Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)

NCT01826487 | Completed Phase 3 Results DMC

• 2 other identifiers: PTC124-GD-020-DMD2012-004527-20
• Study Type: interventional
• Target: 230
• Locations: 18 countries
• Sites: 55

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.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in 6MWD at 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.

  Baseline, Week 48

Secondary Outcomes (5)

• Time to 10 Percent (%) Persistent Worsening in 6MWD

  Baseline to 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

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

  Baseline up to Week 54

Other Outcomes (5)

• Change From Baseline in Physical Function Total Score as Measured by NSAA at Week 48

  Baseline, Week 48

• Number of Participants With Change From Baseline in Activities of Daily Living and Disease Status at Week 48, as Assessed by a Standardized Survey Administered by Site Personnel

  Baseline, Week 48

• Change From Baseline in PODCI Transfers/Basic Mobility and Sports/Physical Functioning Scores at Week 48

  Baseline, Week 48

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Participants will receive placebo matching to ataluren orally 3 times a day (TID) at morning, midday, and evening for 48 weeks.

Drug: Placebo

Ataluren

EXPERIMENTAL

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.

Drug: Ataluren

Interventions

Ataluren DRUG

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

Also known as: PTC124

Ataluren

Placebo DRUG

Placebo will be administered as per the schedule specified in the arm.

Placebo

Eligibility Criteria

• Age: 7 Years - 16 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• PTC Therapeutics: lead

Study Sites (55)

University of California, Los Angeles

Los Angeles, California, 90095, United States

Location

UC Davis Medical Center

Sacramento, California, 95817, United States

Location

Children's Hospital Colorado - Center for Cancer and Blood Disorders

Aurora, Colorado, 80045, United States

Location

Child Neurology Center of Northwest Florida

Gulf Breeze, Florida, 32561, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Children's Hospital Boston

Boston, Massachusetts, 02115, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Washington University School of Medicine, Division of Endocrinology, Metabolism and Lipid Research

St Louis, Missouri, 63110, United States

Location

Columbia University College of Physicians & Surgeons

New York, New York, 10032, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229-3039, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43209, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15224, United States

Location

Childrens Medical Center Dallas, Texas

Dallas, Texas, 75207, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

University of Utah

Salt Lake City, Utah, 84112, United States

Location

Seattle Children's Hospital - Childhood Cancer and Blood Disorders

Seattle, Washington, 98105, United States

Location

The Children's Hospital at Westmead

Westmead, New South Wales, 2145, Australia

Location

The Royal Children's Hospital

Parkville, Victoria, 3052, Australia

Location

UZ Leuven

Leuven, 3000, Belgium

Location

Universidade Federal do Rio de Janeiro - Instituto de Puericultura e Pediatria Martagao Gesteira

Rio de Janeiro, 21.941-912, Brazil

Location

Sao Paulo University -HC/FMUSP

São Paulo, 05403-900, Brazil

Location

Alberta Children's Hospital

Calgary, Alberta, T3B 6A8, Canada

Location

British Columbia Children's Hospital

Vancouver, British Columbia, V6H 3V4, Canada

Location

Children's Hospital of Western Ontario

London, Ontario, N6A 2E3, Canada

Location

Hospital Luis Calvo Mackenna

Santiago, Santiago Metropolitan, Chile

Location

Hospital Clinico Universidad Catolica

Santiago, 8330073, Chile

Location

University Hospital Brno

Brno, 635 00, Czechia

Location

Motol University Hospital

Prague, 150 06, Czechia

Location

Hospital de la Timone

Marseille, 13385, France

Location

CHU de Nantes

Nantes, 44093, France

Location

Hopital Necker - Enfants Malades

Paris, 75015, France

Location

Groupe Hospitalier La Pitie-Salpetriere

Paris, 75651, France

Location

University of Essen-Duisburg

Essen, 45122, Germany

Location

University Hospital Medical Center Freiburg

Freiburg im Breisgau, 79106, Germany

Location

Hadassah University Hospital

Jerusalem, 91240, Israel

Location

Policlinico Universitario G. Martino

Messina, Sicily, 98125, Italy

Location

Fondazione IRCS Ca Granda Ospedale Maggiore Policlinico di Milano

Milan, 20122, Italy

Location

Bambino Gesu Hospital

Rome, 00165, Italy

Location

U.O. Complessa di Neuropsichiatria Infantile

Rome, 00168, Italy

Location

Medical University of Warsaw

Warsaw, 85- 822, Poland

Location

Seoul National University Hospital

Seoul, 110-744, South Korea

Location

Hospital Sant Joan de Deu

Barcelona, 08950, Spain

Location

Hospital Universitari i Politecnic la Fe

Valencia, 46026, Spain

Location

Queen Silvia Children's Hospital

Gothenburg, SE-416 85, Sweden

Location

Astrid Lindgren Childrens Hospital

Stockholm, 17176, Sweden

Location

CHUV Lausanne

Lausanne, 1011, Switzerland

Location

Hacettepe Childrens Hospital

Ankara, 06100, Turkey (Türkiye)

Location

University College London Institute of Child Health

London, WC1N 1EH, United Kingdom

Location

Royal Manchester Children's Hospital

Manchester, M13 9WL, United Kingdom

Location

The Newcastle upon Tyne Hospitals, NHS Foundation Trust

Newcastle upon Tyne, NE1 3BZ, United Kingdom

Location

Related Publications (4)

• 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

• McDonald CM, Wei LJ, Flanigan KM, Elfring G, Trifillis P, Muntoni F; ACT DMD Clinical Evaluator Training Group; ACT DMD Study Group. Evaluating longitudinal therapy effects via the North Star Ambulatory Assessment. Muscle Nerve. 2021 Nov;64(5):614-619. doi: 10.1002/mus.27396. Epub 2021 Sep 2.

  PMID: 34383312 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

• McDonald CM, Campbell C, Torricelli RE, Finkel RS, Flanigan KM, Goemans N, Heydemann P, Kaminska A, Kirschner J, Muntoni F, Osorio AN, Schara U, Sejersen T, Shieh PB, Sweeney HL, Topaloglu H, Tulinius M, Vilchez JJ, Voit T, Wong B, Elfring G, Kroger H, Luo X, McIntosh J, Ong T, Riebling P, Souza M, Spiegel RJ, Peltz SW, Mercuri E; Clinical Evaluator Training Group; ACT DMD Study Group. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Sep 23;390(10101):1489-1498. doi: 10.1016/S0140-6736(17)31611-2. Epub 2017 Jul 17.

  PMID: 28728956 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

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

Interventions

ataluren

Condition Hierarchy (Ancestors)

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

• Robert Spiegel, M.D.

  PTC Therapeutics

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 3
• 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: March 26, 2013
• First Posted: April 8, 2013
• Study Start: March 26, 2013
• Primary Completion: August 20, 2015
• Study Completion: August 20, 2015
• Last Updated: August 4, 2020
• Results First Posted: August 4, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

CA (3); FR (4); BR (2); TU (1); DE (2); BE (1); KR (1); CH (1); IT (4); CZ (2); ES (2); IL (1); AU (2); SE (2); PL (1); GB (3); US (21); CL (2)