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

NCT00592553 | Completed Phase 2 Results DMC

• 2 other identifiers: PTC124-GD-007-DMD2007-005478-29
• Study Type: interventional
• Target: 174
• Locations: 11 countries
• Sites: 37

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.

Conditions

Duchenne Muscular Dystrophy; Becker Muscular Dystrophy

Keywords

Duchenne muscular dystrophy; Becker muscular dystrophy; Nonsense mutation; Premature stop codon; DMD/BMD; PTC124

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in 6MWD at Week 48

  The 6MWD test was performed in a 30 meters long flat corridor, where the participant was 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.

  Baseline, Week 48

Secondary Outcomes (20)

• Change From Baseline in Time to Stand From Supine Position at Week 48

  Baseline, Week 48

• Change From Baseline in Time to Walk/Run 10 Meters at Week 48

  Baseline, Week 48

• Change From Baseline in Time to Climb 4 Stairs at Week 48

  Baseline, Week 48

• Change From Baseline in Time to Descend 4 Stairs at Week 48

  Baseline, Week 48

• Change From Baseline in Force Exerted During Knee Flexion and Extension, Elbow Flexion and Extension, and Shoulder Abduction at Week 48, as Assessed by Myometry

  Baseline, Week 48

Other Outcomes (2)

• Percentage of Participants With Treatment-Emergent Adverse Events (AEs)

  Baseline up to Week 54

• Study Drug Compliance

  Baseline to Week 48

Study Arms (3)

High-Dose Ataluren

EXPERIMENTAL

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.

Drug: Ataluren

Low-Dose Ataluren

EXPERIMENTAL

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.

Drug: Ataluren

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Ataluren DRUG

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

Also known as: PTC124

High-Dose Ataluren; Low-Dose Ataluren

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 5 Years+
• Gender Eligibility Details: Consistent with the X-linked genetic basis and natural history of DBMD, all of the participants were males.
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• PTC Therapeutics: lead

Study Sites (37)

University of California-Davis

Sacramento, California, United States

Location

The Children's Hospital

Aurora, Colorado, United States

Location

Child Neurology Center of Pensacola

Pensacola, Florida, United States

Location

University of Iowa Healthcare

Iowa City, Iowa, United States

Location

University of Kansas Medical Centre

Kansas City, Kansas, United States

Location

Children's Hospital of Boston/Harvard Medical School

Boston, Massachusetts, United States

Location

University of Minnesota

Minneapolis, Minnesota, United States

Location

Washington University School of Medicine

St Louis, Missouri, United States

Location

Columbia University Medical School

New York, New York, United States

Location

Duke University Medical Center

Durham, North Carolina, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229-3039, United States

Location

Shriners Hospital for Children

Portland, Oregon, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Location

Southwestern University

Dallas, Texas, United States

Location

University of Utah

Salt Lake City, Utah, United States

Location

Royal Children's Hospital

Parkville, Victoria, Australia

Location

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

Westmead, Australia

Location

University Hospital KU Leuven

Leuven, Belgium

Location

Alberta Children's Hospital

Calgary, Alberta, Canada

Location

British Columbia Children's Hospital

Vancouver, British Columbia, Canada

Location

London Health Sciences Center

London, Ontario, Canada

Location

Service de Neuropediatrie, hôpital La Timone

Marseille, France

Location

Neuromuscular center of Nantes

Nantes, France

Location

Groupe Hospitalier La Pitie-Salpetriere

Paris, France

Location

University Clinic for Children, University of Essen

Essen, Germany

Location

University Hospital

Freiburg im Breisgau, Germany

Location

Hadassah Medical Center, Hebrew University Hospital

Jerusalem, Israel

Location

Ospedale Maggiore Policlinico in Milan

Milan, Italy

Location

Ospedale Pediatrico Bambino Gesu

Rome, Italy

Location

U.O. Complessa di Neuropsichiatria Infantile

Rome, Italy

Location

Hospital Sant Joan de déu

Barcelona, Spain

Location

Hospital Universitari La Fe

Valencia, Spain

Location

Queen Silvia Children's Hospital

Gothenburg, Sweden

Location

Astrid Lindgren Pediatric Hospital

Stockholm, Sweden

Location

Imperial College London, Hammersmith Hospital

London, United Kingdom

Location

Univ of Newcastle, Institute of Human Genetics

Newcastle, United Kingdom

Location

Robert Jones and Agnes Hunt Orthopaedic NHS Trust

Oswestry, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 37236246 DERIVED

• 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.

  PMID: 34693725 DERIVED

• 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.

  PMID: 32851872 DERIVED

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne

Interventions

ataluren

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Patient Advocacy
• Organization: PTC Therapeutics, Inc.

medinfo@ptcbio.com

1-866-562-4620

Study Officials

• Leone Atkinson, MD, PhD

  PTC Therapeutics

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 1, 2008
• First Posted: January 14, 2008
• Study Start: February 29, 2008
• Primary Completion: December 31, 2009
• Study Completion: December 31, 2009
• Last Updated: April 7, 2020
• Results First Posted: April 7, 2020

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will not share

Locations

GB (3); DE (2); BE (1); CA (3); AU (2); FR (3); US (15); IL (1); IT (3); ES (2); SE (2)