Epilepsy
Conditions
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.
Interventions
DRUGataluren
Powder formulation
DRUGPlacebo
Powder formulation
Sponsors
PTC Therapeutics
NYU Langone Health
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 2 years old and ≤ 12 years old, male or female, at Week 0 (at time informed consent/assent is signed) 2. 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 3. 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). 4. VNS must be on stable settings for a minimum of 3 months prior to the Baseline visit 5. If on ketogenic or modified Atkins diet, must be on stable ratio for a minimum of 3 months prior to the Baseline visit 6. Written consent obtained from the patient or patient's legal representative must be obtained prior to performing any study procedures 7. 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
1. Patient is \< 2 years old or ≥ 12 years old 2. Epilepsies associated with genetic disorders other than Dravet syndrome or CDKL5 deficiency 3. Patient has Dravet or CDKL5 genetic mutations that are NOT nonsense mutations 4. Felbatol has been initiated within the past 12 months prior to the Screening Visit 5. Patients who are currently or have participated in clinical trials in the 30 days prior to enrollment (Baseline Visit) 6. 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. 7. Ongoing intravenous administration of aminoglycosides or vancomycin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in 28-Day Convulsive Seizure Frequency During Ataluren Treatment Period | Baseline, Week 12 of Ataluren Treatment (Up to Week 28) | 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 | Baseline, Week 12 of Placebo Treatment (Up to Week 28) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ataluren Followed By Placebo 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).
ataluren: Powder formulation
Placebo: Powder formulation | 9 |
| Placebo Followed by Ataluren 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).
ataluren: Powder formulation
Placebo: Powder formulation | 6 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-Blind Phase (Week 0 - Week 28) | Adverse Event | 1 | 0 |
| Open-Label Extension (Week 28-Week 124) | Adverse Event | 1 | 1 |
| Open-Label Extension (Week 28-Week 124) | Lost to Follow-up | 0 | 1 |
| Open-Label Extension (Week 28-Week 124) | Parental/Legal Guardian withdrawal of consent | 1 | 1 |
Baseline characteristics
| Characteristic | Ataluren Followed By Placebo | Total | Placebo Followed by Ataluren |
|---|---|---|---|
| Age, Continuous | 9.3 years STANDARD_DEVIATION 4.7 | 10.4 years STANDARD_DEVIATION 5.1 | 12.0 years STANDARD_DEVIATION 0 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 13 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 6 Participants | 11 Participants | 5 Participants |
| Region of Enrollment United States | 9 participants | 15 participants | 6 participants |
| Sex: Female, Male Female | 7 Participants | 13 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 14 |
| other Total, other adverse events | 13 / 15 | 5 / 14 |
| serious Total, serious adverse events | 7 / 15 | 1 / 14 |
Outcome results
Primary
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.
Time frame: Baseline, Week 12 of Ataluren Treatment (Up to Week 28)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ataluren | Percent Change From Baseline in 28-Day Convulsive Seizure Frequency During Ataluren Treatment Period | 723.17 percent change | Standard Deviation 279.912 |
Primary
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.
Time frame: Baseline, Week 12 of Placebo Treatment (Up to Week 28)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ataluren | Percent Change From Baseline in 28-Day Convulsive Seizure Frequency During Placebo Treatment Period | 0.72 percent change | Standard Deviation 222.82 |