Clinical Trial Results:
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)
Summary
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EudraCT number |
2021-002480-22 |
Trial protocol |
Outside EU/EEA IT FR ES LV GR NL BE PL HU DE |
Global end of trial date |
11 Apr 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
26 Dec 2024
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First version publication date |
26 Dec 2024
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
TAK-935-3001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04940624 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
jRCT: jRCT2051210074 | ||
Sponsors
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Sponsor organisation name |
Takeda Development Center Americas, Inc.
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Sponsor organisation address |
95 Hayden Avenue, Lexington, MA, United States, 02421
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Public contact |
Study Director, Takeda, TrialDisclosures@takeda.com
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Scientific contact |
Study Director, Takeda, TrialDisclosures@takeda.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-002572-PIP02-19 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
11 Apr 2024
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
11 Apr 2024
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the efficacy of soticlestat in reducing convulsive seizure frequency as add-on therapy to Standard of Care (SOC) compared with placebo during the maintenance period only.
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Protection of trial subjects |
All study participants were required to read and sign an Informed Consent Form.
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Background therapy |
NA | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
28 Oct 2021
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Australia: 2
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Country: Number of subjects enrolled |
Brazil: 11
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Country: Number of subjects enrolled |
Canada: 6
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Country: Number of subjects enrolled |
China: 30
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Country: Number of subjects enrolled |
France: 5
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Country: Number of subjects enrolled |
Germany: 7
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Country: Number of subjects enrolled |
Hungary: 3
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Country: Number of subjects enrolled |
Italy: 4
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Country: Number of subjects enrolled |
Japan: 18
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Country: Number of subjects enrolled |
Latvia: 6
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Country: Number of subjects enrolled |
Netherlands: 3
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Country: Number of subjects enrolled |
Poland: 15
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Country: Number of subjects enrolled |
Russian Federation: 2
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Country: Number of subjects enrolled |
Serbia: 6
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Country: Number of subjects enrolled |
Spain: 5
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Country: Number of subjects enrolled |
Ukraine: 4
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Country: Number of subjects enrolled |
United States: 17
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Worldwide total number of subjects |
144
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EEA total number of subjects |
48
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
95
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Adolescents (12-17 years) |
32
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Adults (18-64 years) |
17
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 144 participants participated in the study at multiple investigative sites globally from 28 October 2021 to 11 April 2024. | |||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 144 participants with a diagnosis of Dravet Syndrome (DS) were randomized in a 1:1 ratio to receive either soticlestat or placebo. | |||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Data analyst, Carer | |||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||||||||||||||
Arm description |
Soticlestat placebo-matching mini-tablets or tablets, orally or via gastrostomy tube (G-tube) or low-profile gastric tube (MIC-KEY) button or jejunostomy tube (J-tube),twice daily (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 decided to discontinue the treatment. | |||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
Placebo
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Administered for 16 weeks in the Treatment Period.
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Arm title
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Soticlestat | |||||||||||||||||||||||||||
Arm description |
Participants weighing <45 kg: Soticlestat, mini-tablets, at the dose of 40 mg to 200 mg, orally or via G-tube or MIC-KEY button or J-tube, BID based on the 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 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 dose tapered down if participants decided to discontinue the treatment. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Soticlestat
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Investigational medicinal product code |
TAK-935
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Gastroenteral use, Oral use
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Dosage and administration details |
Administered for 16 weeks in the Treatment Period.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Soticlestat placebo-matching mini-tablets or tablets, orally or via gastrostomy tube (G-tube) or low-profile gastric tube (MIC-KEY) button or jejunostomy tube (J-tube),twice daily (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 decided to discontinue the treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Soticlestat
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Reporting group description |
Participants weighing <45 kg: Soticlestat, mini-tablets, at the dose of 40 mg to 200 mg, orally or via G-tube or MIC-KEY button or J-tube, BID based on the 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 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 dose tapered down if participants decided to discontinue the treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Soticlestat placebo-matching mini-tablets or tablets, orally or via gastrostomy tube (G-tube) or low-profile gastric tube (MIC-KEY) button or jejunostomy tube (J-tube),twice daily (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 decided to discontinue the treatment. | ||
Reporting group title |
Soticlestat
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Reporting group description |
Participants weighing <45 kg: Soticlestat, mini-tablets, at the dose of 40 mg to 200 mg, orally or via G-tube or MIC-KEY button or J-tube, BID based on the 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 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 dose tapered down if participants decided to discontinue the treatment. |
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End point title |
Percent Change From Baseline in Convulsive Seizure Frequency per 28 days During the Full Treatment Period | ||||||||||||
End point description |
Convulsive seizure frequency per 28 days was defined as 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 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. Modified Intent-to-Treat (mITT) Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period.
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End point type |
Primary
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End point timeframe |
Baseline; Full Treatment Period: Weeks 1 to 16
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Statistical analysis title |
Full Treatment Period | ||||||||||||
Comparison groups |
Placebo v Soticlestat
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Number of subjects included in analysis |
144
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.061 [1] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Hodges-Lehmann Location Shift Estimate | ||||||||||||
Point estimate |
-15.64
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-31.3 | ||||||||||||
upper limit |
0.24 | ||||||||||||
Notes [1] - The p-value was computed using Rank Analysis of Covariance (ANCOVA) model using treatment group, age stratum (≤6 years, >6 years), and rank of Baseline seizure frequency per 28 days as predictors. |
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End point title |
Percent Change From Baseline in Convulsive Seizure Frequency per 28 days During the Maintenance Period | ||||||||||||
End point description |
Convulsive seizure frequency per 28 days was defined as 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. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period. Overall number of participants analysed indicates the number of participants with data available for analyses.
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End point type |
Primary
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End point timeframe |
Baseline; Maintenance Period: Weeks 5 to 16
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Statistical analysis title |
Maintenance Period | ||||||||||||
Comparison groups |
Placebo v Soticlestat
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Number of subjects included in analysis |
137
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.089 [2] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Hodges-Lehmann Location Shift Estimate | ||||||||||||
Point estimate |
-14.29
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-30.51 | ||||||||||||
upper limit |
1.53 | ||||||||||||
Notes [2] - The p-value was computed using Rank ANCOVA model using treatment group, age stratum (≤6 years, >6 years), and rank of baseline seizure frequency per 28 days as predictors. |
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End point title |
Percentage of Responders During Maintenance Period | ||||||||||||
End point description |
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. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period. Overall number of participants analysed indicates the number of participants with data available for analyses.
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End point type |
Secondary
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End point timeframe |
Maintenance Period: Weeks 5 to 16
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Statistical analysis title |
Maintenance Period | ||||||||||||
Comparison groups |
Placebo v Soticlestat
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Number of subjects included in analysis |
137
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.01 [3] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
3.22
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
1.3 | ||||||||||||
upper limit |
7.96 | ||||||||||||
Notes [3] - The p-value was based on Cochran-Mantel-Haenszel (CMH) test stratified by age stratum (≤6 years, >6 years). |
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End point title |
Percentage of Responders During the Full Treatment Period | ||||||||||||
End point description |
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. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period.
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End point type |
Secondary
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End point timeframe |
Full Treatment Period: Weeks 1 to 16
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Statistical analysis title |
Full Treatment Period | ||||||||||||
Comparison groups |
Placebo v Soticlestat
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Number of subjects included in analysis |
144
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.008 [4] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
3.59
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
1.36 | ||||||||||||
upper limit |
9.49 | ||||||||||||
Notes [4] - The p-value was based on CMH test stratified by age stratum (<=6 years, >6 years). |
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End point title |
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 | |||||||||||||||||||||||||||
End point description |
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. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period.
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End point type |
Secondary
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End point timeframe |
Full Treatment Period: Weeks 1 to 16
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No statistical analyses for this end point |
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End point title |
Percentage of Participants With Caregiver Global Impression of Improvement (Care GI-I) Scale Responses as Per the Parent/Caregiver Reported Impression at Week 16 | |||||||||||||||||||||||||||||||||
End point description |
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 will completed the Care GI-I via interview. Higher score indicates worse symptoms. Percentages were rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period. Overall number of participants analysed indicates the number of participants with data available for analyses.
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End point type |
Secondary
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End point timeframe |
Week 16
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Statistical analysis title |
Care GI-I Scale Responses | |||||||||||||||||||||||||||||||||
Comparison groups |
Placebo v Soticlestat
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Number of subjects included in analysis |
134
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||||||||||||||||||||
P-value |
= 0.004 [5] | |||||||||||||||||||||||||||||||||
Method |
Cumulative Logit Model | |||||||||||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||||||||||||||||||||
Point estimate |
2.51
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Confidence interval |
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level |
95% | |||||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
1.33 | |||||||||||||||||||||||||||||||||
upper limit |
4.72 | |||||||||||||||||||||||||||||||||
Notes [5] - P-value was computed using Cumulative Logit model including treatment and age group as factors. |
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End point title |
Percentage of Participants With Clinical Global Impression of Improvement (CGI-I) Scale Responses as Per the Investigator Reported Impression at Week 16 | |||||||||||||||||||||||||||||||||
End point description |
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. Higher score indicates worse symptoms. Percentages were rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period. Overall number of participants analysed indicates the number of participants with data available for analyses.
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End point type |
Secondary
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End point timeframe |
Week 16
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Statistical analysis title |
CGI-I Scale Responses | |||||||||||||||||||||||||||||||||
Comparison groups |
Placebo v Soticlestat
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Number of subjects included in analysis |
142
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||||||||||||||||||||
P-value |
= 0.003 [6] | |||||||||||||||||||||||||||||||||
Method |
Cumulative Logit Model | |||||||||||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||||||||||||||||||||
Point estimate |
2.58
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Confidence interval |
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level |
95% | |||||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
1.37 | |||||||||||||||||||||||||||||||||
upper limit |
4.87 | |||||||||||||||||||||||||||||||||
Notes [6] - P-value was computed using Cumulative Logit model including treatment and age group as factors. |
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End point title |
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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). Higher score indicates worse symptoms. Percentages were rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period. Overall number of participants analysed indicates the number of participants with data available for analyses.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Week 16
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Statistical analysis title |
CGI-I Nonseizure Symptoms Alertness Domain | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Comparison groups |
Placebo v Soticlestat
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
142
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.741 [7] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Method |
Cumulative Logit Model | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Point estimate |
1.12
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
level |
95% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
lower limit |
0.56 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
upper limit |
2.26 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [7] - P-value was computed using Cumulative Logit model including treatment and age group as factors. |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Statistical analysis title |
CGI-I Nonseizure Symptoms Behaviors Domain | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Comparison groups |
Placebo v Soticlestat
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
142
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.693 [8] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Method |
Cumulative Logit Model | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Point estimate |
1.15
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
level |
95% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
lower limit |
0.58 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
upper limit |
2.28 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [8] - P-value was computed using Cumulative Logit model including treatment and age group as factors. |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Statistical analysis title |
CGI-I Nonseizure Symptoms Communication Domain | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Comparison groups |
Placebo v Soticlestat
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
142
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.901 [9] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Method |
Cumulative Logit Model | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Point estimate |
1.04
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
level |
95% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
lower limit |
0.54 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
upper limit |
2.02 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [9] - P-value was computed using Cumulative Logit model including treatment and age group as factors. |
|
|||||||||||||
End point title |
Change From Baseline in Quality of Life Inventory-Disability (QI-Disability) Total Score at Week 16 | ||||||||||||
End point description |
The QI-Disability tool is a parent/caregiver-reported questionnaire that 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.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Change From Baseline in QI-Disability Total Score | ||||||||||||
Comparison groups |
Placebo v Soticlestat
|
||||||||||||
Number of subjects included in analysis |
109
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.189 [10] | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-3.03
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-7.59 | ||||||||||||
upper limit |
1.52 | ||||||||||||
Notes [10] - P-value was based on MMRM analysis with change from baseline as outcome and baseline score as fixed continuous effect; treatment group, age stratum, analysis visit, and analysis visit by treatment group interaction as fixed categorical effects. |
|
||||||||||||||||||||||||||||||||||
End point title |
Percentage of Participants With CGI-I Seizure Intensity and Duration Instrument Responses as Per the Parent/Caregiver Reported Impression at Week 16 | |||||||||||||||||||||||||||||||||
End point description |
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 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). Higher score indicates worse symptoms. Percentages were rounded off to the nearest single decimal place. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period. Overall number of participants analysed indicates the number of participants with data available for analyses.
|
|||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||
End point timeframe |
Week 16
|
|||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
Statistical analysis title |
CGI-I Seizure Intensity and Duration | |||||||||||||||||||||||||||||||||
Comparison groups |
Placebo v Soticlestat
|
|||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
134
|
|||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||||||||||||||
P-value |
< 0.001 [11] | |||||||||||||||||||||||||||||||||
Method |
Cumulative Logit Model | |||||||||||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||||||||||||||||||||
Point estimate |
3.65
|
|||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||
level |
95% | |||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||
lower limit |
1.87 | |||||||||||||||||||||||||||||||||
upper limit |
7.13 | |||||||||||||||||||||||||||||||||
Notes [11] - P-value was computed using Cumulative Logit model including treatment and age group as factors. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Frequency of All Seizures Per 28 Days During the Maintenance Period | ||||||||||||
End point description |
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. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period. Overall number of participants analysed indicates the number of participants with data available for analyses.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline; Maintenance Period: Weeks 5 to 16
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Maintenance Period | ||||||||||||
Comparison groups |
Placebo v Soticlestat
|
||||||||||||
Number of subjects included in analysis |
137
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.565 [12] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Hodges-Lehmann Location Shift Estimate | ||||||||||||
Point estimate |
-9.97
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-29.01 | ||||||||||||
upper limit |
7.87 | ||||||||||||
Notes [12] - The p-value was computed using rank ANCOVA model using treatment group, age stratum (<=6 years, >6 years), and rank of Baseline seizure frequency per 28 days as predictors. |
|
|||||||||||||
End point title |
Percent Change From Baseline in Frequency of All Seizures Per 28 Days During the Full Treatment Period | ||||||||||||
End point description |
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 Treatment Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline; Full Treatment Period: Weeks 1 to 16
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Full Treatment Period | ||||||||||||
Comparison groups |
Placebo v Soticlestat
|
||||||||||||
Number of subjects included in analysis |
144
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.637 [13] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Hodges-Lehmann Location Shift Estimate | ||||||||||||
Point estimate |
-8.13
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-26.31 | ||||||||||||
upper limit |
10.13 | ||||||||||||
Notes [13] - The p-value was computed using rank ANCOVA model using treatment group, age stratum (<=6 years, >6 years), and rank of Baseline seizure frequency per 28 days as predictors. |
|
|||||||||||||
End point title |
Change from Baseline in Percentage of Convulsive Seizure-free Days During the Full Treatment Period | ||||||||||||
End point description |
Convulsive seizure-free days was defined as number of days a participant remained convulsive seizure free after initiation of the treatment. The percentage of convulsive seizure-free days during a period was defined as the number of non-missing seizure diary days when no convulsive seizures occurred during the period divided by the number of non-missing diary days during the period. The change from baseline was defined as the percentage of convulsive seizure -free days during the period minus the percentage of convulsive seizure-free days during the Baseline Period. A linear model with treatment group and age stratum as factors and baseline percentage as a covariate was used for analysis. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline up to Week 16
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Full Treatment Period | ||||||||||||
Comparison groups |
Placebo v Soticlestat
|
||||||||||||
Number of subjects included in analysis |
144
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
Method |
|||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
0.79
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-3.81 | ||||||||||||
upper limit |
5.4 |
|
|||||||||||||
End point title |
Longest Convulsive Seizure-free Interval During the Full Treatment Period | ||||||||||||
End point description |
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. mITT Analysis Set included all randomised participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Full Treatment Period: Weeks 1 to 16
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Full Treatment Period | ||||||||||||
Comparison groups |
Placebo v Soticlestat
|
||||||||||||
Number of subjects included in analysis |
144
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
Method |
|||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
5.6
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.1 | ||||||||||||
upper limit |
11.2 |
|
|||||||||||||
End point title |
Number of Days When Rescue Antiseizure Medication (ASM) is Used During the Full Treatment Period | ||||||||||||
End point description |
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. mITT Analysis Set included all randomized participants who had received at least one dose of study drug and had been assessed for seizures for at least one day in the Full Treatment Period.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Full Treatment Period: Weeks 1 to 16
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Number of Days Rescue ASM is Used | ||||||||||||
Comparison groups |
Placebo v Soticlestat
|
||||||||||||
Number of subjects included in analysis |
144
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
Method |
|||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-1.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-3.1 | ||||||||||||
upper limit |
1 |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From the first dose up to Week 19
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Safety Analysis Set included all participants who had taken at least one dose of study drug.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Soticlestat
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants weighing <45 kg: Soticlestat, mini-tablets, at the dose of 40 mg to 200 mg, orally or via G-tube or MIC-KEY button or J-tube, BID based on the 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 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 dose tapered down if participants decided to discontinue the treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
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Reporting group description |
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 decided to discontinue the treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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22 Apr 2022 |
The following changes were made as per Amendment 2: 1. Changed the number of estimated sites from 65 to 100. 2. Removed ophthalmological evaluations from safety endpoints. 3. Changed "convulsive seizures" to the "most impactful seizures", increased the number of convulsive seizures from ≥4 to ≥12 over 12 weeks before screening. 4. Broadened option to have virtual visits to allow more flexibility for participants/parents or caregivers who may have difficulties with travel for clinic visits, such as coronavirus disease 2019 (COVID-19) restrictions or other extenuating circumstances. 5. Updated the inclusion/exclusion criteria. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |