Study of Adjunctive Ganaxolone Treatment in Children and Young Adults With CDKL5 Deficiency Disorder

Study Overview
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Brief Summary
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A clinical study to evaluate the efficacy, safety, and tolerability of adjunctive ganaxolone therapy compared to placebo for the treatment of seizures in children and young adults with genetically confirmed CDKL5 gene mutation.

Detailed Description
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The Marigold Study is a global, double-blind, placebo-controlled, Phase 3 clinical trial that will enroll approximately 70 patients between the ages of 2 and 21 with a confirmed disease-related CDKL5 gene variant. Patients will undergo a baseline period before being randomized to receive, in addition to their existing anti-seizure treatment, either ganaxolone or placebo for 17 weeks. Following the treatment period, all patients that meet certain eligibility requirements will have the opportunity to receive ganaxolone in the open label phase of the study. The study's primary efficacy endpoint is percent reduction in seizures. Secondary outcome measures will include non-seizure-related endpoints to capture certain behavioral and sleep disturbances that have been seen in previous clinical studies with ganaxolone.

Official Title
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A Double-blind, Randomized, Placebo-controlled Trial of Adjunctive Ganaxolone Treatment in Children and Young Adults With Cyclin-dependent Kinase-like 5 (CDKL5) Deficiency Disorder (CDD) Followed by Long-term Open-label Treatment

Conditions
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CDKL5 Deficiency Disorder

Intervention / Treatment
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* Drug: ganaxolone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Genetically confirmed CDKL5 gene mutation, seizure onset by 1 year of age and lack of independent ambulation by 2 years of age Failure to control seizures despite 2 or more anti-seizure medications At least 16 seizures per 28 days of primary seizure types On a stable regimen of 0-4 anti-seizure medications (Vagus nerve stimulator, ketogenic diet, and modified Atkins diet do not count towards this limit) Additional Inclusion Criteria apply and can be discussed with study team Exclusion Criteria: Previous exposure to ganaxolone West Syndrome with hypsarrhythmia pattern on EEG or seizures predominantly of Infantile Spasms type Use of adrenocorticotropic hormone (ACTH), prednisone or other glucocorticoid or use of moderate or strong inducers or inhibitors of CYP3A4/5/7 are prohibited Use of tetrahydrocannabinol (THC) or cannabidiol (CBD) is prohibited during the double-blind phase, unless patient has a prescription of Epidiolex® Exposure to any other investigational drug within 30 days or fewer than 5 half-lives prior to screening Plasma allopregnanolone-sulfate (Allo-S) levels greater than or equal to 6.0 ng/ml at screening visit Additional Exclusion Criteria apply and can be discussed with study team

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 21 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
Interventional Model Description: The double-blind phase will randomize subjects to adjunctive ganaxolone or placebo at a 1:1 ratio to standard of care
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ganaxolone<br>ganaxolone suspension (50 mg/ml) 3x's /day for 17 weeks | Drug: ganaxolone<br>* active drug<br>|
| Placebo Comparator: Placebo<br>placebo suspension 3x's /day for 17 weeks | Drug: Placebo<br>* inactive<br>* Other names: Placebo (for ganaxolone);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of 28-day Seizure Frequency for Major Motor Seizure Types | Summary of 28-day seizure frequency for Major Motor Seizure Types during the double-blind treatment period relative to the 6-week prospective baseline period Note: Summaries are based on the sum of the individual seizures, the countable seizures, and the clusters with uncountable seizures (each cluster with uncountable seizures counts as 1 seizure). Within the baseline and post baseline intervals, 28-day seizure frequency was calculated as the total number of seizures in the interval divided by the number of days with available seizure data in the interval, multiplied by 28. | End of the double-blind 17 week treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Caregiver Global Impression of Change in Attention | Caregiver global impression of change in attention during the double-blind treatment period of ganaxolone compared to placebo. Investigators and caregivers reported improvements in attention, mood, behavior and sleep via investigator narratives | End of the double-blind 17 week treatment period | 
| Caregiver Global Impression of Change in Target Behavior | Caregiver global impression of change in target behavior during the double-blind treatment period of ganaxolone compared to placebo. Investigators and caregivers reported improvements in attention, mood, behavior and sleep via investigator narratives. | End of the double-blind 17 week treatment period | 
| Clinical Global Impression of Improvement - Parent/Caregiver | Clinical global impression of improvement during the double-blind treatment period of ganaxolone compared to placebo. The CGI is rated on a 7-point scale, with the severity of illness scale using a range of responses. | End of the double-blind 17 week treatment period | 
| Clinical Global Impression of Improvement - Clinician | Clinical global impression of improvement during the double-blind treatment period of ganaxolone compared to placebo | [Time Frame: End of the double-blind 17 week treatment period] | 
| Percentage of Seizure-free Days for Major Motor Seizure Types | Percentage of Seizure-free Days for Major Motor Seizure types during the double-blind treatment period of ganaxolone compared to placebo. The major motor seizure types include bilateral tonic (sustained motor activity = 3 seconds), generalized tonic-clonic, atonic/drop, bilateral clonic, and focal to bilateral tonic-clonic. | End of the double-blind 17 week treatment period | 
| Arithmetic Change in Longest Seizure Free Interval, Based on Primary Seizure Types | Arithmetic change in longest seizure free interval, based on primary seizure types during the double-blind treatment period of ganaxolone compared to placebo | End of the double-blind 17 week treatment period | 
| Caregiver Global Impression of Change in Seizure Intensity and Duration | Caregiver global impression of change in seizure intensity and duration during the double-blind treatment period of ganaxolone compared to placebo. CGI-C is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. | End of the double-blind 17 week treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory seizures, genetic pediatric encephalopathies, epilepsy in children, seizure disorder