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

Takeda270 enrolled

Overview

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.

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Eligibility

Sex: ALLMin age: 2 YearsMax age: 55 Years

Medical Language ↔ Plain English

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.

Locations (98)

Phoenix Childrens Hospital

Phoenix, Arizona, United States

Center For Neurosciences

Tucson, Arizona, United States

David Geffen School of Medicine at UCLA

Los Angeles, California, United States

University of California Benioff Children's Hospital

San Francisco, California, United States

Children's Hospital Colorado.

Denver, Colorado, United States

Outcomes

Primary Outcomes

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 was defined as the total number of MMD 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.

Time frame: Baseline; Full Treatment Period: Weeks 1 to 16

Percent Change From Baseline in Major Motor Drop (MMD) Seizure Frequency Per 28 Days During the Maintenance Period

MMD seizure frequency per 28 days was defined as the 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 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.

Time frame: Baseline; Maintenance Period: Weeks 5 to 16

Secondary Outcomes

Percentage of Responders During the Maintenance Period

Responders are defined as those with ≥50% reduction from Baseline in MMD seizures during the Maintenance Period. Percentages are rounded off to the nearest single decimal place.

Time frame: Maintenance Period: Weeks 5 to 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. Percentages are rounded off to the nearest single decimal place.

Time frame: Full Treatment Period: Weeks 1 to 16

Percentage of Participants With ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, >75% to ≤100% Reduction in MMD Seizure During the Full Treatment Period

Percent reduction from Baseline (%) is defined as \[(Full Treatment Period MMD Seizure Frequency - Baseline MMD Seizure Frequency) divided by Baseline MMD Seizure Frequency\] multiplied by 100. Data is reported as reduction of ≤0%, \>0% to ≤25%, \>25% to ≤50%, \>50% to ≤75%, \>75% to ≤100% or more in seizures from Baseline. Percentages are rounded off to the nearest single decimal place.

Time frame: 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 are rounded off to the nearest single decimal place.

Time frame: 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 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 will complete the CGI-I. Lower scores indicate improvement. Percentages are rounded off to the nearest single decimal place.

Time frame: 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 nonseizure symptoms instrument is a series of single-item assessments that the investigator used to rate improvement in the symptoms and impacts in select nonseizure 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 are rounded off to the nearest single decimal place.

Time frame: 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 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.

Time frame: 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 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 are rounded off to the nearest single decimal place.

Time frame: Week 16

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.

Time frame: Baseline; Maintenance Period: Weeks 5 to 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 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.

Time frame: Baseline; Full Treatment Period: Weeks 1 to 16

Change From Baseline in Percentage of MMD Seizure-free Days During the Full Treatment Period

MMD Seizure-free days was defined as the number of days the participant remained MMD seizure free after initiation of the treatment. The change from baseline in percentage of MMD 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.

Time frame: Baseline up to Week 16

Longest MMD Seizure-free Interval During the Full Treatment Period

Longest MMD Seizure-free Interval was defined as the longest time period that the participant remained MMD seizure-free after initiation of the treatment. A linear model with treatment group and age stratum as factors was used for analysis.

Time frame: 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.

Time frame: Full Treatment Period: Weeks 1 to 16

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

Overview

Conditions

Interventions

Eligibility

Locations (98)

Outcomes

Primary Outcomes

Secondary Outcomes