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Phase 3 Study of Ataluren in Patients With Nonsense Mutation Duchenne Muscular Dystrophy

key information

study id #: NCT01826487

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

status: completed


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% 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.

intervention: Ataluren, Placebo

mechanism of action: Stop codon read through to promote dystrophin production

results: https://clinicaltrials.gov/ct2/show/results/NCT01826487

last updated: April 27, 2019

study details

start date: March 2013

estimated completion: August 2015

phase of development: Phase 3

size / enrollment: 230

study description:
This study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to determine the efficacy and safety of ataluren 10, 10, 20 mg/kg in patients with nonsense-mutation (nm) dystrophinopathy. Patients will be randomized in a 1:1 ratio to ataluren 10-, 10-, 20-mg/kg dose level or placebo. Patients will receive study drug TID at morning, midday, and evening. It is planned that 220 patients will be enrolled and patients will undergo 48 weeks of blinded treatment prior to the final analysis. Study assessments will be performed at clinic visits every 8 weeks. It is anticipated that an open-label extension study will be available to patients (who successfully complete the double-blind study) in countries where ataluren is not commercially available.

primary outcomes:

  • Changes in the distance walked during a 6-minute walk test [ Time Frame: Baseline and 48 weeks ]

secondary outcomes:

  • Physical function [ Time Frame: Baseline and 48 weeks ]
    -North Star Ambulatory Assessment and Timed Function Testing
  • Patient and/or parent-reported activities of daily living and disease symptoms [ Time Frame: Baseline and 48 weeks ]
  • Quality of Life [ Time Frame: Baseline and 48 weeks ]
  • Safety [ Time Frame: Baseline and 48 weeks ]
    -Safety profile characterized by type, frequency, severity, timing, and relationship to study drug of any adverse events, or of abnormalities of laboratory tests, vital signs, physical examinations, or ECGs
  • Ataluren blood levels [ Time Frame: Baseline and 48 weeks ]
  • Compliance [ Time Frame: Baseline and 48 weeks ]

inclusion criteria:

• Eligible Sexes:

• Ability to provide written informed consent (parental/guardian consent if applicable)/assent per local requirements.
• Male sex.
• Age >=7 and <=16 years.
• Phenotypic evidence of dystrophinopathy based on the onset of characteristic clinical symptoms or signs (eg. 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.
• Ability to walk >=150 meters unassisted during the screening 6-minute walk test. Patients need to be below the protocol-specified threshold for %-predicted 6MWD.
• 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% reduction 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 (eg, 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 (eg. 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 (eg, scoliosis surgery) during the 12-month treatment period of the study.
• Requirement for daytime ventilator assistance. Note: Evening ventilator assistance and use of bi-level positive airway pressure (Bi-PAP) therapy is allowed.
• Uncontrolled clinical symptoms and signs of CHF (American College of Cardiology/American Heart Association Stage C or Stage D).
• Prior or ongoing medical condition (eg, concomitant illness, psychiatric condition, behavioral disorder, alcoholism, drug abuse), medical history, physical findings (eg. lower limb injury that may affect 6MWT performance), ECG findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the subject, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results.

study contacts

sponsor: PTC Therapeutics

investigators: Robert Spiegel, MD

trial center locations: United States, Australia, Belgium, Brazil, Canada, Chile, Czechia, France, Germany, Israel, Italy, Republic of Korea, Poland, Spain, Sweden, Switzerland, Turkey, United Kingdom