Trial Outcomes & Findings for A Study of Soticlestat as an Add-on Therapy in Children, Teenagers, and Adults With Lennox-Gastaut Syndrome (NCT NCT04938427)

Last Updated: 2024-08-21

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

270 participants

Primary outcome timeframe

Baseline; Full Treatment Period: Weeks 1 to 16

Results posted on

2024-08-21

Participant Flow

Participants took part in the study at 84 investigative sites in Australia, Belgium, Canada, China, France, Germany, Greece, Hungary, Italy, Japan, Latvia, Netherlands, Poland, Russian Federation, Serbia, Spain, Ukraine and the United States from 08 November 2021 to 25 January 2024.

A total of 270 participants with a diagnosis of Lennox-Gastaut syndrome were randomized in a 1:1 ratio to receive either soticlestat or placebo.

Participant milestones

Participant milestones
Measure	Placebo 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 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.	Soticlestat Participants weighing \<45 kilograms (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 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.
Overall Study STARTED	136	134
Overall Study COMPLETED	126	114
Overall Study NOT COMPLETED	10	20

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo 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 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.	Soticlestat Participants weighing \<45 kilograms (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 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.
Overall Study Adverse Event	5	19
Overall Study Withdrawal by Parent/Guardian	2	0
Overall Study Withdrawal by Subject	1	0
Overall Study Reason Not Specified	2	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=136 Participants 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 decided to discontinue the treatment.	Soticlestat n=134 Participants 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 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.	Total n=270 Participants Total of all reporting groups
Age, Continuous	12.5 years STANDARD_DEVIATION 6.68 • n=5 Participants	13.4 years STANDARD_DEVIATION 9.35 • n=7 Participants	12.9 years STANDARD_DEVIATION 8.11 • n=5 Participants
Sex: Female, Male Gender · Female	52 Participants n=5 Participants	55 Participants n=7 Participants	107 Participants n=5 Participants
Sex: Female, Male Gender · Male	84 Participants n=5 Participants	79 Participants n=7 Participants	163 Participants n=5 Participants
Ethnicity (NIH/OMB) Ethnicity · Hispanic or Latino	4 Participants n=5 Participants	7 Participants n=7 Participants	11 Participants n=5 Participants
Ethnicity (NIH/OMB) Ethnicity · Not Hispanic or Latino	130 Participants n=5 Participants	124 Participants n=7 Participants	254 Participants n=5 Participants
Ethnicity (NIH/OMB) Ethnicity · Unknown or Not Reported	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) Race · American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Race · Asian	44 Participants n=5 Participants	42 Participants n=7 Participants	86 Participants n=5 Participants
Race (NIH/OMB) Race · Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Race · Black or African American	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Race · White	81 Participants n=5 Participants	86 Participants n=7 Participants	167 Participants n=5 Participants
Race (NIH/OMB) Race · More than one race	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Race · Unknown or Not Reported	6 Participants n=5 Participants	5 Participants n=7 Participants	11 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline; Full Treatment Period: Weeks 1 to 16

Population: Modified Intent-to-treat (mITT) Analysis Set included all randomized participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 day in the Full Treatment Period.

Outcome measures

Outcome measures
Measure	Placebo n=136 Participants 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 decided to discontinue the treatment.	Soticlestat n=134 Participants 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 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.
Percent Change From Baseline in Major Motor Drop (MMD) Seizure Frequency Per 28 Days During the Full Treatment Period	-6.69 percent change Interval -26.41 to 24.26	-6.11 percent change Interval -38.02 to 31.99

PRIMARY outcome

Timeframe: Baseline; Maintenance Period: Weeks 5 to 16

Population: mITT Analysis Set included all randomized participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 day in the Full Treatment Period. Overall number of participants analyzed indicates the number of participants with data available for analyses.

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.

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants 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 decided to discontinue the treatment.	Soticlestat n=124 Participants 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 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.
Percent Change From Baseline in Major Motor Drop (MMD) Seizure Frequency Per 28 Days During the Maintenance Period	-9.63 percent change Interval -30.15 to 23.71	-5.24 percent change Interval -41.94 to 42.29

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants 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 decided to discontinue the treatment.	Soticlestat n=124 Participants 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 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.
Percentage of Responders During the Maintenance Period	11.4 percentage of participants	19.4 percentage of participants

SECONDARY outcome

Timeframe: Full Treatment Period: Weeks 1 to 16

Population: mITT Analysis Set included all randomized participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 day in the Full Treatment Period.

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

Outcome measures

Outcome measures
Measure	Placebo n=136 Participants 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 decided to discontinue the treatment.	Soticlestat n=134 Participants 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 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.
Percentage of Responders During the Full Treatment Period	9.6 percentage of participants	16.4 percentage of participants

SECONDARY outcome

Timeframe: Full Treatment Period: Weeks 1 to 16

Population: mITT Analysis Set included all randomized participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 day in the Full Treatment Period.

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

Outcome measures

Outcome measures
Measure	Placebo n=136 Participants 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 decided to discontinue the treatment.	Soticlestat n=134 Participants 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 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.
Percentage of Participants With ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, >75% to ≤100% Reduction in MMD Seizure During the Full Treatment Period ≤0% Reduction	43.4 percentage of participants	43.3 percentage of participants
Percentage of Participants With ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, >75% to ≤100% Reduction in MMD Seizure During the Full Treatment Period >0% to ≤ 25% Reduction	29.4 percentage of participants	24.6 percentage of participants
Percentage of Participants With ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, >75% to ≤100% Reduction in MMD Seizure During the Full Treatment Period >25% to ≤ 50% Reduction	17.6 percentage of participants	15.7 percentage of participants
Percentage of Participants With ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, >75% to ≤100% Reduction in MMD Seizure During the Full Treatment Period >50% to ≤ 75% Reduction	6.6 percentage of participants	11.2 percentage of participants
Percentage of Participants With ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, >75% to ≤100% Reduction in MMD Seizure During the Full Treatment Period >75% to ≤ 100% Reduction	2.9 percentage of participants	5.2 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=130 Participants 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 decided to discontinue the treatment.	Soticlestat n=122 Participants 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 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.
Percentage of Participants With Caregiver Global Impression of Improvement (Care GI-I) Scale Responses as Per the Parent/Caregiver Reported Impression at Week 16 Score 1: Very Much Improved	0.8 percentage of participants	1.6 percentage of participants
Percentage of Participants With Caregiver Global Impression of Improvement (Care GI-I) Scale Responses as Per the Parent/Caregiver Reported Impression at Week 16 Score 2: Much Improved	13.1 percentage of participants	20.5 percentage of participants
Percentage of Participants With Caregiver Global Impression of Improvement (Care GI-I) Scale Responses as Per the Parent/Caregiver Reported Impression at Week 16 Score 3: Minimally Improved	25.4 percentage of participants	26.2 percentage of participants
Percentage of Participants With Caregiver Global Impression of Improvement (Care GI-I) Scale Responses as Per the Parent/Caregiver Reported Impression at Week 16 Score 4: No Change	46.2 percentage of participants	36.9 percentage of participants
Percentage of Participants With Caregiver Global Impression of Improvement (Care GI-I) Scale Responses as Per the Parent/Caregiver Reported Impression at Week 16 Score 5: Minimally Worse	11.5 percentage of participants	6.6 percentage of participants
Percentage of Participants With Caregiver Global Impression of Improvement (Care GI-I) Scale Responses as Per the Parent/Caregiver Reported Impression at Week 16 Score 6: Much Worse	3.1 percentage of participants	5.7 percentage of participants
Percentage of Participants With Caregiver Global Impression of Improvement (Care GI-I) Scale Responses as Per the Parent/Caregiver Reported Impression at Week 16 Score 7: Very Much Worse	0.0 percentage of participants	2.5 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=133 Participants 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 decided to discontinue the treatment.	Soticlestat n=132 Participants 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 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.
Percentage of Participants With Clinical Global Impression of Improvement (CGI-I) Scale Responses as Per the Investigator Reported Impression at Week 16 Score 1: Very Much Improved	1.5 percentage of participants	3.0 percentage of participants
Percentage of Participants With Clinical Global Impression of Improvement (CGI-I) Scale Responses as Per the Investigator Reported Impression at Week 16 Score 2: Much Improved	11.3 percentage of participants	15.9 percentage of participants
Percentage of Participants With Clinical Global Impression of Improvement (CGI-I) Scale Responses as Per the Investigator Reported Impression at Week 16 Score 3: Minimally Improved	17.3 percentage of participants	24.2 percentage of participants
Percentage of Participants With Clinical Global Impression of Improvement (CGI-I) Scale Responses as Per the Investigator Reported Impression at Week 16 Score 4: No Change	60.2 percentage of participants	43.2 percentage of participants
Percentage of Participants With Clinical Global Impression of Improvement (CGI-I) Scale Responses as Per the Investigator Reported Impression at Week 16 Score 5: Minimally Worse	5.3 percentage of participants	7.6 percentage of participants
Percentage of Participants With Clinical Global Impression of Improvement (CGI-I) Scale Responses as Per the Investigator Reported Impression at Week 16 Score 6: Much Worse	4.5 percentage of participants	4.5 percentage of participants
Percentage of Participants With Clinical Global Impression of Improvement (CGI-I) Scale Responses as Per the Investigator Reported Impression at Week 16 Score 7: Very Much Worse	0.0 percentage of participants	1.5 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=133 Participants 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 decided to discontinue the treatment.	Soticlestat n=132 Participants 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 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.
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Communication: Score 3: Minimally improved	12.8 percentage of participants	18.9 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Alertness: Score 1: Very Much Improved	1.5 percentage of participants	1.5 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Alertness: Score 2: Much Improved	7.5 percentage of participants	13.6 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Alertness: Score 3: Minimally Improved	12.8 percentage of participants	16.7 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Alertness: Score 4: No Change	71.4 percentage of participants	59.1 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Alertness: Score 5: Minimally Worse	4.5 percentage of participants	8.3 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Alertness: Score 6: Much Worse	2.3 percentage of participants	0.8 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Alertness: Score 7: Very Much Worse	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Communication: Score 1: Very Much Improved	1.5 percentage of participants	2.3 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Communication: Score 2: Much Improved	7.5 percentage of participants	10.6 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Communication: Score 4: No Change	71.4 percentage of participants	61.4 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Communication: Score 5: Minimally Worse	4.5 percentage of participants	6.1 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Communication: Score 6: Much Worse	2.3 percentage of participants	0.8 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Communication: Score 7: Very Much Worse	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Disruptive Behaviors: Score 1: Very Much Improved	0.0 percentage of participants	1.5 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Disruptive Behaviors: Score 2: Much Improved	1.5 percentage of participants	6.1 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Disruptive Behaviors: Score 3: Minimally improved	8.3 percentage of participants	10.6 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Disruptive Behaviors: Score 4: No Change	79.7 percentage of participants	75.0 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Disruptive Behaviors: Score 5: Minimally Worse	6.8 percentage of participants	3.8 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Disruptive Behaviors: Score 6: Much Worse	3.8 percentage of participants	2.3 percentage of participants
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Disruptive Behaviors: Score 7: Very Much Worse	0.0 percentage of participants	0.8 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=112 Participants 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 decided to discontinue the treatment.	Soticlestat n=107 Participants 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 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.
Change From Baseline in Quality of Life Inventory-Disability (QI-Disability) Total Score at Week 16	-1.66 score on a scale Standard Deviation 10.314	-1.17 score on a scale Standard Deviation 12.042

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=131 Participants 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 decided to discontinue the treatment.	Soticlestat n=122 Participants 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 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.
Percentage of Participants With CGI-I Seizure Intensity and Duration Instrument Responses as Per the Parent/Caregiver Reported Impression at Week 16 Score 1: Very Much Improved	0.8 percentage of participants	1.6 percentage of participants
Percentage of Participants With CGI-I Seizure Intensity and Duration Instrument Responses as Per the Parent/Caregiver Reported Impression at Week 16 Score 2: Much Improved	9.9 percentage of participants	18.9 percentage of participants
Percentage of Participants With CGI-I Seizure Intensity and Duration Instrument Responses as Per the Parent/Caregiver Reported Impression at Week 16 Score 3: Minimally Improved	24.4 percentage of participants	28.7 percentage of participants
Percentage of Participants With CGI-I Seizure Intensity and Duration Instrument Responses as Per the Parent/Caregiver Reported Impression at Week 16 Score 4: No Change	51.1 percentage of participants	39.3 percentage of participants
Percentage of Participants With CGI-I Seizure Intensity and Duration Instrument Responses as Per the Parent/Caregiver Reported Impression at Week 16 Score 5: Minimally Worse	9.9 percentage of participants	4.1 percentage of participants
Percentage of Participants With CGI-I Seizure Intensity and Duration Instrument Responses as Per the Parent/Caregiver Reported Impression at Week 16 Score 6: Much Worse	3.8 percentage of participants	5.7 percentage of participants
Percentage of Participants With CGI-I Seizure Intensity and Duration Instrument Responses as Per the Parent/Caregiver Reported Impression at Week 16 Score 7: Very Much Worse	0.0 percentage of participants	1.6 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants 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 decided to discontinue the treatment.	Soticlestat n=124 Participants 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 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.
Percent Change From Baseline in Frequency of All Seizures Per 28 Days During the Maintenance Period	-9.92 percent change Interval -30.55 to 15.55	-16.82 percent change Interval -40.93 to 20.6

SECONDARY outcome

Timeframe: Baseline; Full Treatment Period: Weeks 1 to 16

Population: mITT Analysis Set included all randomized participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 day in the Full Treatment Period.

Seizure frequency per 28 days was defined as the total number of seizures reported during the period divided by the number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline was defined as (frequency of seizures per 28 days during the full Treatment Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.

Outcome measures

Outcome measures
Measure	Placebo n=136 Participants 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 decided to discontinue the treatment.	Soticlestat n=134 Participants 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 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.
Percent Change From Baseline in Frequency of All Seizures Per 28 Days During the Full Treatment Period	-6.45 percent change Interval -28.11 to 16.16	-16.71 percent change Interval -39.84 to 18.53

SECONDARY outcome

Timeframe: Baseline up to Week 16

Population: mITT Analysis Set included all randomized participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 day in the Full Treatment Period.

MMD Seizure-free days was defined as the number of days the participant remained MMD seizure free after initiation of the treatment. The change from baseline in percentage of MMD seizure-free days, was defined as the percentage of seizure-free days during the Full Treatment Period minus the percentage of seizure-free days during the Baseline. A linear model with treatment group and age stratum as factors and baseline percentage as a covariate was used for analysis.

Outcome measures

Outcome measures
Measure	Placebo n=136 Participants 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 decided to discontinue the treatment.	Soticlestat n=134 Participants 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 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.
Change From Baseline in Percentage of MMD Seizure-free Days During the Full Treatment Period	5.37 percentage of days Standard Error 1.661	7.84 percentage of days Standard Error 1.676

SECONDARY outcome

Timeframe: Full Treatment Period: Weeks 1 to 16

Population: mITT Analysis Set included all randomized participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 day in the Full Treatment Period.

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

Outcome measures

Outcome measures
Measure	Placebo n=136 Participants 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 decided to discontinue the treatment.	Soticlestat n=134 Participants 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 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.
Longest MMD Seizure-free Interval During the Full Treatment Period	5.5 days Standard Error 1.39	10.9 days Standard Error 1.41

SECONDARY outcome

Timeframe: Full Treatment Period: Weeks 1 to 16

Population: mITT Analysis Set included all randomized participants who had received at least 1 dose of study drug and had been assessed for seizures for at least 1 day in the Full Treatment Period.

Use of rescue ASM was recorded in the case report form (CRF) along with start and end date of medication. Based on the start and end dates for all rescue ASMs taken by a participant, the number of days during the Full Treatment Period when rescue ASM was used was derived.

Outcome measures

Outcome measures
Measure	Placebo n=136 Participants 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 decided to discontinue the treatment.	Soticlestat n=134 Participants 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 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.
Number of Days When Rescue Antiseizure Medication (ASM) is Used During the Full Treatment Period	3.4 days Standard Error 1.12	2.5 days Standard Error 1.14

Adverse Events

Placebo

Serious events: 10 serious events

Other events: 51 other events

Deaths: 0 deaths

Soticlestat

Serious events: 11 serious events

Other events: 69 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=136 participants at risk 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 decided to discontinue the treatment.	Soticlestat n=134 participants at risk 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 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.
Infections and infestations COVID-19	2.2% 3/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	6.0% 8/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Nervous system disorders Change in seizure presentation	5.1% 7/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	12.7% 17/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Gastrointestinal disorders Constipation	2.2% 3/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	5.2% 7/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Metabolism and nutrition disorders Decreased appetite	2.2% 3/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	6.0% 8/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Injury, poisoning and procedural complications Fall	3.7% 5/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	5.2% 7/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
General disorders Fatigue	3.7% 5/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	6.0% 8/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Infections and infestations Nasopharyngitis	8.1% 11/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	7.5% 10/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
General disorders Pyrexia	8.1% 11/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	7.5% 10/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Nervous system disorders Somnolence	7.4% 10/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	14.2% 19/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Infections and infestations Upper respiratory tract infection	5.1% 7/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	8.2% 11/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.

Additional Information

Study Director

Takeda

Phone: +1-877-825-3327

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Placebo n=136 participants at risk 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 decided to discontinue the treatment.	Soticlestat n=134 participants at risk 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 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.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	1.5% 2/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Infections and infestations Bronchitis	0.74% 1/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.00% 0/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Infections and infestations COVID-19	0.74% 1/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.00% 0/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Infections and infestations COVID-19 pneumonia	0.00% 0/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.75% 1/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Eye disorders Cataract	0.00% 0/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.75% 1/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Nervous system disorders Change in seizure presentation	0.00% 0/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	1.5% 2/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Gastrointestinal disorders Diarrhoea	0.00% 0/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.75% 1/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Injury, poisoning and procedural complications Femur fracture	0.74% 1/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.00% 0/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Infections and infestations Influenza	0.00% 0/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.75% 1/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Respiratory, thoracic and mediastinal disorders Negative pressure pulmonary oedema	0.74% 1/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.00% 0/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Gastrointestinal disorders Oesophagitis	0.74% 1/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.00% 0/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Investigations Oxygen saturation decreased	0.00% 0/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.75% 1/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Infections and infestations Pneumonia	0.74% 1/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.75% 1/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Infections and infestations Pneumonia aspiration	0.74% 1/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.00% 0/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Infections and infestations Pneumonia bacterial	0.74% 1/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.00% 0/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Infections and infestations Pyelonephritis	0.00% 0/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.75% 1/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.74% 1/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.00% 0/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Infections and infestations Respiratory syncytial virus bronchitis	0.74% 1/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.00% 0/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Infections and infestations Rhinovirus infection	0.00% 0/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.75% 1/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Injury, poisoning and procedural complications Skin laceration	0.74% 1/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.00% 0/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Nervous system disorders Status epilepticus	0.74% 1/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	1.5% 2/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Injury, poisoning and procedural complications Tongue injury	0.74% 1/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.00% 0/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Infections and infestations Urinary tract infection	0.00% 0/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.75% 1/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.
Gastrointestinal disorders Vomiting	0.00% 0/136 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.	0.75% 1/134 • From the first dose up to Week 19 Safety Analysis Set included all participants who took at least 1 dose of the study drug.