrome.

Patients will have the opportunity to enroll in an open label extension study and receive zorevunersen if they meet eligibility criteria at the end of the study.

• Study Type: Interventional
• Enrollment (Estimated): 170
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Emperor Information Center; Phone Number: 1-781-430-8200; Email: info@emperorstudy.com

Study Locations

• China
  • Beijing, China
    • Recruiting
    • Peking University First Hospital
    • Contact: Study Coordinator
  • Guangzhou, China
    • Recruiting
    • The Second Affiliated Hospital of Guangzhou Medical University
    • Contact: Study Coordinator
  • Wuhan, China
    • Recruiting
    • Wuhan Children's Hospital
    • Contact: Study Coordinator
• France
  • Marseille, France
    • Active, not recruiting
    • Hopital De La Timone
  • Paris, France
    • Active, not recruiting
    • Hôpital Necker - Enfants Malades
  • Paris, France
    • Active, not recruiting
    • Hôpital Robert Debré - Paris
• Germany
  • Berlin, Germany
    • Active, not recruiting
    • Charité - Campus Virchow-Klinikum
  • Bonn, Germany
    • Active, not recruiting
    • Universitaetsklinikum Bonn AoeR
  • Frankfurt, Germany
    • Active, not recruiting
    • Universitaetsklinikum Frankfurt Goethe-Universitaet
  • Friedberg, Germany
    • Active, not recruiting
    • Universitaetsklinikum Freiburg
  • Heidelberg, Germany
    • Active, not recruiting
    • Universitaetsklinikum Heidelberg
  • München, Germany
    • Active, not recruiting
    • Integriertes Sozialpaediatrisches Zentrum
• Italy
  • Florence, Italy
    • Active, not recruiting
    • Azienda Ospedaliero Universitaria Ospedale Pediatrico Meyer
  • Genova, Italy
    • Active, not recruiting
    • Istituto Giannina Gaslini-Ospedale Pediatrico IRCCS
  • Roma, Italy
    • Active, not recruiting
    • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
  • Roma, Italy
    • Active, not recruiting
    • Ospedale Pediatrico Bambino Gesu
• Japan
  • Fukuoka, Japan
    • Active, not recruiting
    • Fukuoka Children's Hospital
  • Hokkaido, Japan
    • Active, not recruiting
    • Hokkaido University Hospital
  • Kyoto, Japan
    • Active, not recruiting
    • Kyoto University Hospital
  • Nagoya, Japan
    • Active, not recruiting
    • Nagoya University Hospital
  • Niigata, Japan
    • Active, not recruiting
    • National Hospital Organization Nishi Niigata Central Hospital
  • Okayama, Japan
    • Active, not recruiting
    • Okayama University Hospital
  • Osaka, Japan
    • Active, not recruiting
    • Osaka City General Hospital
  • Shimotsuke, Japan
    • Active, not recruiting
    • Jichi Medical University Hospital
  • Shizuoka, Japan
    • Active, not recruiting
    • NHO Shizuoka
  • Tokyo, Japan
    • Active, not recruiting
    • National Center of Neurology and Psychiatry
  • Yokohama, Japan
    • Active, not recruiting
    • Yokohama City University Medical Center
• Spain
  • Madrid, Spain
    • Active, not recruiting
    • Hospital Blua Sanitas Valdebebas
  • Madrid, Spain
    • Active, not recruiting
    • Hospital Ruber Internacional
  • Pamplona, Spain
    • Active, not recruiting
    • Clinica Universidad de Navarra
• United Kingdom
  • Glasgow, United Kingdom, G51 4TF
    • Active, not recruiting
    • Royal Hospital for Children
  • London, United Kingdom, WC1N 3JH
    • Active, not recruiting
    • Great Ormond Street Hospital for Children
  • Sheffield, United Kingdom, S10 2TH
    • Active, not recruiting
    • Sheffield Children's Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Active, not recruiting
      • Phoenix Children's Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Active, not recruiting
      • Arkansas Children's Hospital
  • California
    • Los Angeles, California, United States, 90048
      • Active, not recruiting
      • Cedars Sinai Medical Center
    • Orange, California, United States, 92868
      • Active, not recruiting
      • Children's Hospital of Orange County
    • San Francisco, California, United States, 94158
      • Active, not recruiting
      • USCF Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Active, not recruiting
      • Children's Hospital Colorado
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Active, not recruiting
      • Children's National Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Active, not recruiting
      • Nemours Children's Health
    • Miami, Florida, United States, 33155
      • Active, not recruiting
      • Nicklaus Children's Hospital
    • Orlando, Florida, United States, 32804
      • Active, not recruiting
      • Advent Health Neuroscience Research Institute
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Active, not recruiting
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Active, not recruiting
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Active, not recruiting
      • Boston Children's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Active, not recruiting
      • CS Mott Children's Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Active, not recruiting
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10016
      • Active, not recruiting
      • NYU Langone Health
    • New York, New York, United States, 10021
      • Active, not recruiting
      • Weill Cornell Medicine
    • Rochester, New York, United States, 14642
      • Active, not recruiting
      • University of Rochester Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • Active, not recruiting
      • University of North Carolina at Chapel Hill
    • Durham, North Carolina, United States, 27705
      • Active, not recruiting
      • Duke University Health System
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Active, not recruiting
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43205
      • Active, not recruiting
      • Nationwide Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Active, not recruiting
      • Oregon Health & Science University (OHSU)
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • Active, not recruiting
      • LeBonheur Children's Hospital
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Active, not recruiting
      • Cook Children's Medical Center
    • Houston, Texas, United States, 77030
      • Active, not recruiting
      • Texas Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Active, not recruiting
      • University of Utah Primary Children's Hospital
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • Active, not recruiting
      • UVA Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Patients must be ≥2 and <18 years of age.

2. Patients must have a clinical diagnosis of DS confirmed by the Epilepsy Study Consortium, Inc. (ESCI) and as defined by:

   Onset, prior to 12 months (inclusive, <13 months), of age, of recurrent focal with motor signs, hemiclonic, or generalized tonic-clonic seizures. No other known etiology causing clinical DS manifestations..

3. Patient must have a documented pathogenic, likely pathogenic variant, or variant of uncertain significance in the sodium voltage-gated channel type 1 alpha subunit (SCN1A) gene. Patients who have SCN1A testing results of Negative (no variants identified) cannot be randomized.
4. Patient must experience the required number of major motor seizures during the 6-week Observation Period. Major motor seizure types included are Seizure types included in counts are Hemiclonic, Focal with Motor Signs, Focal to Bilateral Tonic-Clonic, Generalized Tonic-Clonic, Tonic, Tonic/Atonic (Drop Attacks with fall or risk of fall), and Bilateral Clonic.
5. Patient must have used at least 2 prior interventions for seizures. These can include anti-seizure medications (ASMs), ketogenic diet and/or vagus nerve stimulation (VNS) with either lack of adequate seizure control or discontinued due to an AE(s). These interventions can be ongoing therapies.
6. Patient must be taking at least one ASM. Benzodiazepines or ASMs used on a standing basis (i.e., not as needed [PRN]) for any indication will be considered an ASM.
7. Patients' maintenance ASMs and interventions for seizures (i.e., ketogenic diet or VNS), as well as any marijuana- or cannabinoid-based products, must have been stable (unless adjusted for weight) during the Baseline Period.

Key Exclusion Criteria:

1. Patient has documented variant in the SCN1A gene associated with gain-of-function
2. Patient is currently treated with a maintenance ASM acting primarily as a sodium channel blocker, including but not limited to phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide, rufinamide, or cenobamate, given the mechanism of action of zorevunersen.
3. Patient is currently treated with neuromodulation techniques (e.g., responsive neurostimulation, deep brain stimulation, or transcranial magnetic stimulation), with the exception of VNS.
4. Patient has emergence of a new seizure type or reemergence of a past seizure type (seizure types that last occurred more than 12 months before Screening Visit A) during the Baseline Period, or has more than 1 hospitalization for seizures during the Baseline Period.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Sham Comparator; Eligible patients will be randomly assigned in a 1:1 ratio to zorevunersen:sham	Other: Sham Comparator; Treatment Period 1: Sham group will not have drug administered. Sham group will have a procedure intended to mimic the drug administration. Treatment Period 2: Group assigned to sham in Treatment Period 1 will receive 70 mg of zorevunersen on Day 393 (Week 56) and on Day 477 (Week 68), and 45 mg of zorevunersen Day 589 (Week 84).
Experimental: Zorevunersen; Eligible patients will be randomly assigned in a 1:1 ratio to zorevunersen:sham in Treatment Period 1 (approximately 52 weeks). Upon the completion of Treatment Period 1 all eligible patients, will enter Treatment Period 2 and receive zorevunersen, regardless of initial treatment assignment.	Drug: zorevunersen; Treatment Period 1: Zorevunersen group will receive study drug by intrathecal (IT) administration on Day 1 (after the 8-week Baseline Period), Day 57 (Week 8), Day 169 (Week 24), and Day 281 (Week 40) at a dose level of 70 mg on Day 1 and Day 57, and 45 mg on Day 169 and Day 281. Treatment Period 2: Group assigned to zorevunersen in Treatment Period 1 will receive 45 mg of zorevunersen on Day 393 (Week 56), Day 477 (Week 68), and Day 589 (Week 84).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of Seizure Change	Measured by daily seizure diary	Week 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of Seizure Change	Measured by daily seizure diary	Week 52
Multi-component Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) Outcome Score	Measurement of change from baseline for multi-component score. Scoring is non-parametric and based on rank between treatment and sham groups. Individual items are scored on a scale of 0, 1, or 2, indicating never, sometimes, or usually or often, or on a scale of 0 or 2, indicating no or yes, with higher scores indicating greater performance	Week 52
Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) Subdomain Score	Measurement of change from baseline for individual subdomains. Scoring is point-based on a scale that varies, depending on subdomain, Individual items are scored on a scale of 0, 1, or 2, indicating never, sometimes, or usually or often, or on a scale of 0 or 2, indicating no or yes, with higher scores indicating greater performance.	Week 52

Collaborators and Investigators

• Sponsor: Stoke Therapeutics, Inc

Study record dates

Study Major Dates

• Study Start (Actual): June 4, 2025
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: March 6, 2025
• First Submitted That Met QC Criteria: March 6, 2025
• First Posted (Actual): March 12, 2025

Study Record Updates

• Last Update Posted (Actual): August 24, 2026
• Last Update Submitted That Met QC Criteria: August 20, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Pediatric epilepsy; Epileptic Encephalopathies; Refractory Myoclonic Epilepsy; Severe Myoclonic Epilepsy in Infancy; STK-001
• Additional Relevant MeSH Terms: Epileptic Syndromes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy, Generalized; Epilepsy; Epilepsies, Myoclonic
• Other Study ID Numbers: STK-001-DS-301; 2024-519555-28 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No