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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 Young Adult Subjects With Dravet Syndrome (DS)

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

144

There was no clinically meaningful difference between the treatment groups at baseline. Over 50% (56.9%) of participants were White and 35.4% of participants were Asian. The sex of participants was evenly divided (72 male participants, 72 female participants). Mean age was 10.3 years.

A total of 144 participants were randomly assigned to treatment with soticlestat (73 participants) or placebo (71 participants); 60 (82.2%) participants on soticlestat and 63 (88.7%) participants on placebo completed study treatment. A total of 21 (14.6%) participants discontinued study drug (and the study) prematurely. Reasons for treatment discontinuation included AEs (15 [10.4%] participants), withdrawal by parent/guardian (3 [2.1%] participants), physician decision, lost to follow-up, and other (1 [0.7%] participant, each). There were no premature discontinuations from the study related to COVID-19.

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 DS 2 years and older. TEAEs occurred at a similar incidence for soticlestat-treated participants compared to placebo-treated participants (80.8% versus 74.6%, respectively) and were generally mild to moderate in severity. A higher incidence of TEAEs considered related to study drug was observed for soticlestat-treated participants compared to placebo-treated participants (43.8% versus 26.8%, respectively). In the soticlestat group, treatment-related TEAE reported by >=5% of participants were somnolence (12.3%), change in seizure presentation (9.6%), decreased appetite (6.8%), and insomnia (5.5%). The treatment-related TEAE reported by >=5% of participants in the placebo group were somnolence (11.3%) and change in seizure presentation (5.6%). Among the treatment-related TEAEs reported by >1 participant, events reported for participants in the soticlestat group only (ie, not reported in the placebo group) were aggression and sleep disorder (2.7%, each). One participant on soticlestat had a fatal TEAE (SUDEP), which was considered not related to study drug. The incidences of SAEs were comparable between the two treatment groups (9.6% for the soticlestat group versus 14.1% for the placebo group). In the soticlestat group, SAEs reported by >1 participant were status epilepticus and seizure cluster (2 [2.7%] participants, each). The SAE reported by >1 participant in the placebo group was status epilepticus (4 [5.6%] participants). All other SAEs were reported by at most 1 participant in each treatment group. All but 1 SAE was resolved. The incidence of TEAEs leading to study drug discontinuation was higher for soticlestat-treated participants compared to placebo-treated participants (15.1% versus 5.6%, respectively). The TEAEs leading to study drug discontinuation that were reported by >1 participant in the soticlestat group and in the placebo were change in seizure presentation (5 [6.8%] and 2 [2.8%] participants, respectively). Few treatment-emergent AESIs were reported in the study. No clinically meaningful treatment differences were observed for clinical laboratory results, vital signs, ECGs, 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. Soticlestat treatment did not result in significant weight loss or weight gain.

Efficacy Results: Soticlestat showed a median reduction from baseline in convulsive seizure frequency per 28 days over the full 16-week treatment period of 22.16% with soticlestat (n=73) and 8.64% with placebo (n=71). The placebo-adjusted median reduction from baseline was 15.64% (p=0.061). During the maintenance period, a median reduction of 23.29% for soticlestat versus 11.99% for placebo was observed. The placebo-adjusted median reduction from baseline was 14.29% (p=0.089). Because soticlestat was not statistically significantly better than placebo for the primary endpoint (ie, not a positive outcome), statistically significant differences could not be declared for any of the key secondary endpoints. However, due to scientific interest, p-values were computed for each endpoint. Soticlestat showed clinically meaningful and nominally significant (ie, p<0.05 without multiplicity control) results in 4 key secondary endpoints. - The proportion of >=50% responders in convulsive seizures during the full treatment period was 27.4% with soticlestat and 9.9% with placebo (odds ratio 3.59; p=0.008). Of note, 13.7% of soticlestat participants compared with 1.4% participants in the placebo group had a reduction of 75% or more. - Care GI-I showed improvement at the end of the full treatment period with 60.6% participants with soticlestat as compared to 35.3% with placebo (odds ratio 2.51; p=0.004). - CGI-I showed improvement at the end of the full treatment period with 52.1% participants on soticlestat versus 26.8% on placebo (odds ratio 2.58; p=0.003). - CGI-I seizure intensity and duration at the end of the full treatment period showed improvement in 58.5% in participants with soticlestat versus 24.6% with placebo (odds ratio 3.65; p <0.001). - No meaningful differences were observed between treatment groups in CGI-I nonseizure symptoms (ie, alertness, communication, disruptive behaviors) and QI-Disability scale A greater proportion of participants receiving soticlestat had a >=25% and >=75% reduction from baseline in convulsive seizure frequency during the full treatment period compared to placebo (soticlestat group: 35 [47.9%] and 10 [13.7%], respectively versus placebo group: 20 [28.2%] and 1 [1.4%], respectively). There was no meaningful effect on all seizure frequency per 28 days for participants receiving soticlestat versus placebo during the full treatment period (placebo-adjusted median reduction: 8.13%) and the maintenance period (placebo-adjusted median reduction: 9.97%). Both treatment groups experienced an increase in percentage of convulsive seizure-free days; the difference between groups was not meaningful (soticlestat LS mean change from baseline [SE]: 3.54% [1.719%]; placebo LS mean change from baseline: 2.74% [1.784%]; LS Mean Difference [SE]: 0.79% [2.331%]). The mean longest convulsive seizure-free interval was greater in the soticlestat group (LS mean 22.3 days; 95% CI: 18.2, 26.4) compared to placebo (LS mean 16.7 days; 95% CI: 12.4, 20.9). The number and proportion of days when rescue ASM was used during the full treatment period were lower in the soticlestat group compared to placebo (LS mean [SE] 2.9 [0.78] days versus 4.0 [0.81] days and 2.75% [0.730%] versus 3.67% [0.752%], respectively). Safety Results: Refer to 'Adverse events'.

In conclusion, while the primary endpoint narrowly missed statistical significance, the totality of the results provides clinically meaningful and relevant evidence for soticlestat for the treatment of seizures of patients with DS 2 years of age and older. Observed treatment effects on primary and multiple secondary endpoints, and the demonstration of favorable safety and tolerability profile support the therapeutic value of soticlestat.

Feb. 05, 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/jRCT2051210074

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

Oct. 28, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Has documented clinical diagnosis of DS.
2. Had >=12 convulsive seizures over 12 weeks before screening based on the historical information and 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 antiseizure medication (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 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.

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.

Both

Dravet 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 the body weight up to 4 weeks in Titration Period. Participants continued 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 (Full Treatment Period) with dose tapered down if participants decided 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 during titration. Participants continued to receive 300mg BID for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with 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 the 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 Convulsive Seizure Frequency per 28 days During the Full Treatment Period
Time Frame: Baseline; Full Treatment Period: Weeks 1 to 16
Convulsive seizure frequency per 28 days was defined as the total number of convulsive 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 Convulsive Seizure Frequency per 28 days During the Maintenance Period
Time Frame: Baseline; Maintenance Period: Weeks 5 to 16
Convulsive seizure frequency per 28 days was defined as the 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 was 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.

1. Percentage of Responders During Maintenance Period
Time Frame: Maintenance Period: Weeks 5 to 16
Responders were defined as those with >=50% reduction from baseline in convulsive seizures during the Maintenance Period. Percentages were 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 were defined as those with >=50% reduction from baseline in convulsive seizures during the full Treatment Period. Percentages were 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 Convulsive Seizures During the Full Treatment Period
Time Frame: Full Treatment Period: Weeks 1 to 16
Percent reduction from Baseline (%) was defined as [(Full Treatment Period Convulsive Seizure Frequency - Baseline Convulsive Seizure Frequency) divided by Baseline Convulsive Seizure Frequency] multiplied by 100. Data was reported as reduction of =<0%, >0% to =<25%, >25% to =<50%, >50% to =<75%, >75% to =<100% or more in seizures from Baseline. Percentages were 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 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 were 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 used 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 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 completed the CGI-I. Lower scores indicate improvement. Percentages were 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 non-seizure symptoms instrument is a series of single-item assessments that the investigator used to rate improvement in the symptoms and impacts in select non-seizure 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 were 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 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. 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 improvement in intensity and/or duration of the most impactful seizures from the first assessment. The participant's symptoms were 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). Lower scores indicate improvement. Percentages were 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 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.
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 Convulsive Seizure-free Days During the Full Treatment Period
Time Frame: Baseline up to Week 16
Convulsive seizure-free days was defined as number of days a participant remained convulsive-seizure free after initiation of the treatment. The change from baseline in percentage of convulsive 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 Convulsive Seizure-free Interval During the Full Treatment Period
Time Frame: Full Treatment Period: Weeks 1 to 16
Longest convulsive seizure-free interval was defined as the longest time period that the participant remained convulsive 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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