A Study of Soticlestat as an Add-on Therapy in Children and Young Adults With Dravet Syndrome

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy, Safety, and Tolerability of Soticlestat as Adjunctive Therapy in Pediatric and Young Adult Subjects With Dravet Syndrome (DS)

The main aim of the study is to learn if soticlestat, when given as an add-on therapy, reduces the number of convulsive seizures in children and young adults with DS.

Participants will receive their standard antiseizure therapy, plus either a tablet of soticlestat or placebo for 16 weeks. A placebo looks just like soticlestat but will not have any medicine in it.

Participants may continue treatment in an extension study, based on the extension study's entry criteria. Those that want to stop treatment will have a gradual dose reduction during 1 week and then be followed up for 2 weeks.

Study Overview

• Status: Completed
• Conditions: Dravet Syndrome (DS)
• Intervention / Treatment: Drug: Soticlestat; Drug: Placebo

Detailed Description

The drug being tested in this study is called soticlestat (TAK-935). Soticlestat as an adjunctive therapy will be assessed for efficacy, safety, and tolerability in pediatric and adult participants with DS.

The study will enroll approximately 142 pediatric and young adult patients. Participants will be randomized at a 1:1 ratio to receive standard of care (SOC) plus one of the following adjunctive therapies:

• Soticlestat or
• Placebo

The total daily dose of study drug will be calculated based on body weight in the 4 weeks Titration Period. Following the Titration Period, participants will continue to receive the same dose in the 12-weeks Maintenance Period.

This multi-center trial will be conducted worldwide. The overall time to participate in the study will be from 22-25 weeks. At the end of the Full Treatment Period, participants have the option to either complete the study and taper off the investigational product or to enter the OLE if they meet eligibility requirements. If participants discontinue, they will be followed-up on phone call approximately 14 days after the last dose of study drug for safety.

• Study Type: Interventional
• Enrollment (Actual): 144
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Queensland Childrens Hospital
• Brazil
  • Sao Paulo, Brazil, 04039-032
    • Universidade de Sao Paulo
  • Parana
    • Curitiba, Parana, Brazil, 81210-310
      • Instituto de Neurologia de Curitiba (INC)
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90610-000
      • Hospital Sao Lucas Da Pontificia Universidade Catolica Do Rio Grande Do Sul (PUCRS)
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Childrens Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4H4
      • Child and Family Research Institute
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
• China
  • Beijing
    • Beijing, Beijing, China, 100034
      • Peking University First Hospital
    • Beijing, Beijing, China, 100045
      • Beijing Children's Hospital,Capital Medical University
  • Chongqing
    • Chongqing, Chongqing, China, 400014
      • Children's Hospital of Chongqing Medical University
  • Guangdong
    • Guangzhou, Guangdong, China, 510260
      • The Second Affiliated Hospital of Guangzhou Medical University
    • Shenzhen, Guangdong, China, 518026
      • Shenzhen Children's Hospital
  • Hubei
    • Wuhan, Hubei, China, 430010
      • Wuhan Childrens hospital
  • Hunan
    • Changsha, Hunan, China, 410008
      • Xiangya Hospital Central South University
  • Jilin
    • Changchun, Jilin, China, 130021
      • The First Hospital of Jilin University
  • Shanghai
    • Shanghai, Shanghai, China, 201102
      • Children's Hospital of Fudan University
    • Shanghai, Shanghai, China, 200040
      • Children's Hospital of Shanghai
• France
  • Marseille, France, 13386
    • Hopitaux de La Timone
  • Paris, France, 75019
    • Hopital Robert Debre
  • Paris, France, 75015
    • Hopital Necker - Enfants Malades
• Germany
  • Bayern
    • Vogtareuth, Bayern, Germany, 83569
      • Schön Klinik Vogtareuth
  • Hessen
    • Frankfurt am Main, Hessen, Germany, 60528
      • Klinikum der Johann-Wolfgang Goethe-Universitat
  • Nordrhein-Westfalen
    • Bielefeld, Nordrhein-Westfalen, Germany, 33617
      • Krankenhaus Mara gGmbH - Epilepsiezentrum Bethel
• Greece
  • Attiki
    • Chaidari, Attiki, Greece, 124 62
      • Attikon University General Hospital
• Hungary
  • Budapest, Hungary, 1145
    • Orszagos Mentalis, Ideggyogyaszati es Idegsebeszeti Intezet
• Italy
  • Lazio
    • Roma, Lazio, Italy, 168
      • Fondazione Policlinico Universitario A Gemelli
    • Roma, Lazio, Italy, 164
      • IRCCS Ospedale Pediatrico Bambino Gesu - INCIPIT - PIN
  • Lombardia
    • Pavia, Lombardia, Italy, 27100
      • ASST di Pavia - Fondazione Istituto Neurologico Mondino IRCCS
  • Toscana
    • Firenze, Toscana, Italy, 50139
      • Azienda Ospedaliero Universitaria A Meyer - INCIPIT - PIN
• Japan
  • Aiti
    • Nagakute-Shi, Aiti, Japan, 480-1195
      • Aichi Medical University Hospital
  • Kumamoto
    • Kumamoto-Shi, Kumamoto, Japan, 862-0947
      • Kumamoto-Ezuko Medical Center for The Severely Disabled
  • Nagasaki
    • Omura-Shi, Nagasaki, Japan, 856-0835
      • National Hospital Organization Nagasaki Medical Center
  • Niigata
    • Niigata-Shi, Niigata, Japan, 950-2074
      • National Hospital Organization Nishi-Niigata Chuo National Hospital
  • Osaka
    • Osaka-Shi, Osaka, Japan, 534-0021
      • Osaka City General Hospital
    • Suita-Shi, Osaka, Japan, 565-0871
      • Osaka University Hospital
  • Sizuoka
    • Shizuoka-Shi, Sizuoka, Japan, 420-0953
      • National Hospital Organization Shizuoka Institute of Epilepsy and Neurological Disorders
  • Tokyo
    • Chuo-Ku, Tokyo, Japan, 104-0045
      • Hokkaido University Hospital
    • Kodaira-Shi, Tokyo, Japan, 187-0031
      • National Center of Neurology and Psychiatry
• Latvia
  • Riga, Latvia, LV-1004
    • Childrens University Hospital
• Netherlands
  • Noord-Brabant
    • Heeze, Noord-Brabant, Netherlands, 5591 VE
      • Kempenhaeghe - PPDS
  • Overijssel
    • Zwolle, Overijssel, Netherlands, 8025 BV
      • Stichting Epilepsie Instellingen Nederland
• Poland
  • Gdansk, Poland, 80-952
    • Uniwersyteckie Centrum Kliniczne
  • Poznan, Poland, 60-355
    • Szpital Kliniczny im. H.Swiecickiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu
  • Malopolskie
    • Krakow, Malopolskie, Poland, 30-363
      • Centrum Medyczne Plejady
  • Mazowieckie
    • Warszawa, Mazowieckie, Poland, 02-952
      • Neurosphera SP. Z O.O
• Russian Federation
  • Krasnoyarsk, Russian Federation, 660022
    • Krasnoyarsk State Medical University n.a. V.F. Voyno-Ysenetskiy
  • Moskva
    • Moscow, Moskva, Russian Federation, 117437
      • Russian National Research Medical University n.a. N.I.Pirogov
• Serbia
  • Belgrade, Serbia, 11000
    • Clinic for Neurology and Psychiatry for Children and Youth
  • Belgrade, Serbia, 11000
    • Mother and Child Health Care Institute of Serbia Dr Vukan Cupic
  • Nis, Serbia, 18 000
    • University Clinical Center Nis
• Spain
  • Barcelona, Spain, 8035
    • Hospital Universitario Vall d'Hebron - PPDS
  • Malaga, Spain, 29010
    • Hospital Regional Universitario de Malaga Hospital General
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe de Valencia
• Ukraine
  • Ivano-Frankivsk, Ukraine, 76018
    • Communal Non-commercial Enterprise Iv-Frank Regional Childrens Clinical Hosp of Iv-Frank RC
  • Kyiv, Ukraine, 4080
    • CNPE Clinical Hospital Psychiatry of the Executive Body of the Kyiv City Council KCSA
  • Dnipropetrovs'ka Oblast
    • Dnipro, Dnipropetrovs'ka Oblast, Ukraine, 49101
      • Communal Non-profit Enterprise City Childrens Clinical Hospital #6 of DCC
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016-7710
      • Phoenix Childrens Hospital
  • California
    • Los Angeles, California, United States, 90095-3075
      • David Geffen School of Medicine at UCLA
    • San Francisco, California, United States, 94143-2350
      • University of California Benioff Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30328
      • Clinical Integrative Research Center of Atlanta
  • Iowa
    • Iowa City, Iowa, United States, 52242-1009
      • University of Iowa Hospitals & Clinics - (CRS)
  • New York
    • New York, New York, United States, 10016
      • NYU Comprehensive Epilepsy Center
  • Ohio
    • Toledo, Ohio, United States, 43606-3818
      • University of Toledo
  • South Carolina
    • Charleston, South Carolina, United States, 29403
      • Medical University of South Carolina
  • Washington
    • Seattle, Washington, United States, 98105-3901
      • Seattle Children's Hospital
    • Tacoma, Washington, United States, 98405
      • Multicare Health System - Mary Bridge Pediatrics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Has documented clinical diagnosis of DS.
2. Had ≥12 convulsive seizures over 12 weeks before screening based on the historical information and has had ≥4 convulsive seizures per 28 days during the 4- to 6-week prospective baseline period.
3. Weighs ≥10 kg at the screening visit (Visit 1).
4. Failure to control seizures despite appropriate trials of at least 1 ASM based on historical information and is currently on an antiseizure therapy or other treatment options considered as SOC.
5. Artisanal cannabidiols are allowed at a stable dose for at least 4 weeks before the screening visit (Visit 1); the dosing regimen and manufacturer should remain constant throughout the study (Artisanal cannabidiols will not be counted as ASMs.).
6. Currently taking 0 to 4 ASMs at stable doses for at least 4 weeks before the screening visit (Visit 1); benzodiazepines used chronically (daily) to treat seizures are considered ASMs. Fenfluramine and cannabidiol (Epidiolex) are allowed where available and should be counted as an ASM. ASM dosing regimen must remain constant throughout the study.

Exclusion Criteria:

1. Unstable, clinically significant neurologic (other than the disease being studied), psychiatric, cardiovascular, ophthalmologic, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, hematopoietic, endocrine disease, malignancy including progressive tumors, or other abnormality that may impact the ability to participate in the study or that may potentially confound the study results. It is the responsibility of the investigator to assess the clinical significance; however, consultation with the medical monitor may be warranted.

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
Placebo Comparator: Placebo; Soticlestat placebo-matching mini-tablets or tablets, orally or via gastrostomy tube (G-tube) or low-profile gastric tube (MIC-KEY) button or jejunostomy tube (J-tube), twice daily (BID), up to 4 weeks during titration. Participants continued to receive the soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.	Drug: Placebo; Soticlestat placebo-matching mini-tablets or tablets.
Experimental: Soticlestat; Participants weighing <45 kg: Soticlestat, mini-tablets, at the dose of 40 mg to 200 mg, orally or via G-tube or MIC-KEY button or J-tube, BID based on the body weight up to 4 weeks during titration. Participants continued to receive the dose that they were on at the end of the titration, for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with dose tapered down if participants decided to discontinue the treatment. Participants weighing ≥45 kg: Soticlestat mini-tablets or tablets with a starting dose of 100 mg BID followed by 200 mg BID and, then 300 mg BID, up to 4 weeks during titration. Participants continued to receive 300 mg BID for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with dose tapered down if participants decided to discontinue the treatment.	Drug: Soticlestat; Soticlestat mini-tablets or tablets.; Other Names: TAK-935

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Convulsive Seizure Frequency Per 28 Days During the Full Treatment Period	Convulsive seizure frequency per 28 days was defined as the total number of convulsive seizures reported during the period divided by the number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline was defined as (frequency of seizures per 28 days during the Full Treatment Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.	Baseline; Full Treatment Period: Weeks 1 to 16
Percent Change From Baseline in Convulsive Seizure Frequency Per 28 Days During the Maintenance Period	Convulsive seizure frequency per 28 days was defined as the total number of convulsive seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline was defined as (frequency of seizures per 28 days during Maintenance Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.	Baseline; Maintenance Period: Weeks 5 to 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Frequency of All Seizures Per 28 Days During the Maintenance Period	Seizure frequency per 28 days was defined as the total number of seizures reported during the period divided by the number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline was defined as (frequency of seizures per 28 days during the Maintenance Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.	Baseline; Maintenance Period: Weeks 5 to 16
Percentage of Responders During Maintenance Period	Responders were defined as those with ≥50% reduction from Baseline in convulsive seizures during the Maintenance Period. Percentages were rounded off to the nearest single decimal place.	Maintenance Period: Weeks 5 to 16
Percentage of Responders During the Full Treatment Period	Responders were defined as those with ≥50% reduction from Baseline in convulsive seizures during the Full Treatment Period. Percentages were rounded off to the nearest single decimal place.	Full Treatment Period: Weeks 1 to 16
Percentage of Participants With ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, and >75% to ≤100% Reduction in Convulsive Seizures During the Full Treatment Period	Percent reduction from Baseline (%) was defined as [(Full Treatment Period Convulsive Seizure Frequency - Baseline Convulsive Seizure Frequency) divided by Baseline Convulsive Seizure Frequency] multiplied by 100. Data was reported as reduction of ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, >75% to ≤100% or more in seizures from Baseline. Percentages were rounded off to the nearest single decimal place.	Full Treatment Period: Weeks 1 to 16
Percentage of Participants With Caregiver Global Impression of Improvement (Care GI-I) Scale Responses as Per the Parent/Caregiver Reported Impression at Week 16	The Care GI-I is a 7-point Likert scale that the caregiver used to rate improvement in overall seizure control, behavior, safety and tolerability after the initiation of study drug relative to Baseline (before treatment with the study drug). The participant was rated as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). The parent/caregiver completed the Care GI-I via interview. Lower scores indicate improvement. Percentages were rounded off to the nearest single decimal place.	Week 16
Percentage of Participants With Clinical Global Impression of Improvement (CGI-I) Scale Responses as Per the Investigator Reported Impression at Week 16	The CGI-I (Clinician) is a 7-point Likert scale that the investigator used to rate a participant's change (improvement) in overall seizure control, behavior, safety and tolerability, after the initiation of study drug relative to Baseline (before treatment with the study drug). The participant was rated as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). The investigator or designee completed the CGI-I. Lower scores indicate improvement. Percentages were rounded off to the nearest single decimal place.	Week 16
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16	The CGI-I non-seizure symptoms instrument is a series of single-item assessments that the investigator used to rate improvement in the symptoms and impacts in select non-seizure domains (alertness, communication, and disruptive behaviors) since initiating the study drug. The participant was rated by the investigator for each domain as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). Lower scores indicated improvement. Data for percentage of participants categorized based on the responses for each domain are presented. Percentages were rounded off to the nearest single decimal place.	Week 16
Change From Baseline in Quality of Life Inventory-Disability (QI-Disability) Total Score at Week 16	The QI-Disability tool is a parent/caregiver-reported questionnaire that evaluated the quality of life in children with intellectual disabilities. It contains 32 items covering 6 domains of quality of life: physical health, positive emotions, negative emotions, social interaction, leisure and the outdoors, and independence. Each QI-Disability item is rated on a Likert scale of: Never, Rarely, Sometimes, Often, and Very Often. Items were linearly transformed to a scale of 0 to 100, with higher scores representing better quality of life. Domain scores are calculated by averaging item scores. The domain scores are summed and divided by 6 to yield a total score. The total score ranges from 0 to 100, with higher scores indicating a better quality of life. A negative change from Baseline implies deteriorating quality of life. Mixed-effects model for repeated measures (MMRM) was used for analysis.	Baseline, Week 16
Percentage of Participants With CGI-I Seizure Intensity and Duration Instrument Responses as Per the Parent/Caregiver Reported Impression at Week 16	The CGI-I seizure intensity and duration instrument was used by the parent/caregiver to rate changes in intensity and/or duration of the most impactful seizures from the first assessment. The participant's symptoms were rated on 7-point scale as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). Lower scores indicate improvement. Percentages were rounded off to the nearest single decimal place.	Week 16
Percent Change From Baseline in Frequency of All Seizures Per 28 Days During the Full Treatment Period	Seizure frequency per 28 days was defined as the total number of seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline was defined as (frequency of seizures per 28 days during the Full Treatment Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.	Baseline; Full Treatment Period: Weeks 1 to 16
Change From Baseline in Percentage of Convulsive Seizure-free Days During the Full Treatment Period	Convulsive seizure-free days was defined as number of days a participant remained convulsive seizure-free after initiation of the treatment. The change from baseline in percentage of convulsive seizure-free days, was defined as the percentage of seizure-free days during the Full Treatment Period minus the percentage of seizure-free days during the Baseline. A linear model with treatment group and age stratum as factors and baseline percentage as a covariate was used for analysis.	Baseline up to Week 16
Longest Convulsive Seizure-free Interval During the Full Treatment Period	Longest convulsive seizure-free interval was defined as the longest time period that the participant remained convulsive seizure free after initiation of the treatment. A linear model with treatment group and age stratum as factors was used for analysis.	Full Treatment Period: Weeks 1 to 16
Number of Days When Rescue Antiseizure Medication (ASM) is Used During the Full Treatment Period	Use of rescue ASM was recorded in the case report form (CRF) along with start and end date of medication. Based on the start and end dates for all rescue ASMs taken by a participant, the number of days during the Full Treatment Period when rescue ASM was used was derived.	Full Treatment Period: Weeks 1 to 16

Collaborators and Investigators

• Sponsor: Takeda
• Investigators: Study Director: Study Director, Takeda

Publications and helpful links

Helpful Links

• To obtain more information on the study, click here/on this link

Study record dates

Study Major Dates

• Study Start (Actual): October 28, 2021
• Primary Completion (Actual): April 11, 2024
• Study Completion (Actual): April 11, 2024

Study Registration Dates

• First Submitted: June 16, 2021
• First Submitted That Met QC Criteria: June 18, 2021
• First Posted (Actual): June 25, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 10, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Drug Therapy
• Additional Relevant MeSH Terms: Epileptic Syndromes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Disease; Epilepsy, Generalized; Epilepsy; Syndrome; Epilepsies, Myoclonic
• Other Study ID Numbers: TAK-935-3001; jRCT2051210074 (Registry Identifier: jRCT); 2021-002480-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

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.: Yes