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A Study of Soticlestat as an Add-on Therapy in Children, Teenagers, and Adults With Lennox-Gastaut Syndrome

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ClinicalTrials.gov Identifier: NCT04938427
Recruitment Status : Completed
First Posted : June 24, 2021
Last Update Posted : February 28, 2024
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Description
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Brief Summary:

The aims of the study are:

  • to learn if soticlestat, when given as add-on therapy, reduces the number of major motor drop seizures in children, teenagers, and adults with Lennox-Gastaut Syndrome.
  • to assess the safety profile of soticlestat when given in combination with other therapies.

Participants will receive their standard antiseizure therapy, plus either tablets of soticlestat or placebo. A placebo looks just like soticlestat but will not have any medicine in it. Participants will take soticlestat or placebo for 16 weeks, followed by a gradual dose reduction for 1 week. Then, participants will be followed up for 2 weeks.


Condition or disease Intervention/treatment Phase
Lennox Gastaut Syndrome (LGS) Drug: Soticlestat Drug: Placebo Phase 3

Detailed Description:

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

The study will enroll approximately 234 patients. Participants will be randomly assigned (by chance, like flipping a coin) in a 1:1 ratio to receive standard of care (SOC) plus one of the following adjunctive therapies which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

  1. Soticlestat
  2. Placebo (dummy inactive pill - this is a tablet/mini-tablet that looks like the study drug but has no active ingredient)

Participants will receive soticlestat or matching placebo based on their weight in the 4-week Titration Period. Following the Titration Period, participants will continue to receive the same dose in the 12-week Maintenance Period. The dose will then be down-tapered if participants decide to discontinue the treatment and/or are not deemed eligible to continue in Open-label extension (OLE).

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 270 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Adult Subjects With Lennox-Gastaut Syndrome (LGS)
Actual Study Start Date : November 8, 2021
Actual Primary Completion Date : January 25, 2024
Actual Study Completion Date : January 25, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Seizures

Arms and Interventions
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Arm Intervention/treatment
Experimental: Soticlestat

Participants weighing <45 kg: Soticlestat, mini-tablets, at the dose of 40 mg to 200 mg, 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 body weight up to 4 weeks in Titration Period. Participants will continue to receive the dose that they are on at the end of the titration period, for 12 weeks in the Maintenance Period. Total duration of the treatment will be up to 16 weeks (Treatment Period). Dose will be tapered down if participants decide 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 in Titration Period. Participants will continue to receive 300 mg BID for 12 weeks in the Maintenance Period. Total duration of the treatment will be up to 16 weeks (Treatment Period). Dose will be tapered down if participants decide to discontinue the treatment.

 Drug: Soticlestat
Soticlestat mini-tablets or tablets.
Other Name: TAK-935
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 (Treatment Period). Soticlestat matching tapering will be done to maintain the blind if participants decide to discontinue the treatment.
 Drug: Placebo
Soticlestat placebo-matching mini-tablets or tablets.


Outcome Measures
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Primary Outcome Measures :
  1. Percent Change from Baseline in Major Motor Drop (MMD) Seizure Frequency Per 28 Days During the Full Treatment Period [ Time Frame: Baseline up to Week 16 ]
    MMD seizure frequency per 28 days is defined as total number of MMD 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 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.

  2. Percent Change from Baseline in Major Motor Drop (MMD) Seizure Frequency Per 28 Days During the Maintenance Period (EMA Region Specific) [ Time Frame: Baseline up to Week 16 ]
    MMD seizure frequency per 28 days is defined as total number of MMD 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 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. This outcome measure is European Medicines Agency (EMA) region specific.


Secondary Outcome Measures :
  1. Percentage of Responders During the Maintenance Period [ Time Frame: Baseline up to Week 16 ]
    Responders are defined as those with ≥50% reduction from Baseline in MMD seizures during the Maintenance Period.

  2. 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 MMD seizures during the full Treatment Period.

  3. Percentage of Participants with ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, >75% to ≤100% Reduction in MMD Seizure in a Cumulative Response Curve [ Time Frame: Baseline up to Week 16 ]
  4. 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 the 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.

  5. 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 the 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.

  6. 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 by the investigator on the 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.

  7. 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.

  8. 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 changes in intensity and/or duration of the most impactful seizures from the first assessment. The participant's symptoms will be rated on the 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.

  9. 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.

  10. 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 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.

  11. Percent Change from Baseline in MMD Seizure Frequency per 28 Days During the Maintenance Period [ Time Frame: Baseline up to Week 16 ]
    MMD seizure frequency per 28 days is defined as total number of MMD 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.

  12. Change From Baseline in Percentage of MMD Seizure-free Days [ Time Frame: Baseline up to Week 16 ]
    MMD Seizure-free days will be defined as the number of days the participant remained MMD seizure free after initiation of the treatment.

  13. Longest MMD Seizure-free Interval [ Time Frame: Baseline up to Week 16 ]
    Longest MMD Seizure-free Interval will be defined as the longest time period that the participant remained MMD seizure free after initiation of the treatment.

  14. Number of Days When Rescue Antiseizure Medication (ASM) is Used [ Time Frame: Baseline up to Week 16 ]

Eligibility Criteria
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Ages Eligible for Study:   2 Years to 55 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Has documented clinical diagnosis of LGS.
  2. Has had ≥8 MMD seizures each month in the 3 months prior to Screening based on the historical information and has had ≥8 MMD 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 standard of care (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 3 ASMs at stable doses for at least 4 weeks before the Screening Visit (Visit 1); Fenfluramine and cannabidiol (Epidiolex) are allowed where available and counted as an ASM. ASM dosing regimen must remain constant throughout the study.

Exclusion Criteria:

  1. Admitted to a medical facility and intubated for treatment of status epilepticus 2 or more times in the 3 months immediately before Screening (Visit 1). For the purpose of this exclusion criterion, status is defined as continuous seizure activity lasting longer than 5 minutes or repeated seizures without return to Baseline in between seizures.
  2. 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.
  3. Considered by the investigator to be at imminent risk of suicide or injury to self, others, or property, or the participant has attempted suicide within 12 months before the Screening Visit (Visit 1). Participants who have positive answers on item numbers 4 or 5 on the Columbia suicide severity rating scale (C-SSRS) before dosing (Visit 2) are excluded. This scale will only be administered to participants aged ≥6 years.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04938427


Locations
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Sponsors and Collaborators
Takeda
Investigators
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Study Director: Study Director Takeda
More Information
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Additional Information:

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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT04938427    
Other Study ID Numbers: TAK-935-3002
2021-002481-40 ( EudraCT Number )
jRCT2051210073 ( Registry Identifier: jRCT )
First Posted: June 24, 2021    Key Record Dates
Last Update Posted: February 28, 2024
Last Verified: February 2024
Individual Participant Data (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
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
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/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Takeda:
Drug therapy
Additional relevant MeSH terms:
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Lennox Gastaut Syndrome
Syndrome
Disease
Pathologic Processes
Epileptic Syndromes
 Epilepsy
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Genetic Diseases, Inborn