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

JRCT ID: jRCT2051210074

Registered date:04/09/2021

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Dravet Syndrome
• Date of first enrollment: 28/10/2021
• Target sample size: 144
• Countries of recruitment: Ukraine,Japan,United States,Japan,Russia,Japan,Serbia,Japan,Belgium,Japan,France,Japan,Greece,Japan,Hungary,Japan,Italy,Japan,Latvia,Japan,Poland,Japan,Netherlands,Japan,United Kingdom,Japan,Australia,Japan,Canada,Japan,China,Japan,Spain,Japan,Brazil,Japan,Germany,Japan,Mexico,Japan
• Study type: Interventional

Intervention(s)

Soticlestat
Participants weighing <45 kg: Soticlestat, mini-tablets, at the dose of 40 mg to 200 mg, orally or via gastrostomy tube (G-tube) or low-profile gastric tube (MIC-KEY button) or jejunostomy tube (J-tube), twice daily (BID) based on the body weight up to 4 weeks in Titration Period. Participants will continue to receive dose that they are on at the end of Titration Period, for 12 weeks in Maintenance Period. The total duration of the treatment will be up to 16 weeks (Treatment Period). The dose will be tapered down if participants decide to discontinue the treatment. Participants weighing >=45kg: Soticlestat mini-tablets or tablets with a starting dose of 100mg BID followed by 200 mg BID and, then 300mg BID, up to 4 weeks in Titration Period. Participants will continue to receive 300mg BID for 12 weeks in the Maintenance Period. The total duration of the treatment will be up to 16 weeks (Treatment Period). The dose will be tapered down if participants decide to discontinue the treatment.

Placebo
Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks in the Titration Period. Participants will continue to receive the soticlestat placebo-matching mini-tablets or tablets for 12 weeks in the Maintenance Period. The total duration of the treatment will be up to 16 weeks. Soticlestat matching tapering will be done to maintain the blind if participants decide to discontinue the treatment.

Outcome(s)

Primary Outcome

1.Percent Change From Baseline in Convulsive Seizure Frequency per 28 days During the Full Treatment Period
Time Frame: Baseline up to Week 16
Convulsive seizure frequency per 28 days is defined as total number of convulsive seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline will be defined as (frequency of seizures per 28 days during Treatment Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.

2.Percent Change From Baseline in Convulsive Seizure Frequency per 28 days During the Maintenance Period (EMA Region Specific)
Time Frame: Baseline up to Week 16
Convulsive seizure frequency per 28 days is defined as total number of convulsive seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline will be defined as (frequency of seizures per 28 days during Maintenance Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100. This outcome measure is European Medicines Agency (EMA) specific.

Secondary Outcome

1.Percentage of Responders During Maintenance Period
Time Frame: Baseline up to Week 16
Responders are defined as those with >=50% reduction from baseline in convulsive seizures during the Maintenance Period.

2.Percentage of Responders During the Full Treatment Period
Time Frame: Baseline up to Week 16
Responders are defined as those with >=50% reduction from baseline in convulsive seizures during the full Treatment Period.

3.Percentage of Participants with =<0%, >0% to =<25%, >25% to =<50%, >50% to =<75%, and >75% to =<100% Reduction in Convulsive Seizures in a Cumulative Response Curve
Time Frame: Baseline up to Week 16

4.Caregiver Global Impression of Improvement (Care GI-I) Score
Time Frame: Baseline up to Week 16
The Care GI-I is a 7-point Likert scale that the caregiver uses to rate improvement in overall seizure control, behavior, safety and tolerability after the initiation of study drug relative to Baseline (before treatment with study drug). The participant will be rated as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). The parent/caregiver will complete the Care GI-I via interview. Higher score will indicate worse symptoms.

5.Clinical Global Impression of Improvement (CGI-I) Score
Time Frame: Baseline up to Week 16
The CGI-I Clinician is a 7-point Likert scale that the investigator uses to rate a participant's change (improvement) in overall seizure control, behavior, safety and tolerability, after the initiation of study drug relative to Baseline (before treatment with study drug). The participant will be 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). Higher score will indicate worse symptoms.

6.CGI-I Nonseizure Symptoms Score
Time Frame: Baseline up to Week 16
The CGI-I nonseizure symptoms instrument is a series of single-item assessments that the investigator uses to rate improvement in the symptoms and impacts in select nonseizure domains since initiating the study drug. The participant will be rated on 7-point scale by the investigator 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). At baseline, a symptoms form is completed by the clinician in collaboration with the primary caregiver to assess the participants status based on the presence of any nonseizure symptoms. Higher score will indicate worse symptoms.

7.Change in Quality of Life Inventory-Disability (QI-Disability) Score
Time Frame: Baseline up to Week 16
The QI-Disability tool is a parent/caregiver-reported questionnaire that evaluates quality of life in children with intellectual disabilities. It contains 32 items covering 6 domains of quality of life: physical health, positive emotions, negative emotions, social interaction, leisure and the outdoors, and independence. Scores are from a 5-point Likert scale and then are transformed to a scale of 0 to 100. Possible scores range from 0-100, with higher scores indicating better quality of life.

8.CGI-I Seizure Intensity and Duration Score
Time Frame: Baseline up to Week 16
The CGI-I seizure Intensity and duration instrument is used by the parent/caregiver to rate improvement in intensity and/or duration of the most impactful seizures from the first assessment. The participant's symptoms will be rated on 7-point scale as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). Higher score will indicate worse symptoms.

9.Percent Change From Baseline in Frequency of all Seizures per 28 Days During the Maintenance Period
Time Frame: Baseline up to Week 16
Seizure frequency per 28 days is defined as total number of seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline is defined as (frequency of seizures per 28 days during Maintenance Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.

10.Percent Change From Baseline in Frequency of all Seizures per 28 Days During the Full Treatment Period
Time Frame: Baseline up to Week 16
Seizure frequency per 28 days is defined as total number of seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline is defined as (frequency of seizures per 28 days during Treatment Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.

11.Percent Change From Baseline in Convulsive Seizure Frequency per 28 days During the Maintenance Period
Time Frame: Baseline up to Week 16
Convulsive seizure frequency per 28 days is defined as total number of convulsive seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline is defined as (frequency of seizures per 28 days during Maintenance Period - frequency of seizures per 28 days at Baseline) divided by frequency of seizures per 28 days at Baseline multiplied by 100.

12.Change from Baseline in Percentage of Convulsive Seizure-free Days
Time Frame: Baseline up to Week 16
Convulsive seizure-free days will be defined as number of days a participant remained convulsive seizure free after initiation of the treatment.

13.Longest Convulsive Seizure-free Interval
Time Frame: Baseline up to Week 16
Longest convulsive seizure-free interval will be defined as the longest time period that the participant remained convulsive seizure free after initiation of the treatment.

14.Number of Days When Rescue ASM is Used
Time Frame: Baseline up to Week 16

Key inclusion & exclusion criteria

• Age minimum: >= 2age old
• Age maximum: <= 21age old
• Gender: Both

Include criteria

1.Has documented clinical diagnosis of DS.
2.Had >=12 convulsive seizures over 12 weeks before screening based on the historical information and had >=4 convulsive seizures per 28 days during the 4- to 6-week prospective baseline period.
3.Weighs >=10 kg at the screening visit (Visit 1).
4.Failure to control seizures despite appropriate trials of at least 1 antiseizure medication (ASM) based on historical information and is currently on an antiseizure therapy or other treatment options considered as standard of care (SOC).
5.Artisanal cannabidiols are allowed at a stable dose for at least 4 weeks before the screening visit (Visit 1); the dosing regimen and manufacturer should remain constant throughout the study (Artisanal cannabidiols will not be counted as ASMs.).
6.Currently taking 0 to 4 ASMs at stable doses for at least 4 weeks before the screening visit (Visit 1); benzodiazepines used chronically (daily) to treat seizures are considered ASMs. Fenfluramine and cannabidiol (Epidiolex) are allowed where available and should be counted as an ASM. ASM dosing regimen must remain constant throughout the study.

• Exclude criteria: 1. Unstable, clinically significant neurologic (other than the disease being studied), psychiatric, cardiovascular, ophthalmologic, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, hematopoietic, endocrine disease, malignancy including progressive tumors, or other abnormality that may impact the ability to participate in the study or that may potentially confound the study results. It is the responsibility of the investigator to assess the clinical significance; however, consultation with the medical monitor may be warranted.

Related Information

• Primary Sponsor: Nonomura Hidenori
• Secondary ID(s): NCT04940624,2021-002480-22