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ACT DMD

Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

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Year of Publication: 2017

Authors: McDonald CM, Campbell C, Torricelli RE, ..., ACT DMD Study Group

Journal: Lancet

Citation: McDonald CM et al. Lancet. 2017 Sep 23;390(10101):1489-1498. DOI: 10.1016/S0140-6736(17)31611-2. PMID: 28728956. NCT01826487

Link: https://pubmed.ncbi.nlm.nih.gov/28728956/

Clinical Question

Does ataluren (a nonsense mutation read-through agent) improve 6-minute walk distance in boys with nonsense mutation Duchenne muscular dystrophy?

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

FieldAtalurenControl
InterventionAtaluren 40 mg/kg/day orally in 3 divided doses (10/10/20 mg/kg morning/midday/evening)Matching placebo orally TID
Duration48 weeks48 weeks

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change in 6-minute walk distance from baseline to week 48Primary-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)SecondaryDifference: 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)SecondaryDifference: -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)SecondaryDifference: -9.5 m (SE 17.2, 95% CI -43.2 to 24.2)p=0.580 (NS)
Serious adverse eventsAdverse4/115 (3%)4/115 (3%)Similar; all except 1 event considered unrelated to treatment
Overall tolerabilityAdverseGenerally 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

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