Phase 2B Study of PTC124 (Ataluren) in Duchenne/Becker Muscular Dystrophy (DMD/BMD)

NCT ID: NCT00592553

Last Updated: 2020-04-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 174 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-02-29
• Study Completion Date: 2009-12-31

Brief Summary

DMD/BMD is a genetic disorder that 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 during childhood and teenage years. A specific type of mutation, called a nonsense (premature stop codon) mutation is the cause of DMD/BMD in approximately 13 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. This study is a Phase 2b trial that will evaluate the clinical benefit of ataluren in boys with DMD/BMD due to a nonsense mutation. The main goals of the study are to understand whether ataluren can improve walking, activity, muscle function, and strength and whether the drug can safely be given for a long period of time.

Detailed Description

This study is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, efficacy and safety study, designed to document the clinical benefit of ataluren when administered as therapy of patients with DMD/BMD due to a nonsense mutation (premature stop codon) in the dystrophin gene.

Conditions

Duchenne Muscular Dystrophy; Becker Muscular Dystrophy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

High-Dose Ataluren

Participants will receive ataluren suspension orally 3 times a day (TID), 20 milligrams/kilogram (mg/kg) at morning, 20 mg/kg at midday, and 40 mg/kg at evening (total daily dose 80 mg/kg) for 48 weeks.

Group Type: EXPERIMENTAL

Ataluren

Intervention Type: DRUG

Ataluren will be administered as per the dose and schedule specified in the respective arms.

Low-Dose Ataluren

Participants will receive ataluren suspension orally TID, 10 mg/kg at morning, 10 mg/kg at midday, and 20 mg/kg at evening (total daily dose 40 mg/kg) for 48 weeks.

Group Type: EXPERIMENTAL

Ataluren

Intervention Type: DRUG

Ataluren will be administered as per the dose and schedule specified in the respective arms.

Placebo

Participants will receive placebo matched to ataluren orally TID at morning, midday, and evening for 48 weeks.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo matching to ataluren will be administered as the schedule specified in the respective arm.

Interventions

Ataluren

Ataluren will be administered as per the dose and schedule specified in the respective arms.

Intervention Type: DRUG

Placebo

Placebo matching to ataluren will be administered as the schedule specified in the respective arm.

Intervention Type: DRUG

Other Intervention Names

PTC124

Eligibility Criteria

Inclusion Criteria

• Ability to provide written informed consent (parental/guardian consent if applicable)/assent (if <18 years of age).
• Male sex.
• Age ≥5 years.
• Phenotypic evidence of DMD/BMD based on the onset of characteristic clinical symptoms or signs (that is, proximal muscle weakness, waddling gait, and Gowers' maneuver) by 9 years of age, an elevated serum CK level, and ongoing difficulty with ambulation.
• 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.
• Ability to walk ≥75 meters unassisted during the screening 6-minute walk test. Note: Other personal assistance or use of assistive devices for ambulation (for example, short leg braces, long leg braces or walkers) were not permitted.
• Confirmed screening laboratory values within the central laboratory ranges (hepatic, adrenal, renal, and serum electrolytes parameters).
• In participants who were sexually active, willingness to abstain from sexual intercourse or employ a barrier or medical method of contraception during the study drug administration and 6-week follow-up periods.
• Willingness and ability to comply with scheduled visits, drug administration plan, study procedures, laboratory tests, and study restrictions. Note: Psychological, social, familial, or geographical factors that might preclude adequate study participation (in particular, the ability to satisfactorily perform the 6MWT) should have been considered.

Exclusion Criteria

• Treatment with systemic aminoglycoside antibiotics within 3 months prior to start of study treatment.
• Initiation of systemic corticosteroid therapy within 6 months prior to start of study treatment or change in systemic corticosteroid therapy (for example, initiation, change in type of drug, dose modification not related to body weight change, schedule modification, interruption, discontinuation, 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 within 3 months prior to start of study treatment.
• Treatment with warfarin within 1 month prior to start of study treatment.
• Prior therapy with ataluren.
• Known hypersensitivity to any of the ingredients or excipients of the study drug (Litesse® UltraTM [refined polydextrose], polyethylene glycol 3350, Lutrol® micro F127 [poloxamer 407], mannitol 25C, crospovidone XL10, hydroxyethyl cellulose, vanilla, Cab-O-Sil® M5P [colloidal silica], magnesium stearate).
• Exposure to another investigational drug within 2 months prior to start of study treatment.
• History of major surgical procedure within 30 days prior to start of study treatment.
• Ongoing immunosuppressive therapy (other than corticosteroids).
• Ongoing participation in any other therapeutic clinical trial.
• Expectation of major surgical procedure (for example, scoliosis surgery) during the 12-month treatment period of the study.
• Requirement for daytime ventilator assistance.
• Clinical symptoms and signs of congestive heart failure (American College of Cardiology/American Heart Association Stage C or Stage D) or evidence on echocardiogram of clinically significant myopathy.
• Prior or ongoing medical condition (for example, concomitant illness, psychiatric condition, behavioral disorder, alcoholism, drug abuse), medical history, physical findings, electrocardiogram 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.

• Minimum Eligible Age: 5 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

PTC Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Leone Atkinson, MD, PhD

Role: STUDY_DIRECTOR

PTC Therapeutics

Locations

University of California-Davis

Sacramento, California, United States

The Children's Hospital

Aurora, Colorado, United States

Child Neurology Center of Pensacola

Pensacola, Florida, United States

University of Iowa Healthcare

Iowa City, Iowa, United States

University of Kansas Medical Centre

Kansas City, Kansas, United States

Children's Hospital of Boston/Harvard Medical School

Boston, Massachusetts, United States

University of Minnesota

Minneapolis, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

Columbia University Medical School

New York, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Shriners Hospital for Children

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Southwestern University

Dallas, Texas, United States

University of Utah

Salt Lake City, Utah, United States

Royal Children's Hospital

Parkville, Victoria, Australia

Institute For Neuromuscular Research, The Children's Hospital at Westmead

Westmead, , Australia

University Hospital KU Leuven

Leuven, , Belgium

Alberta Children's Hospital

Calgary, Alberta, Canada

British Columbia Children's Hospital

Vancouver, British Columbia, Canada

London Health Sciences Center

London, Ontario, Canada

Service de Neuropediatrie, hôpital La Timone

Marseille, , France

Neuromuscular center of Nantes

Nantes, , France

Groupe Hospitalier La Pitie-Salpetriere

Paris, , France

University Clinic for Children, University of Essen

Essen, , Germany

University Hospital

Freiburg im Breisgau, , Germany

Hadassah Medical Center, Hebrew University Hospital

Jerusalem, , Israel

Ospedale Maggiore Policlinico in Milan

Milan, , Italy

Ospedale Pediatrico Bambino Gesu

Rome, , Italy

U.O. Complessa di Neuropsichiatria Infantile

Rome, , Italy

Hospital Sant Joan de déu

Barcelona, , Spain

Hospital Universitari La Fe

Valencia, , Spain

Queen Silvia Children's Hospital

Gothenburg, , Sweden

Astrid Lindgren Pediatric Hospital

Stockholm, , Sweden

Imperial College London, Hammersmith Hospital

London, , United Kingdom

Univ of Newcastle, Institute of Human Genetics

Newcastle, , United Kingdom

Robert Jones and Agnes Hunt Orthopaedic NHS Trust

Oswestry, , United Kingdom

Countries

United States; Australia; Belgium; Canada; France; Germany; Israel; Italy; Spain; Sweden; United Kingdom

References

Wei YS, Hnaini M, ElAloul B, Zapata E, Campbell C. Duchenne Muscular Dystrophy Fatigue Trajectories. Neuropediatrics. 2024 Feb;55(1):42-48. doi: 10.1055/a-2101-7860. Epub 2023 May 26.

Reference Type: DERIVED

PMID: 37236246 (View on PubMed)

Shieh PB, Elfring G, Trifillis P, Santos C, Peltz SW, Parsons JA, Apkon S, Darras BT, Campbell C, McDonald CM; Members of the Ataluren Phase IIb Study Group; Members of the Ataluren Phase IIb Study Clinical Evaluator Training Group; Members of the ACT DMD Study Group; Members of the ACT DMD Clinical Evaluator Training Group. Meta-analyses of deflazacort versus prednisone/prednisolone in patients with nonsense mutation Duchenne muscular dystrophy. J Comp Eff Res. 2021 Dec;10(18):1337-1347. doi: 10.2217/cer-2021-0018. Epub 2021 Oct 25.

Reference Type: DERIVED

PMID: 34693725 (View on PubMed)

Campbell C, Barohn RJ, Bertini E, Chabrol B, Comi GP, Darras BT, Finkel RS, Flanigan KM, Goemans N, Iannaccone ST, Jones KJ, Kirschner J, Mah JK, Mathews KD, McDonald CM, Mercuri E, Nevo Y, Pereon Y, Renfroe JB, Ryan MM, Sampson JB, Schara U, Sejersen T, Selby K, Tulinius M, Vilchez JJ, Voit T, Wei LJ, Wong BL, Elfring G, Souza M, McIntosh J, Trifillis P, Peltz SW, Muntoni F; PTC124-GD-007-DMD Study Group; ACT DMD Study Group; Clinical Evaluator Training Groups. Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy. J Comp Eff Res. 2020 Oct;9(14):973-984. doi: 10.2217/cer-2020-0095. Epub 2020 Aug 27.

Reference Type: DERIVED

PMID: 32851872 (View on PubMed)

Other Identifiers

2007-005478-29

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PTC124-GD-007-DMD

Identifier Type: -

Identifier Source: org_study_id