Ataluren for Nonsense Mutation in CDKL5 and Dravet Syndrome

Study Overview
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Brief Summary
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This is a phase 2, crossover study of Ataluren for the treatment of nonsense mutation Dravet syndrome or cyclin-dependent kinase-like 5 (CDKL5) deficiency, resulting in drug-resistant epilepsy. Patients will receive 12 weeks of ataluren or placebo during each treatment period. Treatment Period 1 will be followed by a 4-week Washout Period. Based on ataluren PK and pharmacodynamic data, the 4-week washout period is deemed an appropriate length of time to eliminate any ataluren drug effects. Following the Washout Period, patients will crossover to receive the opposite treatment during Treatment Period 2 as follows: Patients receiving ataluren during Treatment Period 1 will receive placebo during Treatment Period 2. Patients receiving placebo during Treatment Period 1 will receive ataluren during Treatment Period 2.

Detailed Description
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Investigators will try to characterize the safety profile of ataluren in patients with CDKL5 or Dravet syndrome resulting from a nonsense mutation and evaluate changes in convulsive and/or drop seizure frequency from Baseline following ataluren treatment in patients with CDKL5 or Dravet syndrome resulting from a nonsense mutation. Investigators will measure changes in minor seizure types (absence, myoclonic, complex partial/focal dyscognitive) following ataluren treatment in patients with CDKL5 or Dravet syndrome resulting from a nonsense mutation and changes from Baseline in cognitive, motor, and behavioral function as well as QOL following ataluren treatment in patients with CDKL5 or Dravet syndrome resulting from a nonsense mutation.

Official Title
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A Phase 2 Randomized, Double-Masked Placebo-Controlled Crossover Safety and Tolerability Study of Ataluren for Drug Resistant Epilepsy in Patients With Nonsense Mutation CDKL5 or Dravet Syndrome

Conditions
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Epilepsy

Intervention / Treatment
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* Drug: ataluren
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 2 years old and ≤ 12 years old, male or female, at Week 0 (at time informed consent/assent is signed) Documentation of a diagnosis of Dravet syndrome or CDKL5 deficiency resulting from a nonsense mutation in 1 allele, as evidenced by medical records, genetic testing, and the following clinical feature: a. Failure to control seizures despite appropriate trial of 2 or more AEDs at therapeutic doses Between 1 to 3 baseline AEDs at stable doses for a minimum for 4 weeks prior to the Baseline visit a. Vagus nerve stimulator (VNS), ketogenic diet, and modified Atkins diet do not count towards this limit but must be unchanged for 3 months prior to enrollment (Baseline). VNS must be on stable settings for a minimum of 3 months prior to the Baseline visit If on ketogenic or modified Atkins diet, must be on stable ratio for a minimum of 3 months prior to the Baseline visit Written consent obtained from the patient or patient's legal representative must be obtained prior to performing any study procedures Minimum of 6 convulsive or drop seizures with duration > 3 seconds over the 4 weeks of diary screening prior to randomization and ≥ 6 convulsive or drop seizures with duration > 3 seconds during the 4 weeks from Screening to Baseline. Exclusion Criteria: Patient is < 2 years old or ≥ 12 years old Epilepsies associated with genetic disorders other than Dravet syndrome or CDKL5 deficiency Patient has Dravet or CDKL5 genetic mutations that are NOT nonsense mutations Felbatol has been initiated within the past 12 months prior to the Screening Visit Patients who are currently or have participated in clinical trials in the 30 days prior to enrollment (Baseline Visit) Prior or ongoing medical condition (eg, concomitant illness, psychiatric condition), medical history, physical findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the patient, makes it unlikely that the course of study drug administration or follow-up would be completed, or could impair the assessment of study results. Ongoing intravenous administration of aminoglycosides or vancomycin.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 12 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ataluren Followed By Placebo<br>Cross Over Design: Treatment Period 1 with Ataluren (Week 0/Day 1 to Week 12), Washout Period (Week 12 to Week 16), crossover to Placebo Treatment Period 2 (Week 16 to Week 28), and Follow-up (Week 28 to Week 32). | Drug: ataluren<br>* Powder formulation<br>* Other names: PTC124;Drug: Placebo<br>* Powder formulation<br>|
| Active Comparator: Placebo Followed by Ataluren<br>Treatment Period 1 with Placebo (Week 0/Day 1 to Week 12), Washout Period (Week 12 to Week 16), crossover to Treatment Period 2 with Ataluren(Week 16 to Week 28). | Drug: ataluren<br>* Powder formulation<br>* Other names: PTC124;Drug: Placebo<br>* Powder formulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in 28-Day Convulsive Seizure Frequency During Ataluren Treatment 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 will be defined as the frequency of seizures per 28 days during the Ataluren Treatment Period minus frequency of seizures per 28 days at Baseline, divided by the frequency of seizures per 28 days at Baseline, multiplied by 100. Negative percent change from Baseline indicates improvement. | Baseline, Week 12 of Ataluren Treatment (Up to Week 28) | 
| Percent Change From Baseline in 28-Day Convulsive Seizure Frequency During Placebo Treatment 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 will be defined as the frequency of seizures per 28 days during the Placebo Treatment Period minus frequency of seizures per 28 days at Baseline, divided by the frequency of seizures per 28 days at Baseline, multiplied by 100. Negative percent change from Baseline indicates improvement. | Baseline, Week 12 of Placebo Treatment (Up to Week 28) |