Journal article
Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
The Lancet (British edition), Vol.390(10101), pp.1489-1498
09/23/2017
DOI: 10.1016/S0140-6736(17)31611-2
PMID: 28728956
Abstract
Duchenne muscular dystrophy (DMD) is a severe, progressive, and rare neuromuscular, X-linked recessive disease. Dystrophin deficiency is the underlying cause of disease; therefore, mutation-specific therapies aimed at restoring dystrophin protein production are being explored. We aimed to assess the efficacy and safety of ataluren in ambulatory boys with nonsense mutation DMD.
We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 54 sites in 18 countries located in North America, Europe, the Asia-Pacific region, and Latin America. Boys aged 7-16 years with nonsense mutation DMD and a baseline 6-minute walk distance (6MWD) of 150 m or more and 80% or less of the predicted normal value for age and height were randomly assigned (1:1), via permuted block randomisation (block size of four) using an interactive voice-response or web-response system, to receive ataluren orally three times daily (40 mg/kg per day) or matching placebo. Randomisation was stratified by age (<9 years vs ≥9 years), duration of previous corticosteroid use (6 months to <12 months vs ≥12 months), and baseline 6MWD (<350 m vs ≥350 m). Patients, parents and caregivers, investigational site personnel, PTC Therapeutics employees, and all other study personnel were masked to group allocation until after database lock. The primary endpoint was change in 6MWD from baseline to week 48. We additionally did a prespecified subgroup analysis of the primary endpoint, based on baseline 6MWD, which is reflective of anticipated rates of disease progression over 1 year. The primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01826487.
Between March 26, 2013, and Aug 26, 2014, we randomly assigned 230 patients to receive ataluren (n=115) or placebo (n=115); 228 patients comprised the intention-to-treat population. The least-squares mean change in 6MWD from baseline to week 48 was -47·7 m (SE 9·3) for ataluren-treated patients and -60·7 m (9·3) for placebo-treated patients (difference 13·0 m [SE 10·4], 95% CI -7·4 to 33·4; p=0·213). The least-squares mean change for ataluren versus placebo in the prespecified subgroups was -7·7 m (SE 24·1, 95% CI -54·9 to 39·5; p=0·749) in the group with a 6MWD of less than 300 m, 42·9 m (15·9, 11·8-74·0; p=0·007) in the group with a 6MWD of 300 m or more to less than 400 m, and -9·5 m (17·2, -43·2 to 24·2; p=0·580) in the group with a 6MWD of 400 m or more. Ataluren was generally well tolerated and most treatment-emergent adverse events were mild to moderate in severity. Eight (3%) patients (n=4 per group) reported serious adverse events; all except one event in the placebo group (abnormal hepatic function deemed possibly related to treatment) were deemed unrelated to treatment.
Change in 6MWD did not differ significantly between patients in the ataluren group and those in the placebo group, neither in the intention-to-treat population nor in the prespecified subgroups with a baseline 6MWD of less than 300 m or 400 m or more. However, we recorded a significant effect of ataluren in the prespecified subgroup of patients with a baseline 6MWD of 300 m or more to less than 400 m. Baseline 6MWD values within this range were associated with a more predictable rate of decline over 1 year; this finding has implications for the design of future DMD trials with the 6-minute walk test as the endpoint.
PTC Therapeutics.
Details
- Title: Subtitle
- Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
- Creators
- Craig M McDonald - University of California Davis School of Medicine, Davis, Sacramento, CA, USA. Electronic address: cmmcdonald@ucdavis.eduCraig Campbell - Schulich School of Medicine and Dentistry, Western University, London, ON, CanadaRicardo Erazo Torricelli - Hospital Luis Calvo Mackenna, Santiago de Chile, ChileRichard S Finkel - Children's Hospital of Philadelphia, Philadelphia, PA, USA; Nemours Children's Hospital, Orlando, FL, USAKevin M Flanigan - Nationwide Children's Hospital, Columbus, OH, USANathalie Goemans - University Hospitals Leuven, KU Leuven, BelgiumPeter Heydemann - Rush University Medical Center, Chicago, IL, USAAnna Kaminska - Medical University of Warsaw, Warsaw, PolandJanbernd Kirschner - Medical Center-University of Freiburg, University of Freiberg, Freiberg, GermanyFrancesco Muntoni - University College London Great Ormond Street Institute of Child Health, London, UKAndrés Nascimento Osorio - Hospital Sant Joan de Déu, Universidad de Barcelona, CIBER, ISCIII, Barcelona, SpainUlrike Schara - University Hospital Essen, University of Duisburg-Essen, Essen, GermanyThomas Sejersen - Karolinska University Hospital, Karolinska Institutet, Stockholm, SwedenPerry B Shieh - University of California, Los Angeles, CA, USAH Lee Sweeney - University of Florida, Gainesville, FL, USAHaluk Topaloglu - Hacettepe Children's Hospital, Ankara, TurkeyMár Tulinius - Gothenburg University, Queen Silvia Children's Hospital, Gothenburg, SwedenJuan J Vilchez - Hospital Universitario y Politécnico La Fe, CIBERER, Valencia, SpainThomas Voit - University College London Great Ormond Street Institute of Child Health, London, UK; National Institute for Health Research Great Ormond Street Hospital University College London Biomedical Research Centre, London, UKBrenda Wong - Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USAGary Elfring - PTC Therapeutics, South Plainfield, NJ, USAHans Kroger - PTC Therapeutics, South Plainfield, NJ, USAXiaohui Luo - PTC Therapeutics, South Plainfield, NJ, USAJoseph McIntosh - PTC Therapeutics, South Plainfield, NJ, USATuyen Ong - PTC Therapeutics, South Plainfield, NJ, USAPeter Riebling - PTC Therapeutics, South Plainfield, NJ, USAMarcio Souza - PTC Therapeutics, South Plainfield, NJ, USARobert J Spiegel - PTC Therapeutics, South Plainfield, NJ, USAStuart W Peltz - PTC Therapeutics, South Plainfield, NJ, USAEugenio Mercuri - Department of Pediatric Neurology, Catholic University, Rome, ItalyClinical Evaluator Training GroupACT DMD Study Group
- Contributors
- Katherine D Mathews (Contributor) - University of Iowa, Stead Family Department of Pediatrics
- Resource Type
- Journal article
- Publication Details
- The Lancet (British edition), Vol.390(10101), pp.1489-1498
- Publisher
- England
- DOI
- 10.1016/S0140-6736(17)31611-2
- PMID
- 28728956
- ISSN
- 0140-6736
- eISSN
- 1474-547X
- Language
- English
- Date published
- 09/23/2017
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984070238202771
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