Ataluren for Nonsense Mutation in CDKL5 and Dravet Syndrome

NCT02758626 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 15-00426
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Epilepsy

Outcome Measures

Primary Outcomes (2)

• 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)

Study Arms (2)

Ataluren Followed By Placebo

ACTIVE COMPARATOR

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; Drug: Placebo

Placebo Followed by Ataluren

ACTIVE COMPARATOR

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; Drug: Placebo

Interventions

ataluren DRUG

Powder formulation

Also known as: PTC124

Ataluren Followed By Placebo; Placebo Followed by Ataluren

Placebo DRUG

Powder formulation

Ataluren Followed By Placebo; Placebo Followed by Ataluren

Eligibility Criteria

• Age: 2 Years - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• NYU Langone Health: lead
• PTC Therapeutics: collaborator

Study Sites (1)

New York University School of Medicine

New York, New York, 10016, United States

Location

Related Publications (1)

• Devinsky O, King L, Bluvstein J, Friedman D. Ataluren for drug-resistant epilepsy in nonsense variant-mediated Dravet syndrome and CDKL5 deficiency disorder. Ann Clin Transl Neurol. 2021 Mar;8(3):639-644. doi: 10.1002/acn3.51306. Epub 2021 Feb 4.

  PMID: 33538404 RESULT

MeSH Terms

Conditions

Epilepsy

Interventions

ataluren

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Results Point of Contact

• Title: Orrin Devinsky, MD
• Organization: NYU Langone Health, Comprehensive Epilepsy Center

Orrin.Devinsky@nyulangone.org

6465580803

Study Officials

• Orrin Devinsky, MD

  NYU Langone Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 4, 2016
• First Posted: May 2, 2016
• Study Start: November 1, 2016
• Primary Completion: February 27, 2021
• Study Completion: February 27, 2021
• Last Updated: February 16, 2023
• Results First Posted: February 16, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)