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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)

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

270

There was no clinically meaningful difference between the treatment groups. Most participants were White (167 [61.9%] participants), male (163 [60.4%] participants), and non-Hispanic or Latino (254 [94.1%] subjects). Mean age was 12.9 years.

A total of 270 participants were randomly assigned to treatment with soticlestat (134 participants) or placebo (136 participants) of which 114 (85.1%) participants on soticlestat and 126 (92.6%) participants on placebo completed study treatment. A total of 30 (11.1%) participants discontinued study drug (and the study) prematurely. Reasons for study drug discontinuation included AEs (24 [8.9%] participants), withdrawal by parent or guardian (2 [0.7%] participants), withdrawal by self (1 [0.4%] participant), and other (3 [1.1%] participants).

Soticlestat was generally well tolerated at doses up to 300 mg BID (or weight-based equivalent dosing for participants weighing <45 kg) in participants with LGS. TEAEs were generally mild to moderate in severity and occurred at a similar incidence for soticlestat-treated participants compared to placebo-treated participants (74.6% vs 68.4%, respectively). A higher incidence of TEAEs considered related to study drug was observed for soticlestat-treated participants compared to placebo-treated participants (39.6% vs 20.6%, respectively). In the soticlestat group, treatment-related TEAE reported by >=5% of participants were somnolence (13.4%), change in seizure presentation (11.2%), and decreased appetite (6.0%). The only treatment-related TEAE reported by >=5% of participants in the placebo group was somnolence (5.9%). Among the treatment-related TEAEs reported by >1 study participant, events reported for participants in the soticlestat group only (i.e., not reported in the placebo group) were decreased appetite (6.0%), constipation (4.5%), diarrhea (1.5%), and weight decreased (1.5%). No participant had a fatal TEAE. The incidence of SAEs were comparable between the two treatment groups (8.2% for participants in the soticlestat group vs 7.4% for participants in the placebo group). The incidence of TEAEs leading to study drug discontinuation was higher for soticlestat-treated participants compared to placebo treated participants (14.2% vs 3.7%, respectively). The TEAEs leading to study drug discontinuation reported by >1 participant in the soticlestat group were change in seizure presentation (7 [5.2%] participants), fatigue (2 [1.5%] participants), and aggression (2 [1.5%] participants). No TEAE leading to study drug discontinuation occurred in >1 participant in the placebo group. Few participants had AESIs. No clinically meaningful treatment differences were observed for clinical laboratory results, vital signs, ECGs, physical examinations, or other safety data. C-SSRS results were not indicative of suicidal ideation or behavior for any participant during the study. Soticlestat treatment did not appear to affect liver function tests (LFTs). Soticlestat treatment did not result in significant weight loss or weight gain.

Efficacy Results: Soticlestat did not significantly reduce MMD seizure frequency compared to placebo for participants with LGS in this study. For participants receiving soticlestat, the placebo-adjusted median MMD seizure frequency change of - 1.17% per 28 days during the full treatment period was not significant (p=0.785). The placebo-adjusted median MMD seizure frequency change of 2.43% per 28 days during the maintenance period was also not significant (p=0.778). Because the results for the primary endpoint were not statistically significant in favor of soticlestat, based on the hierarchical testing method, no other endpoints demonstrated statistical significance. However, nominal p-values were computed for each secondary endpoint and all key secondary endpoints were numerically in favor of soticlestat. Among the key secondary endpoints, CGI-I Nonseizure Symptoms Disruptive Behaviors domain (odds ratio [95% CI] for improved distribution of scores: 1.91 [1.06, 3.43], p=0.032) and CGI-I Seizure Intensity and Duration (odds ratio [95% CI] for improved distribution of scores: 1.67 [1.06, 2.65], p=0.029) had p-values <0.05 (without multiplicity adjustment). Safety Results: Refer to "Adverse events". Brief summary (continued): - The placebo-adjusted median MMD seizure frequency change of -1.17% per 28 days during the full treatment period was not significant (p=0.785). - The placebo-adjusted median MMD seizure frequency change of 2.43% per 28 days during the maintenance period was also not significant (p=0.778). Soticlestat demonstrated nominally significant improvements on 2 of multiple key secondary endpoints: CGI-I Seizure Intensity and Duration (p=0.029) and on the Disruptive Behaviors domain of the key secondary endpoint CGI-I Non-seizure Symptoms (p=0.032). The TEAEs were generally mild to moderate in severity and occurred at a similar frequency for soticlestat-treated participants compared to placebo (74.6% vs 68.4%, respectively). No clinically significant findings were observed for clinical laboratory results, vital signs, or physical examinations. Soticlestat-treatment did not result in significant weight loss or weight gain.

Soticlestat did not significantly reduce MMD seizure frequency compared to placebo for the total LGS population in this study. Soticlestat was generally well tolerated at doses up to 300 mg BID (or weight-based equivalent dosing for participants weighing <45 kg) in participants with LGS.

Jan. 16, 2025

Yes

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.

https://jrct.mhlw.go.jp/latest-detail/jRCT2051210073

Nonomura Hidenori

Takeda Pharmaceutical Company Limited

1-1, Doshomachi 4-chome, Chuo-ku, Osaka

smb.Japanclinicalstudydisclosure@takeda.com

Contact for Clinical Trial Information

Takeda Pharmaceutical Company Limited

1-1, Doshomachi 4-chome, Chuo-ku, Osaka

+81-6-6204-2111

smb.Japanclinicalstudydisclosure@takeda.com

Complete

Nov. 08, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Has documented clinical diagnosis of Lennox-Gastaut Syndrome (LGS).
2. Had >=8 MMD seizures each month in the 3 months prior to Screening based on the historical information and 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 anti-seizure medications (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.

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.

Both

Lennox-Gastaut Syndrome

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 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 the 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 the dose tapered down if participants decided to discontinue the treatment.

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 during titration. Participants continued to receive 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 decide to discontinue the treatment.

1. Percent Change From Baseline in Major Motor Drop (MMD) Seizure Frequency Per 28 days During the Full Treatment Period
Time Frame: Baseline; Full Treatment Period: Weeks 1 to 16
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.

2. Percent Change From Baseline in Major Motor Drop (MMD) Seizure Frequency Per 28 days During the Maintenance Period
Time Frame: Baseline; Maintenance Period: Weeks 5 to 16
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.

1. Percentage of Responders During Maintenance Period
Time Frame: Maintenance Period: Weeks 5 to 16
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.

2. Percentage of Responders During the Full Treatment Period
Time Frame: Full Treatment Period: Weeks 1 to 16
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.

3. Percentage of Participants with =<0%, >0% to =<25%, >25% to =<50%, >50% to =<75%, and >75% to =<100% Reduction in MMD Seizure During the Full Treatment Period
Time Frame: Full Treatment Period: Weeks 1 to 16
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.

4. Percentage of Participants With Caregiver Global Impression of Improvement (Care GI-I) Scale Responses as Per the Parent/Caregiver Reported Impression at Week 16
Time Frame: 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.

5. Percentage of Participants with Clinical Global Impression of Improvement (CGI-I) Scale Responses as Per the Investigator Reported Impression at Week 16
Time Frame: 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.

6. Percentage of Participants with CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16
Time Frame: 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.

7. Change From Baseline in Quality of Life Inventory-Disability (QI-Disability) Total Score at Week 16
Time Frame: Baseline, 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.

8. Percentage of Participants with CGI-I Seizure Intensity and Duration Instrument Responses as Per the Parent/Caregiver Reported Impression at Week 16
Time Frame: 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.

9. Percent Change From Baseline in Frequency of All Seizures per 28 Days During the Maintenance Period
Time Frame: Baseline; Maintenance Period: Weeks 5 to 16
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 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; Full Treatment Period: Weeks 1 to 16
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.

11. Change from Baseline in Percentage of MMD Seizure-free Days During the Full Treatment Period
Time Frame: Baseline up to Week 16
MMD seizure-free days was defined as 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.

12. Longest MMD Seizure-free Interval During the Full Treatment Period
Time Frame: Full Treatment Period: Weeks 1 to 16
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.

13. Number of Days When Rescue Antiseizure Medication (ASM) is Used During the Full Treatment Period
Time Frame: Full Treatment Period: Weeks 1 to 16
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.

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Aug. 23, 2021

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