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

Fecha de publicación: 23/09/2017

Autores de IIS La Fe

Juan Jesús Vílchez Padilla

Autor

Participantes ajenos a IIS La Fe

McDonald, CM
Campbell, C
Torricelli, RE
Finkel, RS
Flanigan, KM
Goemans, N
Heydemann, P
Kaminska, A
Kirschner, J
Muntoni, F
Osorio, AN
Schara, U
Sejersen, T
Shieh, PB
Sweeney, HL
Topaloglu, H
Tulinius, M
Voit, T
Wong, B
Elfring, G
Kroger, H
Luo, XH
McIntosh, J
Ong, T
Riebling, P
Souza, M
Spiegel, RJ
Peltz, SW
Mercuri, E
Clinical Evaluator Training Group
ACT DMD Study Group

Grupos

Patología Neuromuscular y Ataxias

Investigador Principal

Teresa Sevilla Mantecón

Abstract

Background 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. Methods 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. Findings 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. Interpretation 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.

Datos de la publicación

ISSN/ISSNe:: 0140-6736, 1474-547X
Tipo:: Article
Páginas:: 1489-1498
DOI:: 10.1016/S0140-6736(17)31611-2
Factor de Impacto:: 14,934 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

McDonald, CM:: University of California Davis School of Medicine, Davis, Sacramento, CA, USA

Univ Calif Davis, Sch Med, Sacramento, CA 95817 USA
Campbell, C:: Schulich School of Medicine and Dentistry, Western University, London, ON, Canada

Western Univ, Schulich Sch Med & Dent, London, ON, Canada
Torricelli, RE:: Hospital Luis Calvo Mackenna, Santiago de Chile, Chile

Hosp Ninos Luis Calvo Mackenna, Santiago, Chile
Finkel, RS:: Children's Hospital of Philadelphia, Philadelphia, PA, USA

Nemours Children's Hospital, Orlando, FL, USA

Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

Nemours Childrens Hosp, Orlando, FL USA
Flanigan, KM:: Nationwide Children's Hospital, Columbus, OH, USA

Nationwide Childrens Hosp, Columbus, OH USA
Goemans, N:: University Hospitals Leuven, KU Leuven, Belgium

Katholieke Univ Leuven, Univ Hosp Leuven, Leuven, Belgium
Heydemann, P:: Rush University Medical Center, Chicago, IL, USA

Rush Univ, Med Ctr, Chicago, IL 60612 USA
Kaminska, A:: Medical University of Warsaw, Warsaw, Poland

Med Univ Warsaw, Warsaw, Poland
Kirschner, J:: Medical Center-University of Freiburg, University of Freiberg, Freiberg, Germany

Univ Freiberg, Med Ctr, Freiberg, Germany
Muntoni, F:: University College London Great Ormond Street Institute of Child Health, London, UK

UCL, Inst Child Hlth, Great Ormond St, London, England
Osorio, AN:: Hospital Sant Joan de Déu, Universidad de Barcelona, CIBER, ISCIII, Barcelona, Spain

Univ Barcelona, Hosp St Joan de Deu, CIBER, ISCIII, Barcelona, Spain
Schara, U:: University Hospital Essen, University of Duisburg-Essen, Essen, Germany

Univ Duisburg Essen, Univ Hosp Essen, Essen, Germany
Sejersen, T:: Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden
Shieh, PB:: University of California, Los Angeles, CA, USA

Univ Calif Los Angeles, Los Angeles, CA USA
Sweeney, HL:: University of Florida, Gainesville, FL, USA

Univ Florida, Gainesville, FL USA
Topaloglu, H:: Hacettepe Children's Hospital, Ankara, Turkey

Hacettepe Childrens Hosp Med Ctr, Ankara, Turkey
Tulinius, M:: Gothenburg University, Queen Silvia Children's Hospital, Gothenburg, Sweden

Gothenburg Univ, Queen Silvia Childrens Hosp, Gothenburg, Sweden
Vilchez, JJ:: Hospital Universitario y Politécnico La Fe, CIBERER, Valencia, Spain

Hosp Univ & Politecn La Fe, CIBERER, Valencia, Spain
Voit, T:: 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, UK

UCL, Inst Child Hlth, Great Ormond St, London, England

UCL, Great Ormond St Hosp, Natl Inst Hlth Res, Biomed Res Ctr, London, England
Wong, B:: Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA
Elfring, G:: PTC Therapeutics, South Plainfield, NJ, USA

PTC Therapeut, South Plainfield, NJ USA
Kroger, H:: PTC Therapeutics, South Plainfield, NJ, USA

PTC Therapeut, South Plainfield, NJ USA
Luo, XH:: PTC Therapeutics, South Plainfield, NJ, USA

PTC Therapeut, South Plainfield, NJ USA
McIntosh, J:: PTC Therapeutics, South Plainfield, NJ, USA

PTC Therapeut, South Plainfield, NJ USA
Ong, T:: PTC Therapeutics, South Plainfield, NJ, USA

PTC Therapeut, South Plainfield, NJ USA
Riebling, P:: PTC Therapeutics, South Plainfield, NJ, USA

PTC Therapeut, South Plainfield, NJ USA
Souza, M:: PTC Therapeutics, South Plainfield, NJ, USA

PTC Therapeut, South Plainfield, NJ USA
Spiegel, RJ:: PTC Therapeutics, South Plainfield, NJ, USA

PTC Therapeut, South Plainfield, NJ USA
Peltz, SW:: PTC Therapeutics, South Plainfield, NJ, USA

PTC Therapeut, South Plainfield, NJ USA
Mercuri, E:: Department of Pediatric Neurology, Catholic University, Rome, Italy

Catholic Univ, Dept Pediat Neurol, Rome, Italy