A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-935 (OV935) as an Adjunctive Therapy in Pediatric Participants With Developmental and/or Epileptic Encephalopathies

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effect on the frequency of all seizures (convulsive and drop) in participants treated with TAK-935 compared to placebo.

Detailed Description
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The drug being tested in this study is called TAK-935 (OV935). This randomized, double-blind study will assess the effects of TAK-935 (OV935), compared to placebo, on efficacy, safety, and tolerability in pediatric participants with Dravet syndrome (DS) or Lennox Gastaut syndrome (LGS). This multi-center trial will be conducted worldwide and will enroll approximately 126 participants. Participants will be randomized based on their diagnosis in 2 categories; DS or LGS. The study will consist of 2 periods: Screening Period and Treatment Period. The overall duration of Treatment Period is up to 20 weeks including 8-week Dose Optimization Period and 12-week Maintenance Period. The overall time to participants in this study is approximately 30 weeks. Participants completing this study will have an option to enroll in the open-label extension study, under a separate protocol.

Official Title
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A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-935 (OV935) as an Adjunctive Therapy in Pediatric Patients With Developmental and/or Epileptic Encephalopathies

Conditions
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Epilepsy, Dravet Syndrome, Lennox-Gastaut Syndrome

Intervention / Treatment
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* Drug: TAK-935
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants aged greater than or equal to (>=) 2 and less than or equal to (<=) 17 years Clinical diagnosis of DS or LGS Weight of >=10 kilogram (kg) at the Screening visit Currently taking 1 to 4 anti-epileptic drugs (AEDs) at a stable dose Failed to become and remain seizure free with trials of at least 2 AEDs Exclusion Criteria: Has been admitted to a medical facility and intubated for treatment of status epilepticus 2 or more times in the 3 months immediately prior to the screening visit Non-epileptic events that cannot be reliably distinguished from epileptic seizures Participation in a clinical study involving another study drug in the previous month

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>TAK-935 placebo-matching tablets, orally or via gastrostomy tube (G-tube)/percutaneous endoscopic gastrostomy (PEG), twice a day (BID) up to Week 20. | Drug: Placebo<br>* TAK-935 placebo-matching tablets or mini-tablets.<br>|
| Experimental: TAK-935<br>TAK-935 tablets orally or via G-tube/PEG tube, BID. Participants weighing <60 kg received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20. | Drug: TAK-935<br>* TAK-935 tablets or mini-tablets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Seizure Frequency Per 28 Days During the Maintenance Period | Seizure frequency per 28 days is defined as total number of seizures (convulsive seizures for DS, drop seizures for LGS) 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. Negative percent change from Baseline indicates improvement. | Baseline; Maintenance Period: Weeks 9 to 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Seizure Frequency Per 28 Days During the Treatment Period | Seizure Frequency per 28 days is defined as total number of Seizures reported (convulsive seizures for DS, drop seizures for LGS) 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 frequency of seizures per 28 days at baseline multiplied by 100. Negative percent change from Baseline indicates improvement. | Baseline; Treatment Period: Weeks 0 to 20 | 
| Percent Change From Baseline in Convulsive Seizure Frequency Per 28 Days in Participants With Dravet Syndrome Stratum During the Maintenance Period | 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 [(Maintenance Period Convulsive Seizure Frequency - Baseline Period Convulsive Seizure Frequency) divided by Baseline Convulsive Seizure Frequency] multiplied by 100. Negative percent change from Baseline indicates improvement. | Baseline; Maintenance Period: Weeks 9 to 20 | 
| Percent Change From Baseline in Drop Seizure Frequency Per 28 Days in Participants With the Lennox-Gastaut Syndrome (LGS) Stratum During the Maintenance Period | Drop seizure frequency per 28 days is defined as total number of drop 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 [(Maintenance Period Drop Seizure Frequency - Baseline Period Drop Seizure Frequency) divided by Baseline Drop Seizure Frequency] multiplied by 100. Negative percent change from Baseline indicates improvement. | Baseline; Maintenance Period: Weeks 9 to 20 | 
| Percentage of Participants With LGS Stratum Considered Treatment Responders Throughout the Maintenance Period | Responders are defined as having over 50% drop seizure reduction compared to Baseline. Percent Reduction from Baseline (%) is defined as [(Maintenance Period Drop Seizure Frequency - Baseline Period Drop Seizure Frequency) divided by Baseline Drop Seizure Frequency] multiplied by 100. Data is reported as reduction of 25%, 50%, 75% and 100% or more in drop seizures from Baseline. | Maintenance Period: Weeks 9 to 20 | 
| Percentage of Participants With Dravet Syndrome Stratum Considered Treatment Responders Throughout the Maintenance Period | Responders are defined as having over 50% convulsive seizure reduction compared to Baseline. Percent Reduction from Baseline (%) is defined as [(Maintenance Period Convulsive Seizure Frequency - Baseline Period Convulsive Seizure Frequency) divided by Baseline Convulsive Seizure Frequency] multiplied by 100. Data is reported as reduction of 25%, 50%, 75% and 100% or more in drop seizures from Baseline. | Maintenance Period: Weeks 9 to 20 | 
| Change From Baseline in Clinician's Clinical Global Impression of Severity (CGI-S) Responses of Investigator Reported Impression of Efficacy and Tolerability of Study Drug | The CGI-Severity (CGI-S) focuses on clinicians' observations of the participant's cognitive, functional, and behavioral performance since the beginning of the study. The CGI-S is rated on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal) through to 7 (amongst the most severely ill participants). A negative change from Baseline indicates improvement. | Baseline and Week 20 | 
| Percentage of Participants With Clinical Global Impression of Change (CGI-C) Responses as Per the Investigator Reported Impression of Efficacy and Tolerability TAK-935 | CGI-Change (CGI-C) treatment response ratings should take account of both therapeutic efficacy and treatment-related AEs. Each component of the CGI is rated separately; the instrument does not yield a global score. The CGI-C is rated on a 7-point scale, where, 0 = Marked improvement and no side-effects, 1 = Marked improvement and minimal side-effects, 2 = No Change, 3 = Minimal improvement and marked side-effects and 4 = Unchanged or worse and side-effects outweigh the therapeutic effect. Lower scores indicated improvement. | Week 20 | 
| Percentage of Participants With Caregiver Global Impression of Change (Care GI-C) Responses as Per the Parent/Family Reported Impression of Efficacy and Tolerability of TAK-935 | The Care GI-C is rated on a 7-point scale, with the severity of illness scale where, 1 = Very much improved, 2 = Much improved, 3 = Slightly improved, 4 = No change, 5 = Slightly worse, 6 = Much worse and 7 = Very much worse. Lower scores indicated improvement. | Week 20 | 
| Change From Baseline in Plasma 24S-Hydroxycholesterol (24HC) Levels in Participants Treated With TAK-935 as an Adjunctive Therapy | A negative change from Baseline indicates improvement. | Baseline and Week 24 | 
| Change From Baseline in Seizure Frequency in Participants Treated With TAK-935 as an Adjunctive Therapy | Seizure frequency was based on convulsive seizures for the participants in the Dravet Syndrome Indication and Drop Seizures for the participants in the LGS Indication. Seizure frequency per 28 days = (total number of seizures reported during the period) / (number of days during the period seizures were assessed) * 28. A negative change from Baseline indicates improvement. | Baseline and Week 20 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy, Brain Diseases, Central Nervous System Diseases, Tuberous Sclerosis, CDKL5 deficiency disorder, Dup15Q syndrome, Anoxic brain injury, Infantile spams, West syndrome, Cortical dysplasia, SCN1A, OV-935, Cholesterol 24S-hydroxylase inhibitor, Seizure, Anti-epileptic drug, Anticonvulsants, Nervous System Diseases, Drop seizure, Atonic seizure