Clinical trial NCT00759876: Phase 2a Extension Study of Ataluren (PTC124) in Duchenne Muscular Dystrophy (DMD)
Official title: A Phase 2a Extension Study of PTC124 in Subjects With Nonsense-Mutation-Mediated Duchenne Muscular Dystrophy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Duchenne Muscular Dystrophy
Keywords: Duchenne muscular dystrophy
Nonsense mutation
Premature stop codon
DMD
PTC124
Ataluren
Lead sponsor: PTC Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Genzyme, a Sanofi Company
First posted: 2008-09-25
Enrollment: 36
Sex: MALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Duchenne muscular dystrophy (DMD) 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 in approximately 10-15% 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 2a extension trial that will evaluate the long-term safety of ataluren in boys with nonsense mutation DMD, as determined by adverse events and laboratory abnormalities. The study will also assess changes in walking, muscle function, strength, and other important clinical and laboratory measures.

Detailed description: This Phase 2a, multicenter, open-label safety and efficacy study will be performed at 3 sites in the United States. The study will enroll up to 38 participants with nonsense mutation Duchenne muscular dystrophy who participated in a previous Phase 2a study of ataluren (Protocol Number PTC124-GD-004-DMD \[NCT00264888\]). Participants will receive study drug 3 times per day (at breakfast, lunch, and dinner) for approximately 96 weeks (approximately 2 years). Study assessments will be performed at clinic visits during screening, every 6 weeks for the first 24 weeks, and then every 12 weeks until the end of the study. Additional safety laboratory testing, which may be performed at the investigational site or at an accredited local laboratory or clinic, is required every 3 weeks for the first 24 weeks and then every 6 weeks from Week 24 to Week 48. Participants will have a biceps muscle biopsy before ataluren treatment and again after 24 weeks of ataluren treatment to evaluate changes in muscle dystrophin expression. An evaluation of the effects of ataluren on corticosteroid pharmacokinetics will be performed. Associated with this ataluren clinical trial is a substudy that will use magnetic resonance evaluations to assess changes in the composition of muscles of the legs.

Eligibility criteria: Inclusion Criteria:

* Completion of ataluren treatment in the previous Phase 2a study (Protocol PTC124-GD-004-DMD).
* Ability to provide written informed consent (parental/guardian consent if applicable)/assent (if \<18 years of age).
* Confirmed screening laboratory values within the central laboratory ranges.
* In participants who are sexually active, willingness to abstain from sexual intercourse or employ a barrier or medical method of contraception during ataluren 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:

* Treatment with systemic aminoglycoside antibiotics within 3 months prior to start of study treatment.
* Treatment with warfarin within 1 month prior to start of study treatment.
* 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 \[colloidal silica\], and magnesium stearate).
* Exposure to another investigational drug within 2 months prior to start of study treatment.
* History of major surgical procedure within 1 month prior to start of study treatment.
* Ongoing immunosuppressive therapy (other than corticosteroids).
* Ongoing participation in any other clinical trial (except for sub-studies specifically approved by PTC Therapeutics).
* Clinically significant symptoms and signs of congestive heart failure (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, 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: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: Baseline up to Week 89
Secondary outcomes:
measure: Change From Baseline in 6-Minute Walk Distance (6MWD) as Measured by the 6-minute Walk Test (6MWT)
timeFrame: Baseline, Week 48 and Week 60
measure: Change From Baseline in Proximal Muscle Function as Assessed by Speed During Timed Function Tests
timeFrame: Baseline, Week 48 and Week 60
measure: Change From Baseline in Standing From Supine Position as Assessed by Method Scores During Timed Function Tests
timeFrame: Baseline, Week 48 and Week 60
measure: Change From Baseline in Run/Walk 10-Meters as Assessed by Method Scores During Timed Function Tests
timeFrame: Baseline, Week 48 and Week 60
measure: Change From Baseline in Ascending 4 Stairs as Assessed by Method Scores During Timed Function Tests
timeFrame: Baseline, Week 48 and Week 60
measure: Change From Baseline in Descending 4 Stairs as Assessed by Method Scores During Timed Function Tests
timeFrame: Baseline, Week 48 and Week 60
measure: Change From Baseline in Force Exerted During Knee Flexion and Extension, Elbow Flexion and Extension, Shoulder Abduction, and Hand Grip as Assessed by Myometry
timeFrame: Baseline, Week (Wk) 48 and Wk 60
measure: Change in Resting, Active, and Recovery Heart Rate as Assessed by Heart Rate Monitoring With the Polar RS400
timeFrame: Baseline, Week 48 and Week 60
measure: Change From Baseline in Verbal Memory and Attention as Assessed by the Digit Span Task
timeFrame: Baseline, Week 48 and 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) Inventory
timeFrame: Baseline, Week 48 and Week 60
measure: Change From Baseline in Parent- or Caregiver-Reported HRQL as Measured by the PedsQL Inventory
timeFrame: Baseline, Week 48 and Week 60
measure: Change From Baseline in Serum Creatine Kinase (CK) Levels
timeFrame: Baseline, Week 48 and Week 60
measure: Change From Baseline in Dystrophin Expression on Biceps Muscle Biopsy as Measured by Immunofluorescence Staining of the Sarcolemmal Membrane With an Antibody to the C-Terminal Portion of the Dystrophin Protein
timeFrame: Baseline, Week 24
measure: Study Drug Compliance
timeFrame: Baseline up to Week 89
measure: Pharmacokinetics: Ataluren Plasma Exposure in All Participants
timeFrame: 0 (pre-dose), 0.5, 1, 2, 3, and 4 hours post-morning dose and 0 (pre-dose) and 2 hours post-midday dose on Day 2 of Week 1 and Day 2 of Week 6
measure: Pharmacokinetics: Ataluren Plasma Exposure in Ambulatory Participants
timeFrame: 0 (pre-dose), 0.5, 1, 2, 3, and 4 hours post-morning dose and 0 (pre-dose) and 2 hours post-midday dose on Day 2 of Week 1 and Day 2 of Week 6
measure: Corticosteroid Plasma Concentrations as Assessed by a Validated Bioanalytical Method, in Participants Who Received a Daily Corticosteroid Regimen With Prednisone or Deflazacort
timeFrame: 0 (pre-dose), 0.5, 1, 2, 3, and 4 hours post-morning dose and 0 (pre-dose) and 2 hours post-midday dose on Day 2 of Week 1 and Day 2 of Week 6
measure: Change in Muscle Composition as Assessed by Limb Magnetic Resonance (MR) Testing
timeFrame: Baseline, Week 48, Week 60
Other outcomes:
Locations:
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: PTC Therapeutics, Inc.
name: Leone Atkinson
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.