Clinical trial NCT01826487: Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
Official title: A Phase 3 Efficacy and Safety Study of Ataluren in Patients With Nonsense Mutation Dystrophinopathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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
Lead sponsor: PTC Therapeutics
Sponsor class: INDUSTRY
First posted: 2013-04-08
Enrollment: 230
Sex: MALE
Minimum age (years): 7
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change From Baseline in 6MWD at Week 48
timeFrame: Baseline, Week 48
Secondary outcomes:
measure: Time to 10 Percent (%) Persistent Worsening in 6MWD
timeFrame: Baseline to Week 48
measure: Change From Baseline in Time to Walk/Run 10 Meters at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in Time to Climb 4 Stairs at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in Time to Descend 4 Stairs at Week 48
timeFrame: Baseline, Week 48
measure: Percentage of Participants With Treatment-Emergent Adverse Events (AEs)
timeFrame: Baseline up to Week 54
Other outcomes:
measure: Change From Baseline in Physical Function Total Score as Measured by NSAA at Week 48
timeFrame: Baseline, Week 48
measure: 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
timeFrame: Baseline, Week 48
measure: Change From Baseline in PODCI Transfers/Basic Mobility and Sports/Physical Functioning Scores at Week 48
timeFrame: Baseline, Week 48
measure: Ataluren Plasma Concentration
timeFrame: Weeks 8, 16, 24, 32, 40, and 48
measure: Study Drug Compliance
timeFrame: Baseline to Week 48
Locations:
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado - Center for Cancer and Blood Disorders
state: Colorado
city: Gulf Breeze
country: United States
facility: Child Neurology Center of Northwest Florida
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine, Division of Endocrinology, Metabolism and Lipid Research
state: Missouri
city: New York
country: United States
facility: Columbia University College of Physicians & Surgeons
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Dallas
country: United States
facility: Childrens Medical Center Dallas, Texas
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital - Childhood Cancer and Blood Disorders
state: Washington
city: Westmead
country: Australia
facility: The Children's Hospital at Westmead
state: New South Wales
city: Parkville
country: Australia
facility: The Royal Children's Hospital
state: Victoria
city: Leuven
country: Belgium
facility: UZ Leuven
city: Rio de Janeiro
country: Brazil
facility: Universidade Federal do Rio de Janeiro - Instituto de Puericultura e Pediatria Martagao Gesteira
city: São Paulo
country: Brazil
facility: Sao Paulo University -HC/FMUSP
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: London
country: Canada
facility: Children's Hospital of Western Ontario
state: Ontario
city: Santiago
country: Chile
facility: Hospital Luis Calvo Mackenna
state: Región Metropolitana
city: Santiago
country: Chile
facility: Hospital Clinico Universidad Catolica
city: Brno
country: Czechia
facility: University Hospital Brno
city: Praha
country: Czechia
facility: Motol University Hospital
city: Marseille
country: France
facility: Hospital de la Timone
city: Nantes Cedex
country: France
facility: CHU de Nantes
city: Paris
country: France
facility: Hopital Necker - Enfants Malades
city: Paris
country: France
facility: Groupe Hospitalier La Pitie-Salpetriere
city: Essen
country: Germany
facility: University of Essen-Duisburg
city: Freiburg
country: Germany
facility: University Hospital Medical Center Freiburg
city: Jerusalem
country: Israel
facility: Hadassah University Hospital
city: Messina
country: Italy
facility: Policlinico Universitario G. Martino
state: Sicily
city: Milan
country: Italy
facility: Fondazione IRCS Ca Granda Ospedale Maggiore Policlinico di Milano
city: Rome
country: Italy
facility: Bambino Gesu Hospital
city: Rome
country: Italy
facility: U.O. Complessa di Neuropsichiatria Infantile
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Warsaw
country: Poland
facility: Medical University of Warsaw
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Deu
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic la Fe
city: Goteburg
country: Sweden
facility: Queen Silvia Children's Hospital
city: Stockholm
country: Sweden
facility: Astrid Lindgren Childrens Hospital
city: Lausanne
country: Switzerland
facility: CHUV Lausanne
city: Ankara
country: Turkey
facility: Hacettepe Childrens Hospital
city: London
country: United Kingdom
facility: University College London Institute of Child Health
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
city: Newcastle upon Tyne
country: United Kingdom
facility: The Newcastle upon Tyne Hospitals, NHS Foundation Trust
Study officials:
affiliation: PTC Therapeutics
name: Robert Spiegel, M.D.
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.