A Phase 2B Efficacy and Safety Study of PTC124 in Subjects With Nonsense-Mutation-Mediated Duchenne and Becker Muscular Dystrophy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 174
- 试验地点
- 37
- 主要终点
- Change From Baseline in 6MWD at Week 48
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 5 Years 至 —（Child, Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
High-Dose Ataluren
Participants will receive ataluren suspension orally 3 times a day (TID), 20 milligrams/kilogram (mg/kg) at morning, 20 mg/kg at midday, and 40 mg/kg at evening (total daily dose 80 mg/kg) for 48 weeks.
干预措施: Ataluren (Drug)
Low-Dose Ataluren
Participants will receive ataluren suspension orally TID, 10 mg/kg at morning, 10 mg/kg at midday, and 20 mg/kg at evening (total daily dose 40 mg/kg) for 48 weeks.
干预措施: Ataluren (Drug)
Placebo
Participants will receive placebo matched to ataluren orally TID at morning, midday, and evening for 48 weeks.
干预措施: Placebo (Drug)
结局指标
主要结局
Change From Baseline in 6MWD at Week 48
时间窗: Baseline, Week 48
The 6MWD test was performed in a 30 meters long flat corridor, where the participant was instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. Ambulation was assessed via the 6MWD test following standardized procedures by measuring the 6MWD in meters. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test.
次要结局
- Change From Baseline in Time to Descend 4 Stairs at Week 48(Baseline, Week 48)
- Change From Baseline in Participant-Reported HRQL as Measured by the Total Fatigue Scale Score at Week 48(Baseline, Week 48)
- Parent/Caregiver-Reported Treatment Satisfaction Questionnaire for Medication (TSQM) Score(Week 48)
- Change From Baseline in Time to Stand From Supine Position at Week 48(Baseline, Week 48)
- 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(Baseline, Week 48)
- Change From Baseline in Participant/Caregiver-Reported Number of Daily Accidental Falls at Week 48(Baseline, Week 48)
- Change From Baseline in Time to Walk/Run 10 Meters at Week 48(Baseline, Week 48)
- Change From Baseline in Time to Climb 4 Stairs at Week 48(Baseline, Week 48)
- 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(Baseline, Week 48)
- 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(Baseline, Week 48)
- Change From Baseline in Mean Activity Period/Day/Visit at Week 48, as Assessed by Step Activity Monitoring (SAM)(Baseline, Week 48)
- Change From Baseline in Mean Total Step Count/Day/Visit During the Active Periods at Week 48, as Assessed by SAM(Baseline, Week 48)
- Change From Baseline in Mean Total Step Count/Hour During the Active Period at Week 48, as Assessed by SAM(Baseline, Week 48)
- Change From Baseline in Parent/Caregiver- Reported HRQL as Measured by the PedsQL Physical, Emotional, Social, and School Functioning Domain Scores at Week 48(Baseline, Week 48)
- 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(Baseline, Week 48)
- Change From Baseline in Parent/Caregiver-Reported HRQL as Measured by the Total Fatigue Scale Score at Week 48(Baseline, Week 48)
- Change From Baseline in Number of Digits Recalled Forwards and Backwards on Digit Span Task at Week 48(Baseline, Week 48)
- 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(Baseline, Week 48)
- Change From Baseline in Serum Concentration of Creatine Kinase (CK) at Week 48(Baseline, Week 48)
- 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(Pre-Treatment (1 week prior to baseline), post-treatment (Week 36))