Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)

Study Overview
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Brief Summary
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Dystrophinopathy is a disease continuum that includes Duchenne muscular dystrophy, which develops in boys. It is caused by a mutation in the gene for dystrophin, a protein that is important for maintaining normal muscle structure and function. Loss of dystrophin causes muscle fragility that leads to weakness and loss of walking ability. A specific type of mutation, called a nonsense (premature stop codon) mutation is the cause of dystrophinopathy in approximately 10-15 percent (%) of boys with the disease. Ataluren is an orally delivered, investigational drug that has the potential to overcome the effects of the nonsense mutation. The main goal of this Phase 3 study is to evaluate the effect of ataluren on walking ability. The effect of ataluren on physical function, quality of life, and activities of daily living will be evaluated. This study will also provide additional information on the long-term safety of ataluren.

Detailed Description
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This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to determine the efficacy and safety of ataluren in participants with nmDMD.

Official Title
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A Phase 3 Efficacy and Safety Study of Ataluren in Patients With Nonsense Mutation Dystrophinopathy

Conditions
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Muscular Dystrophy, Duchenne, Muscular Dystrophies, Muscular Disorders, Atrophic, Muscular Diseases, Musculoskeletal Diseases, Neuromuscular Diseases, Nervous System Diseases, Genetic Diseases, X-Linked, Genetic Diseases, Inborn

Intervention / Treatment
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* Drug: Ataluren
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide written informed consent (parental/guardian consent if applicable)/assent per local requirements. Phenotypic evidence of dystrophinopathy based on the onset of characteristic clinical symptoms or signs (for example; proximal muscle weakness, waddling gait, and Gowers' maneuver) by 6 years of age, an elevated serum creatinine kinase level, and ongoing difficulty with walking. Documentation of the presence of a nonsense point mutation in the dystrophin gene as determined by gene sequencing from a laboratory certified by the College of American Pathologists (CAP), the Clinical Laboratory Improvement Act/Amendment (CLIA) or an equivalent organization. Documentation that a blood sample has been drawn for confirmation of the presence of a nonsense mutation in the dystrophin gene. Use of systemic corticosteroids (prednisone, prednisolone, or deflazacort) for a minimum of 6 months immediately prior to start of study treatment, with no significant change in dosage or dosing regimen (not related to body weight change) for a minimum of 3 months immediately prior to start of study treatment and a reasonable expectation that dosage and dosing regimen will not change significantly for the duration of the study. Valid Screening 6-minute walk distance (6MWD) greater than or equal to (≥) 150 meters. Valid Screening 6MWD must have been less than or equal to (≤) 80% of predicted for age and height. Results of the 2 Baseline 6MWD results must be determined as valid and results of the Day 2 Baseline 6MWD must be within 20% of the Day 1 Baseline 6MWD. Baseline 6MWD (mean of valid Day 1 and Day 2 values) must be no more than a 20% change from the valid Screening 6MWD. Confirmed screening laboratory values within the central laboratory ranges (hepatic, renal, and serum electrolyte parameters). Willingness to abstain from sexual intercourse or employ an approved method of contraception during the period of study drug administration and 6-week follow-up period. Willingness and ability to comply with scheduled visits, drug administration plan, study procedures, laboratory tests, and study restrictions. Exclusion Criteria: Treatment with systemic aminoglycoside antibiotics within 3 months prior to start of study treatment. Initiation of systemic corticosteroids therapy within 6 months prior to start of study treatment. Change in systemic corticosteroid therapy (for example; change in type of drug, dose modification not related to body weight change, schedule modification, interruption, or reinitiation) within 3 months prior to start of study treatment. Any change (initiation, change in type of drug, dose modification, schedule modification,interruption, discontinuation, or reinitiation) in prophylaxis/treatment for congestive heart failure (CHF) within 3 months prior to start of study treatment. Ongoing use of coumarin-based anticoagulants (for example; warfarin), phenytoin, tolbutamide, or paclitaxel. Prior therapy with ataluren. Known hypersensitivity to any of the ingredients or excipients of the study drug. Exposure to another investigational drug within 3 months prior to start of study treatment. History of major surgical procedure within 6 weeks prior to start of study treatment. Ongoing immunosuppressive therapy (other than corticosteroids). Ongoing participation in any clinical trial (except for studies specifically approved by PTC Therapeutics). Expectation of major surgical procedure (for example; scoliosis surgery) during the 12-month treatment period of the study. Requirement for daytime ventilator assistance. Uncontrolled clinical symptoms and signs of CHF (American College of Cardiology/American Heart Association Stage C or Stage D). Prior or ongoing medical condition (for example; concomitant illness, psychiatric condition, behavioral disorder, alcoholism, drug abuse), medical history, physical findings (for example; lower limb injury that may affect 6MWT performance), electrocardiogram (ECG) findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the participant, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results.

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 16 Years

Sexes Eligible for Study
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Male

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants will receive placebo matching to ataluren orally 3 times a day (TID) at morning, midday, and evening for 48 weeks. | Drug: Placebo<br>* Placebo will be administered as per the schedule specified in the arm.<br>|
| Experimental: Ataluren<br>Participants will receive ataluren suspension orally TID, 10 milligrams/kilogram (mg/kg) at morning, 10 mg/kg at midday, and 20 mg/kg at evening (total daily dose 40 mg/kg) for 48 weeks. | Drug: Ataluren<br>* Ataluren will be administered as per the dose and schedule specified in the arm.<br>* Other names: PTC124;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 6MWD at Week 48 | The 6MWD test is a non-encouraged test performed in a 30 meters long flat corridor, where the participant is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. Ambulation was assessed via the 6MWD test following standardized procedures by measuring the 6MWD in meters. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test. Participants with confirmed loss of ambulation at a particular visit were assigned a 6MWD result of 0. Baseline and Week 48 6MWD values are each the average of two valid 6MWD values, or a single available value if one was missing. | Baseline, Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to 10 Percent (%) Persistent Worsening in 6MWD | The 6MWD test is a non-encouraged test performed in a 30 meters long flat corridor, where the participant is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. Ambulation was assessed via the 6MWD test following standardized procedures by measuring the 6MWD in meters. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test. Time to 10% persistent worsening in 6MWD was defined as the last time that 6MWD was not 10% worse compared with baseline. Time to 10% persistent worsening in 6MWD <300 meters, >=300 to 400 meters, and >=400 meters was evaluated. For participants who did not have 10% 6MWD worsening or who were removed from study, time to 10% 6MWD worsening was censored at the time of the last 6MWD test. Participants who became non-ambulatory were considered to have 10% worsening. | Baseline to Week 48 | 
| Change From Baseline in Time to Walk/Run 10 Meters at Week 48 | During the test for walking/running 10 meters, the method of walk/run used by the participant was categorized as follows: 1. Unable to walk independently; 2. Unable to walk independently but can walk with support from a person or with assistive device (full leg calipers [knee-ankle-foot orthoses ] or walker); 3. Highly adapted gait, wide-based lordotic gait, cannot increase walking speed; 4. Moderately adapted gait, can pick up speed but cannot run; 5. Able to pick up speed but runs with a double stance phase (that is, cannot achieve both feet off the ground); 6. Runs and gets both feet off the ground (with no double stance phase). If the time taken to perform a test exceeded 30 seconds or if a participant could not perform the test due to disease progression, a value of 30 seconds was used. A cumulative change from baseline data has been reported. | Baseline, Week 48 | 
| Change From Baseline in Time to Climb 4 Stairs at Week 48 | During the test for stair-climbing, the method of climbing used by the participant was categorized as follows: 1. Unable to up climb 4 standard stairs; 2. Climbs 4 standard stairs marking time (climbs one foot at a time, with both feet on a step before moving to next step), using both arms on one or both handrails; 3. Climbs 4 standard stairs marking time (climbs one foot at a time, with both feet on a step before moving to next step), using one arm on one handrail; 4. Climbs 4 standard stairs marking time (climbs one foot at a time, with both feet on a step before moving to next step), not needing handrail; 5. Climbs 4 standard stairs alternating feet, needs handrail for support; 6. Climbs 4 standard stairs alternating feet, not needing handrail support. A cumulative change from baseline data has been reported. | Baseline, Week 48 | 
| Change From Baseline in Time to Descend 4 Stairs at Week 48 | During the test for stair-descending, the method of descending used by the participant was categorized as follows: 1. Unable to descend 4 standard stairs; 2. Descends 4 standard stairs marking time (climbs one foot at a time, with both feet on a step before moving to next step), using both arms on one or both handrails; 3. Descends 4 standard stairs marking time (climbs one foot at a time, with both feet on a step before moving to next step), using one arm on one handrail; 4. Descends 4 standard stairs marking time (climbs one foot at a time, with both feet on a step before moving to next step), not needing handrail; 5. Descends 4 standard stairs alternating feet, needs handrail for support; 6. Descends 4 standard stairs alternating feet, not needing handrail support. A cumulative change from baseline data has been reported. | Baseline, Week 48 | 
| Percentage of Participants With Treatment-Emergent Adverse Events (AEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. Treatment-emergent adverse event (TEAE) was defined as an adverse event that occurred or worsened in the period extending from first dose of study drug to 6 weeks after the last dose of study drug. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. | Baseline up to Week 54 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Duchenne muscular dystrophy, Dystrophinopathy, Nonsense mutation, Premature stop codon, Becker muscular dystrophy, DMD/BMD, PTC124, Ataluren