Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
Condition: Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn
MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne; Musculoskeletal Diseases; Muscular Diseases; Muscular Disorders, Atrophic; Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked
Intervention: Ataluren; Placebo
Intervention description: Ataluren will be administered as per the dose and schedule specified in the arm.; Placebo will be administered as per the schedule specified in the arm.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 230.0
Sex: Male
Minimum age: 7 Years
Maximum age: 16 Years
Healthy volunteers: No
Keywords: Duchenne muscular dystrophy; Dystrophinopathy; Nonsense mutation; Premature stop codon; Becker muscular dystrophy; DMD/BMD; PTC124; Ataluren

Summary:

      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.
    

Eligibility criteria:

        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.