Clinical trial NCT00847379: Phase 2B Extension Study of Ataluren (PTC124) in Duchenne/Becker Muscular Dystrophy (DMD/BMD)
Official title: A Phase 2B Extension Study of PTC124 in Subjects With Nonsense-Mutation-Mediated Duchenne and Becker Muscular Dystrophy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Duchenne Muscular Dystrophy
Becker Muscular Dystrophy
Keywords: Duchenne muscular dystrophy
Becker muscular dystrophy
Nonsense mutation
Premature stop codon
DMD
BMD
Ataluren
PTC124
Lead sponsor: PTC Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Genzyme, a Sanofi Company
First posted: 2009-02-19
Enrollment: 173
Sex: MALE
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Duchenne/Becker muscular dystrophy (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 10-15% of boys with the disease. Ataluren (PTC124) is an orally delivered, investigational drug that has the potential to overcome the effects of the nonsense mutation. This study is a Phase 2b extension trial that will evaluate the long-term safety of ataluren (PTC124) in boys with nonsense mutation DMD/BMD, as determined by adverse events and laboratory abnormalities. The study will also assess changes in walking, muscle function, and other important clinical and laboratory measures.

Detailed description: This is a Phase 2b, international, multicenter, open-label extension study for participants who successfully completed blinded study drug in Study 007. This extension study will evaluate the long-term administration of ataluren administered 3 times per day (TID) at morning, midday, and evening doses of 20, 20, and 40 milligrams/kilogram (mg/kg), respectively, in participants with nonsense mutation Duchenne/Becker muscular dystrophy (nmDBMD).

Eligibility criteria: Inclusion Criteria:

* Completion of blinded study drug treatment in the previous Phase 2b study (PTC124-GD-007-DMD).
* Ability to provide written informed consent (parental/guardian consent if applicable)/assent (if less than \[\<\]18 years of age).
* In participants who are sexually active, willingness to abstain from sexual intercourse or employ a barrier or medical method of contraception during PTC124 administration and the 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:

* 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).
* Ongoing participation in any other therapeutic clinical trial.
* Prior or ongoing medical condition (for example, concomitant illness, psychiatric condition, behavioral disorder, alcoholism, drug abuse), medical history, physical findings, ECG findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the subject, 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: Number of Participants With Treatment-Emergent Adverse Events (AEs)
timeFrame: Baseline (Week 48 of Study 007) up to Week 102
measure: Number of Participants With Clinically Significant Abnormal Laboratory Parameters
timeFrame: Baseline (Week 48 of Study 007) up to Week 102
Secondary outcomes:
measure: Change From Baseline in 6-Minute Walk Distance (6MWD) at Week 60
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Mean Activity Period/Day/Visit at Week 60, as Assessed by Step Activity Monitoring (SAM)
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Mean Total Step Count/Day/Visit During the Active Periods at Week 60, as Assessed by SAM
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Mean Total Step Count/Hour During the Active Period at Week 60, as Assessed by SAM
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Maximum Continuous 10-minute, 20-minute, 30-minute, and 60-minute Total Step Count at Week 60, as Assessed by SAM
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Percentage of Time During Active Period Spent at No Activity (0 Steps/Minute[Min]), Low Activity (Less Than or Equal to [≤]15 Steps/Min), Medium Activity (16-30 Steps/Min), and High Activity (Greater Than[>]30 Steps/Min) at Week 60
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Time to Stand From Supine Position at Week 60
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Time to Walk/Run 10 Meters at Week 60
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Time to Climb 4 Stairs at Week 60
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Time to Descend 4 Stairs at Week 60
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Heart Rate Before, During, and After Each 6MWD Test at Week 60, as Assessed by Heart Rate Monitoring With the Polar® RS400
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Number of Digits Recalled Forwards and Backwards on Digit Span Task at Week 60
timeFrame: Baseline (Week 48 of Study 007), Week 60
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 60
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Parent/Caregiver- Reported HRQL as Measured by the PedsQL Physical, Emotional, Social, and School Functioning Domain Scores at Week 60
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Participant-Reported HRQL as Measured by the Total Fatigue Scale Score at Week 60
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Parent/Caregiver-Reported HRQL as Measured by the Total Fatigue Scale Score at Week 60
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Participant and Parent/Caregiver Reported Activities of Daily Living of Participants Who Were Unable to Complete the 6MWT (Nonambulatory Participants), as Measured by the Egen Klassifikation (EK) Scale at Week 60
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Parent/Caregiver-Reported Treatment Satisfaction Questionnaire for Medication (TSQM) Score at Week 60
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Change From Baseline in Serum Concentration of Creatine Kinase (CK) at Week 60
timeFrame: Baseline (Week 48 of Study 007), Week 60
measure: Study Drug Compliance
timeFrame: Baseline (Week 48 of Study 007) to Week 96
measure: Trough Ataluren Plasma Concentration
timeFrame: Pre-morning dose (0 hour) at Baseline (Week 48 of 007 study), Weeks 54, 60, 72, 84, and 96
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California - Davis
state: California
city: Aurora
country: United States
facility: Department of Rehabilitation, The Children's Hospital
state: Colorado
city: Gulf Breeze
country: United States
facility: Child Neurology Center of NW Florida
state: Florida
city: Iowa City
country: United States
facility: University of Iowa Children's Hospital, Division of Child Neurology
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Children's Hospital of Boston
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University Medical School
state: Missouri
city: New York
country: United States
facility: Columbia University
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-Portland
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: The Royal Children's Hospital
state: Victoria
city: Westmead
country: Australia
facility: The Children's Hospital at Westmead
city: Leuven
country: Belgium
facility: UZ Leuven
city: London
country: Canada
facility: Alberta Children's Hospital
state: Ontario
city: London
country: Canada
facility: Children's Hospital of Western Ontario
state: Ontario
city: Vancouver
country: Canada
facility: British Colombia Children's Hopsital
city: Marseille cedex 20
country: France
facility: Hopital d'Enfants CHU Timone
city: Nantes cedex 1
country: France
facility: Laboratoire d'Exploration Fonctionnelles
city: Paris
country: France
facility: Groupe Hospitalier Pitie-Salpetriere, Institut de Myologie
city: Essen
country: Germany
facility: University of Essen - Clinic for Children
city: Freiburg
country: Germany
facility: University Hospital
city: Jerusalem
country: Israel
facility: Hadassah University Hopspital
city: Milano
country: Italy
facility: Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesu
city: Roma
country: Italy
facility: U.O. Complessa di Neuropsichiatria Infantile-Policlinico A. Gemelli-Universita Cattolica
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Deu
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
city: Goteborg
country: Sweden
facility: Queen Silvia Children's Hospital
city: Stockholm
country: Sweden
facility: Astrid Lindgren Pediatric Hospital
city: London
country: United Kingdom
facility: UCL Instititute of Child Health, Dubowitz
city: Newcastle Upon Tyne
country: United Kingdom
facility: University of Newcastle
city: Oswestry
country: United Kingdom
facility: Robert Jones & Agnes Hunt Orthopaedic Hospital
Study officials:
affiliation: PTC Therapeutics
name: Leone Atkinson, M.D., Ph.D.
role: STUDY_DIRECTOR
References:
citation: Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J Clin Pharmacol. 2007 Apr;47(4):430-44. doi: 10.1177/0091270006297140.
citation: Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007 May 3;447(7140):87-91. doi: 10.1038/nature05756. Epub 2007 Apr 22.