Clinical trial NCT00592553: Phase 2B Study of PTC124 (Ataluren) in Duchenne/Becker Muscular Dystrophy (DMD/BMD)
Official title: A Phase 2B Efficacy and Safety Study of PTC124 in Subjects With Nonsense-Mutation-Mediated Duchenne and Becker Muscular Dystrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Duchenne Muscular Dystrophy
Becker Muscular Dystrophy
Keywords: Duchenne muscular dystrophy
Becker muscular dystrophy
Nonsense mutation
Premature stop codon
DMD/BMD
PTC124
Lead sponsor: PTC Therapeutics
Sponsor class: INDUSTRY
First posted: 2008-01-14
Enrollment: 174
Sex: MALE
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: This study is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, efficacy and safety study, designed to document the clinical benefit of ataluren when administered as therapy of patients with DMD/BMD due to a nonsense mutation (premature stop codon) in the dystrophin gene.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Change From Baseline in 6MWD at Week 48
timeFrame: Baseline, Week 48
Secondary outcomes:
measure: Change From Baseline in Time to Stand From Supine Position at Week 48
timeFrame: Baseline, 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: 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
timeFrame: Baseline, Week 48
measure: Change From Baseline in Mean Activity Period/Day/Visit at Week 48, as Assessed by Step Activity Monitoring (SAM)
timeFrame: Baseline, Week 48
measure: Change From Baseline in Mean Total Step Count/Day/Visit During the Active Periods at Week 48, as Assessed by SAM
timeFrame: Baseline, Week 48
measure: Change From Baseline in Mean Total Step Count/Hour During the Active Period at Week 48, as Assessed by SAM
timeFrame: Baseline, Week 48
measure: Change From Baseline in Maximum Continuous 10-minute, 20-minute, 30-minute, and 60-minute Total Step Count at Week 48, as Assessed by SAM
timeFrame: Baseline, Week 48
measure: Change From Baseline in Percentage of Time During the Active Period Spent at Low Activity (Less Than or Equal to [≤] 15 Steps/Minute), Medium Activity (16-30 Steps/Minute), and High Activity (Greater Than [>]30 Steps/Minute) at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in Participant- Reported Health-Related Quality of Life (HRQL) as Measured by the Pediatric Quality of Life Inventory (PedsQL) Physical, Emotional, Social, and School Functioning Domain Scores at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in Parent/Caregiver- Reported HRQL as Measured by the PedsQL Physical, Emotional, Social, and School Functioning Domain Scores at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in Participant-Reported HRQL as Measured by the Total Fatigue Scale Score at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in Parent/Caregiver-Reported HRQL as Measured by the Total Fatigue Scale Score at Week 48
timeFrame: Baseline, Week 48
measure: Parent/Caregiver-Reported Treatment Satisfaction Questionnaire for Medication (TSQM) Score
timeFrame: Week 48
measure: Change From Baseline in Participant/Caregiver-Reported Number of Daily Accidental Falls at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in Number of Digits Recalled Forwards and Backwards on Digit Span Task at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in Heart Rate Before, During, and After Each 6MWT at Week 48, as Assessed by Heart Rate Monitoring With the Polar® RS400
timeFrame: Baseline, Week 48
measure: Change From Baseline in Serum Concentration of Creatine Kinase (CK) at Week 48
timeFrame: Baseline, Week 48
measure: Percent Change From Pre-Treatment Visit (1 Week Prior to Baseline Visit) in Biceps Muscle Dystrophin Expression at Post-Treatment Visit (Week 36), as Determined by Immunofluorescence
timeFrame: Pre-Treatment (1 week prior to baseline), post-treatment (Week 36)
Other outcomes:
measure: Percentage of Participants With Treatment-Emergent Adverse Events (AEs)
timeFrame: Baseline up to Week 54
measure: Study Drug Compliance
timeFrame: Baseline to Week 48
Locations:
city: Sacramento
country: United States
facility: University of California-Davis
state: California
city: Aurora
country: United States
facility: The Children's Hospital
state: Colorado
city: Pensacola
country: United States
facility: Child Neurology Center of Pensacola
state: Florida
city: Iowa City
country: United States
facility: University of Iowa Healthcare
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Centre
state: Kansas
city: Boston
country: United States
facility: Children's Hospital of Boston/Harvard Medical School
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
state: Missouri
city: New York
country: United States
facility: Columbia University Medical School
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Portland
country: United States
facility: Shriners Hospital for Children
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Dallas
country: United States
facility: Southwestern University
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Parkville
country: Australia
facility: Royal Children's Hospital
state: Victoria
city: Westmead
country: Australia
facility: Institute For Neuromuscular Research, The Children's Hospital at Westmead
city: Leuven
country: Belgium
facility: University Hospital KU Leuven
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: London Health Sciences Center
state: Ontario
city: Marseille
country: France
facility: Service de Neuropediatrie, hôpital La Timone
city: Nantes
country: France
facility: Neuromuscular center of Nantes
city: Paris
country: France
facility: Groupe Hospitalier La Pitie-Salpetriere
city: Essen
country: Germany
facility: University Clinic for Children, University of Essen
city: Freiburg
country: Germany
facility: University Hospital
city: Jerusalem
country: Israel
facility: Hadassah Medical Center, Hebrew University Hospital
city: Milan
country: Italy
facility: Ospedale Maggiore Policlinico in Milan
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambino Gesu
city: Rome
country: Italy
facility: U.O. Complessa di Neuropsichiatria Infantile
city: Barcelona
country: Spain
facility: Hospital Sant Joan de déu
city: Valencia
country: Spain
facility: Hospital Universitari La Fe
city: Göteborg
country: Sweden
facility: Queen Silvia Children's Hospital
city: Stockholm
country: Sweden
facility: Astrid Lindgren Pediatric Hospital
city: London
country: United Kingdom
facility: Imperial College London, Hammersmith Hospital
city: Newcastle
country: United Kingdom
facility: Univ of Newcastle, Institute of Human Genetics
city: Oswestry
country: United Kingdom
facility: Robert Jones and Agnes Hunt Orthopaedic NHS Trust
Study officials:
affiliation: PTC Therapeutics
name: Leone Atkinson, MD, PhD
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: 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.