A Phase 2 Study of Radiprodil in Subjects With Drug-resistant Infantile Spasms (IS)

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the safety and tolerability, the pharmacokinetics and the efficacy of radiprodil in abolishing clinical spasms in subjects with drug-resistant infantile spasms

Detailed Description
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The study is divided into 3 parts: Part A - exploratory, Part B - confirmatory, Part C - open label extension

Official Title
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An Open-label Adaptive Study for the Assessment of Safety, Tolerability, Pharmacokinetics, and Efficacy of Multiple Doses of Radiprodil in Subjects With Drug-resistant Infantile Spasms

Conditions
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Infantile Spasms (IS)

Intervention / Treatment
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* Drug: Radiprodil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part A and B: Subject is male or female between 2 and 14 months of age The diagnosis of infantile spasms (IS) Subject has drug-resistant IS Part C: Subject participated in EP0078 Part A and received 2 radiprodil treatment cycles Subject experienced a relapse of spasms during the down taper or within 5 half-lives (3 days) discontinuation of radiprodil treatment in Cycle 2 of Part A Electroencephalogram (EEG) on baseline Part C is compatible with the diagnosis of infantile spasms Exclusion Criteria: Part A and B: More than 6 months have passed since the diagnosis of Infantile Spasms (IS) Current treatment with cannabinoids Subject has hematocrit greater than 60 Subject has any medical condition that, in the opinion of the Investigator, could jeopardize or would compromise the subject's ability to participate in this study Subject has a history or current condition predisposing to respiratory dysfunction Current treatment with felbamate Current treatment with perampanel Ketogenic diet Clinically significant lab abnormalities Clinically significant abnormality on ECG that, in the opinion of the Investigator, increases the safety risks of participating in the study Subject has a lethal or potentially lethal condition other than IS, with a significant risk of death before 18 months of age such as non-ketotic hyperglycinemia Body weight is below 4 kg Known history of severe anaphylactic reaction secondary to medication intake or serious blood dyscrasias Part C: Subject experienced any acute tolerability issues in either treatment cycle in Part A which the investigator and the sponsor medical monitor consider a risk for further participation Subject met any withdrawal criteria in Part A Subject has experienced any adverse effects or developed any new medical conditions since enrollment in Part A which the investigator considers could significantly increase the safety risks of participating in Part C

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 14 Months

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiprodil<br>Each subject will enter an individualized dose titration schedule. | Drug: Radiprodil<br>* Radiprodil at individualized doses.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects with clinical response on Day 14 of treatment with the maintenance dose of radiprodil | Clinical response is defined as no spasms on Day 14 of treatment with the maintenance dose of radiprodil. This is the primary efficacy variable for Part A. | Day 14, counting from the first day of radiprodil at maintenance dose | 
| Estimates of exposure generated from a population-Pharmacokinetic modelling | This is a primary variable for Part A. | Samples will be taken at baseline (time during Day -14 to -1 prior to dosing) and 3, 4, 5 & 12hr after the 1st dose on Day 1 of radiprodil low, mid & high dose. Blood samples will be taken at same timepoints after 1st dose on Day 2 of radiprodil low dose | 
| Percentage of subjects with electro-clinical response on Day 14 of treatment with the maintenance dose of radiprodil | Electro-clinical response is defined as no spasms and resolution of hypsarrythmia on Day 14 of treatment with the maintenance dose of radiprodil. This is the primary efficacy variable for Part B. | Day 14, counting from the first day of radiprodil at maintenance dose | 
| Incidence of Adverse Events (AEs) during the study | An AE is any untoward medical occurrence in a subject or trial subject that is administered a drug or biologic (medicinal product) or that is using a medical device. The event does not necessarily have a causal relationship with that treatment or usage. This is a primary variable for all parts. | From Baseline (Day -1) to the end of the Post-treatment Period (28 days post last dosing) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects with electro-clinical response on Day 14 of treatment with the maintenance dose of radiprodil | Electro-clinical response is defined as no spasms and resolution of hypsarrythmia on Day 14 of treatment with the maintenance dose of radiprodil. This is the secondary efficacy variable for Part A. | Day 14, counting from the first day of radiprodil at maintenance dose | 
| Percentage of subjects with clinical response on Day 14 of treatment with the maintenance dose of radiprodil | Clinical response is defined as no spasms on Day 14 of treatment with the maintenance dose of radiprodil. This is the secondary efficacy variable for Part B. | Day 14, counting from Day 14 of treatment with the maintenance dose of radiprodil | 
| Estimates of exposure generated from a population-Pharmacokinetic modelling | This is a secondary variable for Part B. | Pharmacokinetic samples will be collected on Day 1 of radiprodil low dose, mid dose and high dose. Additionally, blood samples will be taken after 1st dose on Day 2 of radiprodil low dose. | 
| Time to cessation of spasms | Time to cessation of spasms for clinical responders on Day 14 of treatment with the maintenance dose of radiprodol. This is a secondary efficacy variable for parts A and B. | During the first 14 days of treatment with radiprodil | 
| Percentage of responders with clinical relapse | The percentage of clinical responders on Day 14 of treatment with the maintenance dose of radiprodil with clinical relapse within 12 months. This is a secondary efficacy variable for parts A and B. | 12 months, counting from Day 14 of treatment with the maintenance dose of radiprodil | 
| Time to clinical relapse from the day of spasm cessation | This is a secondary efficacy variable for parts A and B. | From day of spasms cessation up to 42 months of age | 
| Percentage of electro-clinical responders with electro-clinical relapse | The percentage of electro-clinical responders on Day 14 of treatment with the maintenance dose of radiprodil with electro-clinical relapse within 12 months. This is a secondary efficacy variable for parts A and B. | 12 months, counting from Day 14 of treatment with the maintenance dose of radiprodil | 
| Time to electro-clinical relapse from the day of spasm cessation | This is a secondary efficacy variable for parts A and B. | From day of spasms cessation up to 42 months of age | 
| Percentage of subjects with extended clinical response | Extended clinical response is defined as no spasms for 28 consecutive days from Day 14 of treatment with the maintenance dose of radiprodil. This is a secondary efficacy variable for parts A and B. | 28 days, counting from Day 14 (inclusive) of treatment with the maintenance dose of radiprodil | 
| Percentage of subjects with extended electro-clinical response | Extended electro-clinical response is defined as no spasms and resolution of hypsarrythmia for 28 consecutive days from Day 14 of treatment with the maintenance dose of radiprodil. This is a secondary efficacy variable for parts A and B. | 28 days, counting from Day 14 (inclusive) of treatment with the maintenance dose of radiprodil | 
| Percentage of subjects with extended clinical response to each additional treatment cycle on Day 14 of treatment with the maintenance dose of radiprodil | Extended clinical response is defined as no spasms for 28 consecutive days from Day 14 of treatment with the maintenance dose of radiprodil. This is a secondary efficacy variable for part C. | 28 days, counting from Day 14 (inclusive) of maintenance dose | 
| Number of treatment cycles per subject | This is a secondary variable for Part C. | During Part C (Day -1 to Day 28 of the Maintenance Period) | 
| Percentage of subjects with electro-clinical response to each additional treatment cycle on Day 14 of treatment with the maintenance dose of radiprodil | Electro-clinical response is defined as no spasms and resolution of hypsarrythmia on Day 14 of treatment with the maintenance dose of radiprodil. This is a secondary efficacy variable for Part C. | Day 14, counting from the first day of maintenance dose | 
| Time to clinical relapse from the first day of no witnessed spasms for each treatment cycle | This is a secondary efficacy variable for part C. | From day of no witnessed spasms up to 42 months of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radiprodil, Infantile spasms, IS, Infantile, Spasms, Epilepsy, Paediatrics, Drug-resistant, West Syndrome, Hypsarrhythmia