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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01826487




Registration number
NCT01826487
Ethics application status
Date submitted
26/03/2013
Date registered
8/04/2013
Date last updated
4/08/2020

Titles & IDs
Public title
Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
Scientific title
A Phase 3 Efficacy and Safety Study of Ataluren in Patients With Nonsense Mutation Dystrophinopathy
Secondary ID [1] 0 0
2012-004527-20
Secondary ID [2] 0 0
PTC124-GD-020-DMD
Universal Trial Number (UTN)
Trial acronym
ACT DMD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Muscular Dystrophy, Duchenne 0 0
Muscular Dystrophies 0 0
Muscular Disorders, Atrophic 0 0
Muscular Diseases 0 0
Musculoskeletal Diseases 0 0
Neuromuscular Diseases 0 0
Nervous System Diseases 0 0
Genetic Diseases, X-Linked 0 0
Genetic Diseases, Inborn 0 0
Condition category
Condition code
Musculoskeletal 0 0 0 0
Other muscular and skeletal disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Neurological 0 0 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Ataluren
Treatment: Drugs - Placebo

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

Experimental: 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.


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

Treatment: Drugs: Placebo
Placebo will be administered as per the schedule specified in the arm.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change From Baseline in 6MWD at Week 48
Timepoint [1] 0 0
Baseline, Week 48
Secondary outcome [1] 0 0
Time to 10 Percent (%) Persistent Worsening in 6MWD
Timepoint [1] 0 0
Baseline to Week 48
Secondary outcome [2] 0 0
Change From Baseline in Time to Walk/Run 10 Meters at Week 48
Timepoint [2] 0 0
Baseline, Week 48
Secondary outcome [3] 0 0
Change From Baseline in Time to Climb 4 Stairs at Week 48
Timepoint [3] 0 0
Baseline, Week 48
Secondary outcome [4] 0 0
Change From Baseline in Time to Descend 4 Stairs at Week 48
Timepoint [4] 0 0
Baseline, Week 48
Secondary outcome [5] 0 0
Percentage of Participants With Treatment-Emergent Adverse Events (AEs)
Timepoint [5] 0 0
Baseline up to Week 54

Eligibility
Key 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.
Minimum age
7 Years
Maximum age
16 Years
Sex
Males
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
26/03/2013
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
20/08/2015
Sample size
Target
Accrual to date
Final
230
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 0 0
The Royal Children's Hospital - Parkville
Recruitment postcode(s) [1] 0 0
2145 - Westmead
Recruitment postcode(s) [2] 0 0
3052 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Illinois
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United States of America
State/province [5] 0 0
Iowa
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United States of America
State/province [6] 0 0
Kansas
Country [7] 0 0
United States of America
State/province [7] 0 0
Massachusetts
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United States of America
State/province [8] 0 0
Minnesota
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United States of America
State/province [9] 0 0
Missouri
Country [10] 0 0
United States of America
State/province [10] 0 0
New York
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United States of America
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Ohio
Country [12] 0 0
United States of America
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Oregon
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United States of America
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Pennsylvania
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United States of America
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Texas
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United States of America
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Utah
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United States of America
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Washington
Country [17] 0 0
Belgium
State/province [17] 0 0
Leuven
Country [18] 0 0
Brazil
State/province [18] 0 0
Rio de Janeiro
Country [19] 0 0
Brazil
State/province [19] 0 0
São Paulo
Country [20] 0 0
Canada
State/province [20] 0 0
Alberta
Country [21] 0 0
Canada
State/province [21] 0 0
British Columbia
Country [22] 0 0
Canada
State/province [22] 0 0
Ontario
Country [23] 0 0
Chile
State/province [23] 0 0
Región Metropolitana
Country [24] 0 0
Chile
State/province [24] 0 0
Santiago
Country [25] 0 0
Czechia
State/province [25] 0 0
Brno
Country [26] 0 0
Czechia
State/province [26] 0 0
Praha
Country [27] 0 0
France
State/province [27] 0 0
Marseille
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France
State/province [28] 0 0
Nantes Cedex
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France
State/province [29] 0 0
Paris
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Germany
State/province [30] 0 0
Essen
Country [31] 0 0
Germany
State/province [31] 0 0
Freiburg
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Israel
State/province [32] 0 0
Jerusalem
Country [33] 0 0
Italy
State/province [33] 0 0
Sicily
Country [34] 0 0
Italy
State/province [34] 0 0
Milan
Country [35] 0 0
Italy
State/province [35] 0 0
Rome
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Korea, Republic of
State/province [36] 0 0
Seoul
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Poland
State/province [37] 0 0
Warsaw
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Spain
State/province [38] 0 0
Barcelona
Country [39] 0 0
Spain
State/province [39] 0 0
Valencia
Country [40] 0 0
Sweden
State/province [40] 0 0
Goteburg
Country [41] 0 0
Sweden
State/province [41] 0 0
Stockholm
Country [42] 0 0
Switzerland
State/province [42] 0 0
Lausanne
Country [43] 0 0
Turkey
State/province [43] 0 0
Ankara
Country [44] 0 0
United Kingdom
State/province [44] 0 0
London
Country [45] 0 0
United Kingdom
State/province [45] 0 0
Manchester
Country [46] 0 0
United Kingdom
State/province [46] 0 0
Newcastle upon Tyne

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
PTC Therapeutics
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT01826487
Trial related presentations / publications
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.
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.
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.
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.
Public notes

Contacts
Principal investigator
Name 0 0
Robert Spiegel, M.D.
Address 0 0
PTC Therapeutics
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT01826487