Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
- Conditions
- Muscular DystrophiesMuscular DiseasesMusculoskeletal DiseasesMuscular Dystrophy, DuchenneMuscular Disorders, AtrophicGenetic Diseases, X-LinkedGenetic Diseases, InbornNeuromuscular DiseasesNervous System Diseases
- Interventions
- Drug: Placebo
- Registration Number
- NCT01826487
- Lead Sponsor
- PTC Therapeutics
- Brief 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.
- Detailed Description
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to determine the efficacy and safety of ataluren in participants with nmDMD.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 230
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Participants will receive placebo matching to ataluren orally 3 times a day (TID) at morning, midday, and evening for 48 weeks. Ataluren Ataluren 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.
- Primary Outcome Measures
Name Time Method Change From Baseline in 6MWD at Week 48 Baseline, 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.
- Secondary Outcome Measures
Name Time Method Time to 10 Percent (%) Persistent Worsening in 6MWD Baseline to 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. 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.
Change From Baseline in Time to Descend 4 Stairs at Week 48 Baseline, 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.
Change From Baseline in Time to Walk/Run 10 Meters at Week 48 Baseline, 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.
Change From Baseline in Time to Climb 4 Stairs at Week 48 Baseline, 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.
Percentage of Participants With Treatment-Emergent Adverse Events (AEs) Baseline up to Week 54 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'.
Trial Locations
- Locations (55)
Alberta Children's Hospital
🇨🇦Calgary, Alberta, Canada
Hopital Necker - Enfants Malades
🇫🇷Paris, France
Bambino Gesu Hospital
🇮🇹Rome, Italy
CHU de Nantes
🇫🇷Nantes Cedex, France
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
Policlinico Universitario G. Martino
🇮🇹Messina, Sicily, Italy
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Hospital Luis Calvo Mackenna
🇨🇱Santiago, Región Metropolitana, Chile
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
Sao Paulo University -HC/FMUSP
🇧🇷São Paulo, Brazil
Hadassah University Hospital
🇮🇱Jerusalem, Israel
Children's Hospital of Western Ontario
🇨🇦London, Ontario, Canada
UC Davis Medical Center
🇺🇸Sacramento, California, United States
Children's Hospital Colorado - Center for Cancer and Blood Disorders
🇺🇸Aurora, Colorado, United States
Child Neurology Center of Northwest Florida
🇺🇸Gulf Breeze, Florida, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
Children's Hospital Boston
🇺🇸Boston, Massachusetts, United States
Columbia University College of Physicians & Surgeons
🇺🇸New York, New York, United States
Children's Hospital of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
Texas Children's Hospital
🇺🇸Houston, Texas, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
Seattle Children's Hospital - Childhood Cancer and Blood Disorders
🇺🇸Seattle, Washington, United States
Universidade Federal do Rio de Janeiro - Instituto de Puericultura e Pediatria Martagao Gesteira
🇧🇷Rio de Janeiro, Brazil
The Children's Hospital at Westmead
🇦🇺Westmead, New South Wales, Australia
Hospital de la Timone
🇫🇷Marseille, France
University of Essen-Duisburg
🇩🇪Essen, Germany
University Hospital Medical Center Freiburg
🇩🇪Freiburg, Germany
Motol University Hospital
🇨🇿Praha, Czechia
University Hospital Brno
🇨🇿Brno, Czechia
Groupe Hospitalier La Pitie-Salpetriere
🇫🇷Paris, France
Fondazione IRCS Ca Granda Ospedale Maggiore Policlinico di Milano
🇮🇹Milan, Italy
CHUV Lausanne
🇨🇭Lausanne, Switzerland
Hacettepe Childrens Hospital
🇹🇷Ankara, Turkey
Queen Silvia Children's Hospital
🇸🇪Goteburg, Sweden
Astrid Lindgren Childrens Hospital
🇸🇪Stockholm, Sweden
Hospital Sant Joan de Deu
🇪🇸Barcelona, Spain
Royal Manchester Children's Hospital
🇬🇧Manchester, United Kingdom
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
University of California, Los Angeles
🇺🇸Los Angeles, California, United States
University of Iowa
🇺🇸Iowa City, Iowa, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Washington University School of Medicine, Division of Endocrinology, Metabolism and Lipid Research
🇺🇸Saint Louis, Missouri, United States
The Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Childrens Medical Center Dallas, Texas
🇺🇸Dallas, Texas, United States
The Royal Children's Hospital
🇦🇺Parkville, Victoria, Australia
UZ Leuven
🇧🇪Leuven, Belgium
Hospital Clinico Universidad Catolica
🇨🇱Santiago, Chile
British Columbia Children's Hospital
🇨🇦Vancouver, British Columbia, Canada
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
U.O. Complessa di Neuropsichiatria Infantile
🇮🇹Rome, Italy
Medical University of Warsaw
🇵🇱Warsaw, Poland
Hospital Universitari i Politecnic la Fe
🇪🇸Valencia, Spain
University College London Institute of Child Health
🇬🇧London, United Kingdom
The Newcastle upon Tyne Hospitals, NHS Foundation Trust
🇬🇧Newcastle upon Tyne, United Kingdom
University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States