ACT DMD
Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
Clinical Question
Does ataluren (a nonsense mutation read-through agent) improve 6-minute walk distance in boys with nonsense mutation Duchenne muscular dystrophy?
Study Overview
Objective
To evaluate the efficacy and safety of ataluren in patients with nonsense mutation Duchenne muscular dystrophy
Study Summary
- Primary endpoint not met: 6MWD change -47.7 m vs -60.7 m (difference 13.0 m, p=0.213)
- Prespecified subgroup with baseline 6MWD 300-399 m showed significant benefit (42.9 m, p=0.007)
Intervention
Ataluren 40 mg/kg/day orally three times daily vs placebo
Patients per Arm
115 ataluren, 115 placebo
Bottom Line
Ataluren did not significantly improve 6MWD in the overall ITT population (13.0 m difference, p=0.213). However, a prespecified subgroup with baseline 6MWD 300-399 m showed clinically meaningful and statistically significant benefit (42.9 m, p=0.007). The drug was well tolerated.
Major Points
- Primary endpoint not met: 6MWD change ataluren -47.7 m vs placebo -60.7 m (difference 13.0 m, 95% CI -7.4 to 33.4, p=0.213)
- Prespecified subgroup with baseline 6MWD 300-399 m showed significant benefit: 42.9 m (95% CI 11.8-74.0, p=0.007) -- this subgroup represents the 'declining' phase of DMD
- Subgroups with <300 m (floor effect, too advanced) and >=400 m (ceiling effect, too stable) showed no benefit
- Largest trial to date in nonsense mutation DMD (228 patients at 54 sites in 18 countries)
- Well tolerated; SAEs: 8/228 (3%) patients total, 4 per group, all except 1 unrelated to treatment
Design
Study Type: Phase 3, multicenter, randomized, double-blind, placebo-controlled trial
Randomization: 1
Blinding: Double-blind; permuted block randomization (size 4)
Enrollment Period: March 26, 2013 to August 26, 2014
Follow-up Duration: 48 weeks
Centers: 54
Countries: 18 countries across North America, Europe, South America, Asia-Pacific
Sample Size: 230
Analysis: Intention-to-treat (n=228); stratified by age (<9 vs >=9), prior corticosteroid duration (6-12 vs >=12 months), baseline 6MWD (<350 m vs >=350 m); ANCOVA with stratification factors
Inclusion Criteria
- Boys aged 7 to 16 years
- Nonsense mutation DMD confirmed by genetic testing
- Baseline 6-minute walk distance (6MWD) >=150 m and <=80% predicted for age and height
- Corticosteroid use for >=6 months prior to enrollment
- Stable corticosteroid dose for >=3 months
Exclusion Criteria
- Known aminoglycoside sensitivity
- Prior ataluren exposure in a clinical trial within 6 months
Arms
| Field | Ataluren | Control |
|---|---|---|
| Intervention | Ataluren 40 mg/kg/day orally in 3 divided doses (10/10/20 mg/kg morning/midday/evening) | Matching placebo orally TID |
| Duration | 48 weeks | 48 weeks |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Change in 6-minute walk distance from baseline to week 48 | Primary | -60.7 m (SE 9.3) | -47.7 m (SE 9.3) | 0.213 | |
| 6MWD in prespecified subgroup: baseline 6MWD 300-<400 m (declining phase) | Secondary | Difference: 42.9 m (SE 15.9, 95% CI 11.8-74.0) | p=0.007 | ||
| 6MWD in subgroup: baseline 6MWD <300 m (advanced/floor effect) | Secondary | Difference: -7.7 m (SE 24.1, 95% CI -54.9 to 39.5) | p=0.749 (NS) | ||
| 6MWD in subgroup: baseline 6MWD >=400 m (stable/ceiling effect) | Secondary | Difference: -9.5 m (SE 17.2, 95% CI -43.2 to 24.2) | p=0.580 (NS) | ||
| Serious adverse events | Adverse | 4/115 (3%) | 4/115 (3%) | Similar; all except 1 event considered unrelated to treatment | |
| Overall tolerability | Adverse | Generally well tolerated; mostly mild-moderate AEs |
Subgroup Analysis
Prespecified subgroup analysis by baseline 6MWD: <300 m (n=NS), 300-<400 m (significant benefit of 42.9 m, p=0.007), >=400 m (NS). The 300-399 m subgroup represents the 'declining phase' of DMD where patients are actively losing walking ability -- this is where ataluren appears most effective. Floor and ceiling effects explain lack of benefit in other subgroups.
Criticisms
- Primary endpoint not statistically significant in overall population
- Subgroup benefit limited to narrow baseline range
- Funded by manufacturer (PTC Therapeutics)
Funding
PTC Therapeutics
Based on: ACT DMD (Lancet, 2017)
Authors: McDonald CM, Campbell C, Torricelli RE, ..., ACT DMD Study Group
Citation: McDonald CM et al. Lancet. 2017 Sep 23;390(10101):1489-1498. DOI: 10.1016/S0140-6736(17)31611-2. PMID: 28728956. NCT01826487
Content summarized and formatted by NeuroTrials.ai.