A Study of Soticlestat as an Add-on Therapy in Children,... | NCT04938427

ID	Type	Description	Link
2021-002481-40	EudraCT Number
jRCT2051210073	Registry Identifier	jRCT

Status Module

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Placebo	Placebo Comparator	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.	Drug: Placebo
Soticlestat	Experimental	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.	Drug: Soticlestat

Name	Type	Description	Arm Group Labels	Other Names
Placebo	Drug	Soticlestat placebo-matching mini-tablets or tablets.	Placebo

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Percent Change From Baseline in Major Motor Drop (MMD) Seizure Frequency Per 28 Days During the Full Treatment Period	MMD seizure frequency per 28 days was defined as the total number of MMD seizures reported during the period divided by the number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline was defined as (frequency of seizures per 28 days during the full Treatment Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.	Baseline; Full Treatment Period: Weeks 1 to 16
Percent Change From Baseline in Major Motor Drop (MMD) Seizure Frequency Per 28 Days During the Maintenance Period	MMD seizure frequency per 28 days was defined as the total number of MMD seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline was defined as (frequency of seizures per 28 days during the Maintenance Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.	Baseline; Maintenance Period: Weeks 5 to 16

Secondary Outcomes

Measure	Description	Time Frame
Percentage of Responders During the Maintenance Period	Responders are defined as those with ≥50% reduction from Baseline in MMD seizures during the Maintenance Period. Percentages are rounded off to the nearest single decimal place.	Maintenance Period: Weeks 5 to 16
Percentage of Responders During the Full Treatment Period

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Has documented clinical diagnosis of LGS.
Has had ≥8 MMD seizures each month in the 3 months prior to Screening based on the historical information and has had ≥8 MMD seizures per 28 days during the 4 to 6 week prospective Baseline Period.
Weighs ≥10 kg at the Screening Visit (Visit 1).
Failure to control seizures despite appropriate trials of at least 1 ASM based on historical information, and is currently on an antiseizure therapy or other treatment options considered as standard of care (SOC).
Artisanal cannabidiols are allowed at a stable dose for at least 4 weeks before the screening visit (Visit 1); the dosing regimen and manufacturer should remain constant throughout the study. (Artisanal cannabidiols will not be counted as ASMs.)
Currently taking 0 to 3 ASMs at stable doses for at least 4 weeks before the Screening Visit (Visit 1); Fenfluramine and cannabidiol (Epidiolex) are allowed where available and counted as an ASM. ASM dosing regimen must remain constant throughout the study.

Exclusion Criteria:

Admitted to a medical facility and intubated for treatment of status epilepticus 2 or more times in the 3 months immediately before Screening (Visit 1). For the purpose of this exclusion criterion, status is defined as continuous seizure activity lasting longer than 5 minutes or repeated seizures without return to Baseline in between seizures.
Unstable, clinically significant neurologic (other than the disease being studied), psychiatric, cardiovascular, ophthalmologic, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, hematopoietic, endocrine disease, malignancy including progressive tumors, or other abnormality that may impact the ability to participate in the study or that may potentially confound the study results. It is the responsibility of the investigator to assess the clinical significance; however, consultation with the medical monitor may be warranted.
Considered by the investigator to be at imminent risk of suicide or injury to self, others, or property, or the participant has attempted suicide within 12 months before the Screening Visit (Visit 1). Participants who have positive answers on item numbers 4 or 5 on the Columbia suicide severity rating scale (C-SSRS) before dosing (Visit 2) are excluded. This scale will only be administered to participants aged ≥6 years.

Name	Affiliation	Role
Medical Director	Takeda	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Phoenix Childrens Hospital		Phoenix	Arizona	85016	United States
Center For Neurosciences

Label	URL
Related Info	View source

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Apr 22, 2022	Jul 25, 2024

Arm/Group Information

ID	Title	Description
BG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.
BG001	Soticlestat	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.
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00012.5± 6.68 BG00113.4± 9.35 BG00212.9± 8.11

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Gender

Title	Measurements
Female	BG00052 BG00155 BG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Ethnicity

Title	Measurements
Hispanic or Latino	BG0004 BG0017 BG002

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Race

Title	Measurements
American Indian or Alaska Native	BG0000 BG0010 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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

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

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.

Posted

Median

Inter-Quartile Range

percent change

Baseline; Full Treatment Period: Weeks 1 to 16

ID	Title	Description
OG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.
OG001	Soticlestat	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.

Units	Counts
Participants	OG000136 OG001134

Title

Denominators

Categories

Title	Measurements
	OG000-6.69(-26.41 to 24.26) OG001-6.11(-38.02 to 31.99)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		ANCOVA		=0.785	The p-value was calculated 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.	Hodges-Lehmann Location Shift Estimate	-1.17			2-Sided	95	-13.02	9.99			The location shift between soticlestat and placebo (soticlestat - placebo) and its asymptotic 95% confidence interval (CI) are based on the Hodges-Lehmann estimation.		Superiority

Primary

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

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

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.

Posted

Median

Inter-Quartile Range

percent change

Baseline; Maintenance Period: Weeks 5 to 16

ID	Title	Description
OG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.
OG001	Soticlestat	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.

Secondary

Percentage of Responders During the Maintenance Period

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

Posted

Number

percentage of participants

Maintenance Period: Weeks 5 to 16

ID	Title	Description
OG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.
OG001	Soticlestat	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.

Secondary

Percentage of Responders During the Full Treatment Period

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

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.

Posted

Number

percentage of participants

Full Treatment Period: Weeks 1 to 16

ID	Title	Description
OG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.
OG001	Soticlestat	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.

Secondary

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

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

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.

Posted

Number

percentage of participants

Full Treatment Period: Weeks 1 to 16

ID	Title	Description
OG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.
OG001	Soticlestat	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.

Secondary

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

The Care GI-I is a 7-point Likert scale that the caregiver used to rate improvement in overall seizure control, behavior, safety and tolerability after the initiation of study drug relative to Baseline (before treatment with the study drug). The participant was rated as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). The parent/caregiver completed the Care GI-I via interview. Lower scores indicate improvement. Percentages are rounded off to the nearest single decimal place.

Posted

Number

percentage of participants

Week 16

ID	Title	Description
OG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.
OG001

Secondary

Percentage of Participants With Clinical Global Impression of Improvement (CGI-I) Scale Responses as Per the Investigator Reported Impression at Week 16

The CGI-I (Clinician) is a 7-point Likert scale that the investigator to rate a participant's change (improvement) in overall seizure control, behavior, safety and tolerability after the initiation of study drug relative to Baseline (before treatment with the study drug). The participant was rated as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). The investigator or designee will complete the CGI-I. Lower scores indicate improvement. Percentages are rounded off to the nearest single decimal place.

Posted

Number

percentage of participants

Week 16

ID	Title	Description
OG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.
OG001

Secondary

Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16

The CGI-I nonseizure symptoms instrument is a series of single-item assessments that the investigator used to rate improvement in the symptoms and impacts in select nonseizure domains (alertness, communication, and disruptive behaviors) since initiating the study drug. The participant was rated by the investigator for each domain as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). Lower scores indicated improvement. Data for percentage of participants categorized based on the responses for each domain are presented. Percentages are rounded off to the nearest single decimal place.

Posted

Number

percentage of participants

Week 16

ID	Title	Description
OG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.

Secondary

Change From Baseline in Quality of Life Inventory-Disability (QI-Disability) Total Score at Week 16

The QI-Disability tool is a parent/caregiver-reported questionnaire evaluated the quality of life in children with intellectual disabilities. It contains 32 items covering 6 domains of quality of life: physical health, positive emotions, negative emotions, social interaction, leisure and the outdoors, and independence. Each QI-Disability item is rated on a Likert scale of: Never, Rarely, Sometimes, Often, and Very Often. Items were linearly transformed to a scale of 0 to 100, with higher scores representing better quality of life. Domain scores are calculated by averaging item scores. The domain scores are summed and divided by 6 to yield a total score. The total score ranges from 0 to 100, with higher scores indicating a better quality of life. A negative change from Baseline implies deteriorating quality of life. Mixed-effects model for repeated measures (MMRM) was used for analysis.

Posted

Mean

Standard Deviation

score on a scale

Baseline, Week 16

ID	Title	Description
OG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.

Secondary

Percentage of Participants With CGI-I Seizure Intensity and Duration Instrument Responses as Per the Parent/Caregiver Reported Impression at Week 16

The CGI-I seizure intensity and duration instrument was used by the parent/caregiver to rate changes in intensity and/or duration of the most impactful seizures from the first assessment. The participant's symptoms were rated as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). Lower scores indicate improvement. Percentages are rounded off to the nearest single decimal place.

Posted

Number

percentage of participants

Week 16

ID	Title	Description
OG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.
OG001	Soticlestat

Secondary

Percent Change From Baseline in Frequency of All Seizures Per 28 Days During the Maintenance Period

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

Posted

Median

Inter-Quartile Range

percent change

Baseline; Maintenance Period: Weeks 5 to 16

ID	Title	Description
OG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.
OG001	Soticlestat	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.

Secondary

Percent Change From Baseline in Frequency of All Seizures Per 28 Days During the Full Treatment Period

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

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.

Posted

Median

Inter-Quartile Range

percent change

Baseline; Full Treatment Period: Weeks 1 to 16

ID	Title	Description
OG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.
OG001	Soticlestat	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.

Secondary

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

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

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.

Posted

Least Squares Mean

Standard Error

percentage of days

Baseline up to Week 16

ID	Title	Description
OG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.
OG001	Soticlestat	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.

Secondary

Longest MMD Seizure-free Interval During the Full Treatment Period

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

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.

Posted

Least Squares Mean

Standard Error

days

Full Treatment Period: Weeks 1 to 16

ID	Title	Description
OG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.
OG001	Soticlestat	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.

Secondary

Number of Days When Rescue Antiseizure Medication (ASM) is Used During the Full Treatment Period

Use of rescue ASM was recorded in the case report form (CRF) along with start and end date of medication. Based on

the start and end dates for all rescue ASMs taken by a participant, the number of days during the Full Treatment Period when rescue ASM was used was derived.

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.

Posted

Least Squares Mean

Standard Error

days

Full Treatment Period: Weeks 1 to 16

ID	Title	Description
OG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.
OG001	Soticlestat	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.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.	0	136	10	136	51	136
EG001	Soticlestat	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.	0	134	11	134	69	134

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 26.1	Systematic Assessment	EG0000 affected136 at risk EG0012 affected134 at risk
Bronchitis	Infections and infestations	MedDRA 26.1	Systematic Assessment	EG0001 affected136 at risk EG0010 affected134 at risk
COVID-19	Infections and infestations	MedDRA 26.1	Systematic Assessment	EG0001 affected136 at risk EG0010 affected134 at risk
COVID-19 pneumonia	Infections and infestations	MedDRA 26.1	Systematic Assessment	EG0000 affected136 at risk EG0011 affected134 at risk
Cataract	Eye disorders	MedDRA 26.1	Systematic Assessment	EG0000 affected136 at risk EG0011 affected134 at risk
Change in seizure presentation	Nervous system disorders	MedDRA 26.1	Systematic Assessment	EG0000 affected136 at risk EG0012 affected134 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 26.1	Systematic Assessment	EG0000 affected136 at risk EG0011 affected134 at risk
Femur fracture	Injury, poisoning and procedural complications	MedDRA 26.1	Systematic Assessment	EG0001 affected136 at risk EG0010 affected134 at risk
Influenza	Infections and infestations	MedDRA 26.1	Systematic Assessment	EG0000 affected136 at risk EG0011 affected134 at risk
Negative pressure pulmonary oedema	Respiratory, thoracic and mediastinal disorders	MedDRA 26.1	Systematic Assessment	EG0001 affected136 at risk EG0010 affected134 at risk
Oesophagitis	Gastrointestinal disorders	MedDRA 26.1	Systematic Assessment	EG0001 affected136 at risk EG0010 affected134 at risk
Oxygen saturation decreased	Investigations	MedDRA 26.1	Systematic Assessment	EG0000 affected136 at risk EG0011 affected134 at risk
Pneumonia	Infections and infestations	MedDRA 26.1	Systematic Assessment	EG0001 affected136 at risk EG0011 affected134 at risk
Pneumonia aspiration	Infections and infestations	MedDRA 26.1	Systematic Assessment	EG0001 affected136 at risk EG0010 affected134 at risk
Pneumonia bacterial	Infections and infestations	MedDRA 26.1	Systematic Assessment	EG0001 affected136 at risk EG0010 affected134 at risk
Pyelonephritis	Infections and infestations	MedDRA 26.1	Systematic Assessment	EG0000 affected136 at risk EG0011 affected134 at risk
Respiratory distress	Respiratory, thoracic and mediastinal disorders	MedDRA 26.1	Systematic Assessment	EG0001 affected136 at risk EG0010 affected134 at risk
Respiratory syncytial virus bronchitis	Infections and infestations	MedDRA 26.1	Systematic Assessment	EG0001 affected136 at risk EG0010 affected134 at risk
Rhinovirus infection	Infections and infestations	MedDRA 26.1	Systematic Assessment	EG0000 affected136 at risk EG0011 affected134 at risk
Skin laceration	Injury, poisoning and procedural complications	MedDRA 26.1	Systematic Assessment	EG0001 affected136 at risk EG0010 affected134 at risk
Status epilepticus	Nervous system disorders	MedDRA 26.1	Systematic Assessment	EG0001 affected136 at risk EG0012 affected134 at risk
Tongue injury	Injury, poisoning and procedural complications	MedDRA 26.1	Systematic Assessment	EG0001 affected136 at risk EG0010 affected134 at risk
Urinary tract infection	Infections and infestations	MedDRA 26.1	Systematic Assessment	EG0000 affected136 at risk EG0011 affected134 at risk
Vomiting	Gastrointestinal disorders	MedDRA 26.1	Systematic Assessment	EG0000 affected136 at risk EG0011 affected134 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
COVID-19	Infections and infestations	MedDRA 26.1	Systematic Assessment	EG0003 affected136 at risk EG0018 affected134 at risk
Change in seizure presentation	Nervous system disorders	MedDRA 26.1	Systematic Assessment	EG0007 affected136 at risk EG00117 affected134 at risk
Constipation	Gastrointestinal disorders	MedDRA 26.1	Systematic Assessment	EG0003 affected136 at risk EG0017 affected134 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA 26.1	Systematic Assessment	EG0003 affected136 at risk EG0018 affected134 at risk
Fall	Injury, poisoning and procedural complications	MedDRA 26.1	Systematic Assessment	EG0005 affected136 at risk EG0017 affected134 at risk
Fatigue	General disorders	MedDRA 26.1	Systematic Assessment	EG0005 affected136 at risk EG0018 affected134 at risk
Nasopharyngitis	Infections and infestations	MedDRA 26.1	Systematic Assessment	EG00011 affected136 at risk EG00110 affected134 at risk
Pyrexia	General disorders	MedDRA 26.1	Systematic Assessment	EG00011 affected136 at risk EG00110 affected134 at risk
Somnolence	Nervous system disorders	MedDRA 26.1	Systematic Assessment	EG00010 affected136 at risk EG00119 affected134 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA 26.1	Systematic Assessment	EG0007 affected136 at risk EG00111 affected134 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.

ID	Term
D000073376	Epileptic Syndromes
D004827	Epilepsy
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D030342	Genetic Diseases, Inborn
D009358	Congenital, Hereditary, and Neonatal Diseases and Abnormalities