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

NCT ID: NCT01826487

Last Updated: 2020-08-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 230 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-03-26
• Study Completion Date: 2015-08-20

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.

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

Study Design

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

Study Groups

Placebo

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Ataluren

Intervention Type: DRUG

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

Interventions

Ataluren

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

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

Other Intervention Names

PTC124

Eligibility Criteria

Inclusion Criteria

• 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.

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 (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.

• Minimum Eligible Age: 7 Years
• Maximum Eligible Age: 16 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

PTC Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Robert Spiegel, M.D.

Role: STUDY_DIRECTOR

PTC Therapeutics

Locations

University of California, Los Angeles

Los Angeles, California, United States

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

University of Iowa

Iowa City, Iowa, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

Boston Children's Hospital

Boston, Massachusetts, United States

Children's Hospital Boston

Boston, Massachusetts, United States

University of Minnesota

Minneapolis, Minnesota, United States

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

St Louis, Missouri, United States

Columbia University College of Physicians & Surgeons

New York, New York, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

Oregon Health & Science University

Portland, Oregon, United States

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States

Childrens Medical Center Dallas, Texas

Dallas, Texas, 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

The Children's Hospital at Westmead

Westmead, New South Wales, Australia

The Royal Children's Hospital

Parkville, Victoria, Australia

UZ Leuven

Leuven, , Belgium

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

Rio de Janeiro, , Brazil

Sao Paulo University -HC/FMUSP

São Paulo, , Brazil

Alberta Children's Hospital

Calgary, Alberta, Canada

British Columbia Children's Hospital

Vancouver, British Columbia, Canada

Children's Hospital of Western Ontario

London, Ontario, Canada

Hospital Luis Calvo Mackenna

Santiago, Santiago Metropolitan, Chile

Hospital Clinico Universidad Catolica

Santiago, , Chile

University Hospital Brno

Brno, , Czechia

Motol University Hospital

Prague, , Czechia

Hospital de la Timone

Marseille, , France

CHU de Nantes

Nantes, , France

Hopital Necker - Enfants Malades

Paris, , France

Groupe Hospitalier La Pitie-Salpetriere

Paris, , France

University of Essen-Duisburg

Essen, , Germany

University Hospital Medical Center Freiburg

Freiburg im Breisgau, , Germany

Hadassah University Hospital

Jerusalem, , Israel

Policlinico Universitario G. Martino

Messina, Sicily, Italy

Fondazione IRCS Ca Granda Ospedale Maggiore Policlinico di Milano

Milan, , Italy

Bambino Gesu Hospital

Rome, , Italy

U.O. Complessa di Neuropsichiatria Infantile

Rome, , Italy

Medical University of Warsaw

Warsaw, , Poland

Seoul National University Hospital

Seoul, , South Korea

Hospital Sant Joan de Deu

Barcelona, , Spain

Hospital Universitari i Politecnic la Fe

Valencia, , Spain

Queen Silvia Children's Hospital

Gothenburg, , Sweden

Astrid Lindgren Childrens Hospital

Stockholm, , Sweden

CHUV Lausanne

Lausanne, , Switzerland

Hacettepe Childrens Hospital

Ankara, , Turkey (Türkiye)

University College London Institute of Child Health

London, , United Kingdom

Royal Manchester Children's Hospital

Manchester, , United Kingdom

The Newcastle upon Tyne Hospitals, NHS Foundation Trust

Newcastle upon Tyne, , United Kingdom

Countries

United States; Australia; Belgium; Brazil; Canada; Chile; Czechia; France; Germany; Israel; Italy; Poland; South Korea; Spain; Sweden; Switzerland; Turkey (Türkiye); United Kingdom

References

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)

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.

Reference Type: DERIVED

PMID: 34383312 (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)

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.

Reference Type: DERIVED

PMID: 28728956 (View on PubMed)

Related Links

http://www.ptcbio.com

Related Info

Other Identifiers

2012-004527-20

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PTC124-GD-020-DMD

Identifier Type: -

Identifier Source: org_study_id