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Ataluren for Nonsense Mutation in CDKL5 and Dravet Syndrome

Primary Purpose

Epilepsy

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

ataluren

Placebo

About this trial

This is an interventional treatment trial for Epilepsy

Eligibility Criteria

2 Years - 12 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

New York University School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Ataluren Followed By Placebo

Placebo Followed by Ataluren

Arm Description

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).

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).

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

Full Information

NCT ID

NCT02758626

First Posted

April 4, 2016

Last Updated

January 23, 2023

Sponsor

NYU Langone Health

Collaborators

PTC Therapeutics

1. Study Identification

Unique Protocol Identification Number

NCT02758626

Brief Title

Ataluren for Nonsense Mutation in CDKL5 and Dravet Syndrome

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Completed

Study Start Date

November 2016 (undefined)

Primary Completion Date

February 27, 2021 (Actual)

Study Completion Date

February 27, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

NYU Langone Health

Collaborators

PTC Therapeutics

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Epilepsy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

15 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ataluren Followed By Placebo

Arm Type

Active Comparator

Arm Description

Arm Title

Placebo Followed by Ataluren

Arm Type

Active Comparator

Arm Description

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).

Intervention Type

Drug

Intervention Name(s)

ataluren

Other Intervention Name(s)

PTC124

Intervention Description

Powder formulation

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Powder formulation

Primary Outcome Measure Information:

Title

Percent Change From Baseline in 28-Day Convulsive Seizure Frequency During Ataluren Treatment Period

Description

Time Frame

Baseline, Week 12 of Ataluren Treatment (Up to Week 28)

Title

Percent Change From Baseline in 28-Day Convulsive Seizure Frequency During Placebo Treatment Period

Description

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.

Time Frame

Baseline, Week 12 of Placebo Treatment (Up to Week 28)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

2 Years

Maximum Age & Unit of Time

12 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Orrin Devinsky, MD

Organizational Affiliation

NYU Langone Health

Official's Role

Principal Investigator

Facility Information:

Facility Name

New York University School of Medicine

City

New York

State/Province

New York

ZIP/Postal Code

10016

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

33538404

Citation

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.

Results Reference

result

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Ataluren for Nonsense Mutation in CDKL5 and Dravet Syndrome

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