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

• ClinicalTrials.gov Identifier: NCT04940624
• Recruitment Status: Completed
• First Posted: June 25, 2021
• Last Update Posted: May 1, 2024
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Tracking Information

• First Submitted Date: June 16, 2021
• First Posted Date: June 25, 2021
• Last Update Posted Date: May 1, 2024
• Actual Study Start Date: October 28, 2021
• Actual Primary Completion Date: April 11, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 18, 2021)

• Percent Change From Baseline in Convulsive Seizure Frequency per 28 days During the Full Treatment Period [ Time Frame: Baseline up to Week 16 ]
  Convulsive seizure frequency per 28 days is defined as 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 will be defined as (frequency of seizures per 28 days during Treatment Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.
• Percent Change From Baseline in Convulsive Seizure Frequency per 28 days During the Maintenance Period (EMA Region Specific) [ Time Frame: Baseline up to Week 16 ]
  Convulsive seizure frequency per 28 days is defined as 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 will be 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. This outcome measure is European Medicines Agency (EMA) specific.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 15, 2022)

• Percentage of Responders During Maintenance Period [ Time Frame: Baseline up to Week 16 ]
  Responders are defined as those with ≥50% reduction from baseline in convulsive seizures during the Maintenance Period.
• Percentage of Responders During the Full Treatment Period [ Time Frame: Baseline up to Week 16 ]
  Responders are defined as those with ≥50% reduction from baseline in convulsive seizures during the full Treatment Period.
• Percentage of Participants with ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, and >75% to ≤100% Reduction in Convulsive Seizures in a Cumulative Response Curve [ Time Frame: Baseline up to Week 16 ]
• Caregiver Global Impression of Improvement (Care GI-I) Score [ Time Frame: Baseline up to Week 16 ]
  The Care GI-I is a 7-point Likert scale that the caregiver uses to rate improvement in overall seizure control, behavior, safety and tolerability after the initiation of study drug relative to Baseline (before treatment with study drug). The participant will be 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 will complete the Care GI-I via interview. Higher score will indicate worse symptoms.
• Clinical Global Impression of Improvement (CGI-I) Score [ Time Frame: Baseline up to Week 16 ]
  The CGI-I Clinician is a 7-point Likert scale that the investigator uses 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 study drug). The participant will be 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). Higher score will indicate worse symptoms.
• CGI-I Nonseizure Symptoms Score [ Time Frame: Baseline up to Week 16 ]
  The CGI-I nonseizure symptoms instrument is a series of single-item assessments that the investigator uses to rate improvement in the symptoms and impacts in select nonseizure domains since initiating the study drug. The participant will be rated on 7-point scale by the investigator 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). At baseline, a symptoms form is completed by the clinician in collaboration with the primary caregiver to assess the participants status based on the presence of any nonseizure symptoms. Higher score will indicate worse symptoms.
• Change in Quality of Life Inventory-Disability (QI-Disability) Score [ Time Frame: Baseline up to Week 16 ]
  The QI-Disability tool is a parent/caregiver-reported questionnaire that evaluates 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. Scores are from a 5-point Likert scale and then are transformed to a scale of 0 to 100. Possible scores range from 0-100, with higher scores indicating better quality of life.
• CGI-I Seizure Intensity and Duration Score [ Time Frame: Baseline up to Week 16 ]
  The CGI-I seizure Intensity and duration instrument is used by the parent/caregiver to rate improvement in intensity and/or duration of the most impactful seizures from the first assessment. The participant's symptoms will be 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). Higher score will indicate worse symptoms.
• Percent Change From Baseline in Frequency of all Seizures per 28 Days During the Maintenance Period [ Time Frame: Baseline up to Week 16 ]
  Seizure frequency per 28 days is defined as 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 is 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.
• Percent Change From Baseline in Frequency of all Seizures per 28 Days During the Full Treatment Period [ Time Frame: Baseline up to Week 16 ]
  Seizure frequency per 28 days is defined as 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 is defined as (frequency of seizures per 28 days during Treatment Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.
• Percent Change From Baseline in Convulsive Seizure Frequency per 28 days During the Maintenance Period [ Time Frame: Baseline up to Week 16 ]
  Convulsive seizure frequency per 28 days is defined as 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 is defined as (frequency of seizures per 28 days during Maintenance Period - frequency of seizures per 28 days at Baseline) divided by frequency of seizures per 28 days at Baseline multiplied by 100.
• Change from Baseline in Percentage of Convulsive Seizure-free Days [ Time Frame: Baseline up to Week 16 ]
  Convulsive seizure-free days will be defined as number of days a participant remained convulsive seizure free after initiation of the treatment.
• Longest Convulsive Seizure-free Interval. [ Time Frame: Baseline up to Week 16 ]
  Longest convulsive seizure-free interval will be defined as the longest time period that the participant remained convulsive seizure free after initiation of the treatment.
• Number of Days When Rescue Antiseizure Medication (ASM) is Used [ Time Frame: Baseline up to Week 16 ]

Original Secondary Outcome Measures (submitted: June 18, 2021)

• Percentage of Responders During Maintenance Period [ Time Frame: Baseline up to Week 16 ]
  Responders are defined as those with ≥50% reduction from baseline in convulsive seizures during the Maintenance Period.
• Percentage of Responders During the Full Treatment Period [ Time Frame: Baseline up to Week 16 ]
  Responders are defined as those with ≥50% reduction from baseline in convulsive seizures during the Treatment Period.
• Percent Change From Baseline in Frequency of all Seizures per 28 Days During the Maintenance Period [ Time Frame: Baseline up to Week 16 ]
  Seizure frequency per 28 days is defined as 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 is 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.
• Percent Change From Baseline in Frequency of all Seizures per 28 Days During the Full Treatment Period [ Time Frame: Baseline up to Week 16 ]
  Seizure frequency per 28 days is defined as 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 is defined as (frequency of seizures per 28 days during Treatment Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.
• Percent Change From Baseline in Convulsive Seizure Frequency per 28 days During the Maintenance Period [ Time Frame: Baseline up to Week 16 ]
  Convulsive seizure frequency per 28 days is defined as 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 is defined as (frequency of seizures per 28 days during Maintenance Period - frequency of seizures per 28 days at Baseline) divided by frequency of seizures per 28 days at Baseline multiplied by 100.
• Percentage of Participants with ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, and >75% to ≤100% Reduction in Convulsive Seizures in a Cumulative Response Curve [ Time Frame: Baseline up to Week 16 ]
• Change from Baseline in Percentage of Convulsive Seizure-free Days [ Time Frame: Baseline up to Week 16 ]
  Convulsive seizure-free days will be defined as number of days a participant remained convulsive seizure free after initiation of the treatment.
• Longest Convulsive Seizure-free Interval. [ Time Frame: Baseline up to Week 16 ]
  Longest convulsive seizure-free interval will be defined as the longest time period that the participant remained convulsive seizure free after initiation of the treatment.
• Number of Days When Rescue Antiseizure Medication (ASM) is Used [ Time Frame: Baseline up to Week 16 ]
• Clinical Global Impression of Improvement (CGI-I) Score [ Time Frame: Baseline up to Week 16 ]
  The CGI-I Clinician is a 7-point Likert scale that the investigator uses 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 study drug). The participant will be 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). Higher score will indicate worse symptoms.
• Caregiver Global Impression of Improvement (Care GI-I) Score [ Time Frame: Baseline up to Week 16 ]
  The Care GI-I is a 7-point Likert scale that the caregiver uses to rate improvement in overall seizure control, behavior, safety and tolerability after the initiation of study drug relative to Baseline (before treatment with study drug). The participant will be 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 will complete the Care GI-I via interview. Higher score will indicate worse symptoms.
• CGI-I Seizure Intensity and Duration Score [ Time Frame: Baseline up to Week 16 ]
  The CGI-I seizure Intensity and duration instrument is used by the parent/caregiver to rate improvement in intensity and duration of convulsive seizures from the first assessment. The participant's symptoms will be 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). Higher score will indicate worse symptoms.
• CGI-I Nonseizure Symptoms Score [ Time Frame: Baseline up to Week 16 ]
  The CGI-I nonseizure symptoms instrument is a series of single-item assessments that the investigator uses to rate improvement in the symptoms and impacts in select nonseizure domains since initiating the study drug. The participant will be rated on 7-point scale by the investigator 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). At baseline, a symptoms form is completed by the clinician in collaboration with the primary caregiver to assess the participants status based on the presence of any nonseizure symptoms. Higher score will indicate worse symptoms.
• Change in Quality of Life Inventory-Disability (QI-Disability) Score [ Time Frame: Baseline up to Week 16 ]
  The QI-Disability tool is a parent/caregiver-reported questionnaire that evaluates 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. Scores are from a 5-point Likert scale and then are transformed to a scale of 0 to 100. Possible scores range from 0-100, with higher scores indicating better quality of life.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Soticlestat as an Add-on Therapy in Children and Young Adults With Dravet Syndrome
• Official Title: 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)

Brief Summary

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.

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 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
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Dravet Syndrome (DS)

Intervention

• Drug: Soticlestat
  Soticlestat mini-tablets or tablets.
  Other Name: TAK-935
• Drug: Placebo
  Soticlestat placebo-matching mini-tablets or tablets.

Study Arms

• Experimental: Soticlestat
  Participants weighing <45kg: Soticlestat, mini-tablets, at the dose of 40mg to 200mg, orally or via gastrostomy tube (G-tube) or low-profile gastric tube (MIC-KEY button) or jejunostomy tube (J-tube), twice daily (BID) based on the body weight up to 4 weeks in Titration Period. Participants will continue to receive dose that they are on at the end of Titration Period, for 12 weeks in Maintenance Period. The total duration of the treatment will be up to 16 weeks (Treatment Period). The dose will be tapered down if participants decide to discontinue the treatment. Participants weighing ≥45kg: Soticlestat mini-tablets or tablets with a starting dose of 100mg BID followed by 200 mg BID and, then 300mg BID, up to 4 weeks in Titration Period. Participants will continue to receive 300mg BID for 12 weeks in the Maintenance Period. The total duration of the treatment will be up to 16 weeks (Treatment Period). The dose will be tapered down if participants decide to discontinue the treatment.
  Intervention: Drug: Soticlestat
• Placebo Comparator: Placebo
  Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks in the Titration Period. Participants will continue to receive the soticlestat placebo-matching mini-tablets or tablets for 12 weeks in the Maintenance Period. The total duration of the treatment will be up to 16 weeks. Soticlestat matching tapering will be done to maintain the blind if participants decide to discontinue the treatment.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 18, 2024): 144
• Original Estimated Enrollment (submitted: June 18, 2021): 142
• Actual Study Completion Date: April 11, 2024
• Actual Primary Completion Date: April 11, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Brazil, Canada, China, France, Germany, Greece, Hungary, Italy, Japan, Latvia, Netherlands, Poland, Russian Federation, Serbia, Spain, Ukraine, United States
• Removed Location Countries: Belgium, Mexico

Administrative Information

• NCT Number: NCT04940624
• Other Study ID Numbers: TAK-935-3001; jRCT2051210074 ( Registry Identifier: jRCT ); 2021-002480-22 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• 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.
• URL: https://vivli.org/ourmember/takeda/

• Current Responsible Party: Takeda
• Original Responsible Party: Same as current
• Current Study Sponsor: Takeda
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Study Director; Takeda

• PRS Account: Takeda
• Verification Date: April 2024