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

Study Overview
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Brief Summary
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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.

Detailed Description
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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): Soticlestat 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.

Official Title
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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)

Conditions
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Lennox Gastaut Syndrome (LGS)

Intervention / Treatment
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* Drug: Soticlestat
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has documented clinical diagnosis of LGS. 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. Weighs ≥10 kg at the Screening Visit (Visit 1). 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). 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.) 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: 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Soticlestat<br>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<br>* Soticlestat mini-tablets or tablets.<br>* Other names: TAK-935;|
| Placebo Comparator: Placebo<br>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<br>* Soticlestat placebo-matching mini-tablets or tablets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change from Baseline in Major Motor Drop (MMD) Seizure Frequency Per 28 Days During the Full Treatment Period | 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. | Baseline up to Week 16 | 
| Percent Change from Baseline in Major Motor Drop (MMD) Seizure Frequency Per 28 Days During the Maintenance Period (EMA Region Specific) | 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. | Baseline up to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Responders During the Maintenance Period | Responders are defined as those with ≥50% reduction from Baseline in MMD seizures during the Maintenance Period. | Baseline up to Week 16 | 
| Percentage of Responders During the Full Treatment Period | Responders are defined as those with ≥50% reduction from Baseline in MMD seizures during the full Treatment Period. | Baseline up to Week 16 | 
| 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 |  | Baseline up to Week 16 | 
| Caregiver Global Impression of Improvement (Care GI-I) Score | 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. | Baseline up to Week 16 | 
| Clinical Global Impression of Improvement (CGI-I) Score | 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. | Baseline up to Week 16 | 
| CGI-I Nonseizure Symptoms Score | 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. | Baseline up to Week 16 | 
| Change in Quality of Life Inventory-Disability (QI-Disability) Score | 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. | Baseline up to Week 16 | 
| CGI-I Seizure Intensity and Duration Score | 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. | Baseline up to Week 16 | 
| Percent Change From Baseline in Frequency of All Seizures per 28 Days During the Maintenance Period | 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. | Baseline up to Week 16 | 
| Percent Change from Baseline in Frequency of All Seizures per 28 Days During the Full Treatment Period | 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. | Baseline up to Week 16 | 
| Percent Change from Baseline in MMD Seizure Frequency per 28 Days During the Maintenance Period | 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. | Baseline up to Week 16 | 
| Change From Baseline in Percentage of MMD Seizure-free Days | MMD Seizure-free days will be defined as the number of days the participant remained MMD seizure free after initiation of the treatment. | Baseline up to Week 16 | 
| Longest MMD Seizure-free Interval | 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. | Baseline up to Week 16 | 
| Number of Days When Rescue Antiseizure Medication (ASM) is Used |  | Baseline up to Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy