A Phase 3, Randomized, Double-blind, Placebo-controlled Efficacy and Safety Study of Ataluren in Patients With Nonsense Mutation Duchenne Muscular Dystrophy and Open-Label Extension
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 360
- 试验地点
- 64
- 主要终点
- DB Period: Change From Baseline in 6-Minute Walk Distance (6MWD) at Week 72 - Modified Intention-to-treat (mITT) Population
研究概览
简要总结
This study is a long-term study of ataluren in participants with nonsense mutation Duchenne muscular dystrophy.
详细描述
This study is a randomized, double-blind, placebo-controlled, 72-week study, followed by a 72-week open-label period. The purpose is to characterize the long-term effects of ataluren-mediated dystrophin restoration on disease progression. Participants will be randomized in a 1:1 ratio to ataluren or placebo. Participants will receive blinded study drug three times daily (TID) at morning, midday, and evening for 72 weeks, after which all participants will receive open-label ataluren for an additional 72 weeks (144 weeks in total). Study assessments will be performed at clinic visits every 12 weeks during the double-blind period and every 24 weeks during the open-label period.
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)
盲法说明
A randomized, double-blind, placebo-controlled,72-week study and its 72-week open-label extension
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
- •Age ≥5 years
- •Phenotypic evidence of Duchenne Muscular Dystrophy
- •Nonsense point mutation in the dystrophin gene
- •Use of systemic corticosteroids (prednisone/prednisolone or deflazacort)for a minimum of 12 months immediately prior to start of study treatment, with no significant change in dosage or dosing regimen for a minimum of 3 months immediately prior to start of study treatment
- •6MWD ≥150 meters
- •Ability to perform timed function tests within 30 seconds
- •Willingness and ability to comply with scheduled visits, drug administration plan, study procedures, laboratory tests, and study restrictions.
排除标准
- •Any change in prophylaxis treatment for cardiomyopathy within 1 month prior to start of study treatment.
- •Ongoing intravenous (IV) aminoglycoside or IV vancomycin therapy.
- •Prior or ongoing therapy with ataluren.
- •Known hypersensitivity to any of the ingredients or excipients of the study drug
- •Exposure to another investigational drug within 6 months prior to start of study treatment, or ongoing participation in any interventional clinical trial.
- •History of major surgical procedure within 12 weeks prior to start of study treatment, or expectation of major surgical procedure during the 72-week placebo-controlled treatment period.
- •Requirement for daytime ventilator assistance or any use of invasive mechanical ventilation via tracheostomy.
- •Uncontrolled clinical symptoms and signs of congestive heart failure
- •Elevated serum creatinine or cystatin C at screening.
研究组 & 干预措施
Ataluren
Participants will receive ataluren oral suspension 10 milligrams (mg)/kilogram (kg) in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening each day for 72 weeks in DB treatment period and for an additional 72 weeks in open-label treatment period.
干预措施: Ataluren (Drug)
Placebo
Participants will receive placebo matched to ataluren oral suspension for 72 weeks in DB treatment period. After completion of DB treatment period, participants will receive ataluren oral suspension 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening each day for 72 weeks in open-label treatment period.
干预措施: PLACEBO (Drug)
结局指标
主要结局
DB Period: Change From Baseline in 6-Minute Walk Distance (6MWD) at Week 72 - Modified Intention-to-treat (mITT) Population
时间窗: Baseline, Week 72
The 6MWD test is a non-encouraged test performed in a 30 meters long flat corridor, where the participant is 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. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test. Participants with confirmed loss of ambulation at a particular visit were assigned a 6MWD result of 0. Baseline was defined as the maximum measurement of valid Day 1 and Day 2 6MWD values. Least square (LS) mean and standard error (SE) was calculated using the mixed-model repeated measures (MMRM).
DB Period: Change From Baseline in 6MWD at Week 72 - Intent-to-Treat (ITT) Population
时间窗: Baseline, Week 72
The 6MWD test is a non-encouraged test performed in a 30 meters long flat corridor, where the participant is 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. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test. Participants with confirmed loss of ambulation at a particular visit were assigned a 6MWD result of 0. Baseline was defined as the maximum measurement of valid Day 1 and Day 2 6MWD values. LS mean and SE was calculated using the MMRM.
DB Period: Average Rate of Change From Baseline in 6MWD at Week 72 - mITT Population
时间窗: Baseline, Week 72
The 6MWD test is a non-encouraged test performed in a 30 meters long flat corridor, where the participant is 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. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test. Participants with confirmed loss of ambulation at a particular visit were assigned a 6MWD result of 0. Baseline was defined as the maximum measurement of valid Day 1 and Day 2 6MWD values. LS mean and SE was calculated using the MMRM.
DB Period: Average Rate of Change From Baseline in 6MWD at Week 72 - ITT Population
时间窗: Baseline, Week 72
The 6MWD test is a non-encouraged test performed in a 30 meters long flat corridor, where the participant is 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. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test. Participants with confirmed loss of ambulation at a particular visit were assigned a 6MWD result of 0. Baseline was defined as the maximum measurement of valid Day 1 and Day 2 6MWD values. LS mean and SE was calculated using the MMRM.
次要结局
- DB Period: Change From Baseline in Time to Climb 4 Stairs at Week 72 - mITT Population(Baseline, Week 72)
- DB Period: Change From Baseline in North Start Ambulatory Assessment (NSAA) Total Score at Week 72 - mITT Population(Baseline, Week 72)
- DB Period: Change From Baseline in Time to Run/Walk 10 Meters at Week 72 - mITT Population(Baseline, Week 72)
- DB Period: Change From Baseline in Time to Run/Walk 10 Meters at Week 72 - ITT Population(Baseline, Week 72)
- DB Period: Change From Baseline in Time to Climb 4 Stairs at Week 72 - ITT Population(Baseline, Week 72)
- DB Period: Change From Baseline in Time to Descend 4 Stairs at Week 72 - mITT Population(Baseline, Week 72)
- DB Period: Change From Baseline in Time to Descend 4 Stairs at Week 72 - ITT Population(Baseline, Week 72)
- DB Period: Composite of Average Change From Baseline in TFTs at Week 72 - mITT Population(Baseline, Week 72)
- DB Period: Time to Persistent 10% Worsening in 6MWD - ITT Population(Baseline to approximately Week 72 (Due to COVID, many participants attended the protocol-defined Week 72 visit late))
- DB Period: Composite of Average Change From Baseline in TFTs at Week 72 - ITT Population(Baseline, Week 72)
- DB Period: Composite of Average Rate of Change From Baseline in TFTs at Week 72 - mITT Population(Baseline, Week 72)
- DB Period: Composite of Average Rate of Change From Baseline in TFTs at Week 72 - ITT Population(Baseline, Week 72)
- DB Period: Time to Persistent 10% Worsening in 6MWD at Week 72 - mITT Population(Baseline to Week 72)
- DB Period: Change From Baseline in NSAA Total Score at Week 72 - ITT Population(Baseline, Week 72)
- DB Period: Time to Loss of Ambulation - mITT Population(Baseline up to approximately Week 72 (Due to COVID, many participants attended the protocol-defined Week 72 visit late))
- DB Period: Time to Loss of Ambulation Over 72 Weeks - ITT Population(Baseline up to Week 72)
- DB Period: Time to Loss of Stair-Climbing - mITT Population(Baseline up to approximately Week 72 (Due to COVID, many participants attended the protocol-defined Week 72 visit late))
- DB Period: Number of Participants With Function Loss of NSAA Items at Week 72 - ITT Population(Week 72)
- DB Period: Time to Loss of Stair-Climbing - ITT Population(Baseline up to approximately Week 72 (Due to COVID, many participants attended the protocol-defined Week 72 visit late))
- DB Period: Time to Loss of Stair-Descending - mITT Population(Baseline up to approximately Week 72 (Due to COVID, many participants attended the protocol-defined Week 72 visit late))
- DB Period: Time to Loss of Stair-Descending - ITT Population(Baseline up to approximately Week 72 (Due to COVID, many participants attended the protocol-defined Week 72 visit late))
- DB Period: Number of Participants With Function Loss of NSAA Items at Week 72 - mITT Population(Week 72)
- DB Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs)(Baseline up to Week 76)
- Overall Treatment Period: Change From Baseline in 6MWD at Week 144(Baseline, Week 144)
- Overall Treatment Period: Composite of Average Change From Baseline in TFTs at Week 144(Baseline, Week 144)
- Overall Treatment Period: Change From Baseline in Time to Run/Walk 10 Meters at Week 144(Baseline, Week 144)
- Overall Treatment Period: Change From Baseline in Time to Climb 4 Stairs at Week 144(Baseline, Week 144)
- Overall Treatment Period: Change From Baseline in Time to Descend 4 Stairs at Week 144(Baseline, Week 144)
- Overall Treatment Period: Change From Baseline in NSAA Total Score at Week 144(Baseline, Week 144)
- Overall Treatment Period: Time to Loss of Ambulation Over 144 Weeks(Baseline up to Week 144)
- Overall Treatment Period: Time to Loss of Stair-Climbing Over 144 Weeks(Baseline up to Week 144)
- Overall Treatment Period: Time to Loss of Stair- Descending Over 144 Weeks(Baseline up to Week 144)
- Overall Treatment Period: Number of Participants With Function Loss of NSAA Items at Week 144(Week 144)
- Overall Treatment Period: Number of Participants With TEAEs(Baseline up to Week 148)
- OL Period: Plasma Pharmacokinetic (PK) Concentration of Ataluren(Predose and 2 hours postdose at Week 144)