PMID- 28728956 OWN - NLM STAT- MEDLINE DCOM- 20180927 LR - 20220330 IS - 1474-547X (Electronic) IS - 0140-6736 (Linking) VI - 390 IP - 10101 DP - 2017 Sep 23 TI - Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. PG - 1489-1498 LID - S0140-6736(17)31611-2 [pii] LID - 10.1016/S0140-6736(17)31611-2 [doi] AB - 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. FUNDING: PTC Therapeutics. CI - Copyright (c) 2017 Elsevier Ltd. All rights reserved. FAU - McDonald, Craig M AU - McDonald CM AD - University of California Davis School of Medicine, Davis, Sacramento, CA, USA. Electronic address: cmmcdonald@ucdavis.edu. FAU - Campbell, Craig AU - Campbell C AD - Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. FAU - Torricelli, Ricardo Erazo AU - Torricelli RE AD - Hospital Luis Calvo Mackenna, Santiago de Chile, Chile. FAU - Finkel, Richard S AU - Finkel RS AD - Children's Hospital of Philadelphia, Philadelphia, PA, USA; Nemours Children's Hospital, Orlando, FL, USA. FAU - Flanigan, Kevin M AU - Flanigan KM AD - Nationwide Children's Hospital, Columbus, OH, USA. FAU - Goemans, Nathalie AU - Goemans N AD - University Hospitals Leuven, KU Leuven, Belgium. FAU - Heydemann, Peter AU - Heydemann P AD - Rush University Medical Center, Chicago, IL, USA. FAU - Kaminska, Anna AU - Kaminska A AD - Medical University of Warsaw, Warsaw, Poland. FAU - Kirschner, Janbernd AU - Kirschner J AD - Medical Center-University of Freiburg, University of Freiberg, Freiberg, Germany. FAU - Muntoni, Francesco AU - Muntoni F AD - University College London Great Ormond Street Institute of Child Health, London, UK. FAU - Osorio, Andres Nascimento AU - Osorio AN AD - Hospital Sant Joan de Deu, Universidad de Barcelona, CIBER, ISCIII, Barcelona, Spain. FAU - Schara, Ulrike AU - Schara U AD - University Hospital Essen, University of Duisburg-Essen, Essen, Germany. FAU - Sejersen, Thomas AU - Sejersen T AD - Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. FAU - Shieh, Perry B AU - Shieh PB AD - University of California, Los Angeles, CA, USA. FAU - Sweeney, H Lee AU - Sweeney HL AD - University of Florida, Gainesville, FL, USA. FAU - Topaloglu, Haluk AU - Topaloglu H AD - Hacettepe Children's Hospital, Ankara, Turkey. FAU - Tulinius, Mar AU - Tulinius M AD - Gothenburg University, Queen Silvia Children's Hospital, Gothenburg, Sweden. FAU - Vilchez, Juan J AU - Vilchez JJ AD - Hospital Universitario y Politecnico La Fe, CIBERER, Valencia, Spain. FAU - Voit, Thomas AU - Voit T AD - 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. FAU - Wong, Brenda AU - Wong B AD - Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. FAU - Elfring, Gary AU - Elfring G AD - PTC Therapeutics, South Plainfield, NJ, USA. FAU - Kroger, Hans AU - Kroger H AD - PTC Therapeutics, South Plainfield, NJ, USA. FAU - Luo, Xiaohui AU - Luo X AD - PTC Therapeutics, South Plainfield, NJ, USA. FAU - McIntosh, Joseph AU - McIntosh J AD - PTC Therapeutics, South Plainfield, NJ, USA. FAU - Ong, Tuyen AU - Ong T AD - PTC Therapeutics, South Plainfield, NJ, USA. FAU - Riebling, Peter AU - Riebling P AD - PTC Therapeutics, South Plainfield, NJ, USA. FAU - Souza, Marcio AU - Souza M AD - PTC Therapeutics, South Plainfield, NJ, USA. FAU - Spiegel, Robert J AU - Spiegel RJ AD - PTC Therapeutics, South Plainfield, NJ, USA. FAU - Peltz, Stuart W AU - Peltz SW AD - PTC Therapeutics, South Plainfield, NJ, USA. FAU - Mercuri, Eugenio AU - Mercuri E AD - Department of Pediatric Neurology, Catholic University, Rome, Italy. CN - Clinical Evaluator Training Group CN - ACT DMD Study Group LA - eng SI - ClinicalTrials.gov/NCT01826487 PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial DEP - 20170717 PL - England TA - Lancet JT - Lancet (London, England) JID - 2985213R RN - 0 (Codon, Nonsense) RN - 0 (Dystrophin) RN - 0 (Oxadiazoles) RN - K16AME9I3V (ataluren) SB - IM CIN - Lancet. 2017 Sep 23;390(10101):1467-1468. PMID: 28728957 MH - Adolescent MH - Child MH - Codon, Nonsense/*genetics MH - Double-Blind Method MH - Dystrophin/deficiency/genetics MH - Global Health MH - Humans MH - Male MH - Muscular Dystrophy, Duchenne/*drug therapy/genetics MH - Oxadiazoles/*administration & dosage MH - Treatment Outcome MH - Walking FIR - Alfano, Lindsay N IR - Alfano LN FIR - Eagle, Michelle IR - Eagle M FIR - James, Meredith K IR - James MK FIR - Lowes, Linda IR - Lowes L FIR - Mayhew, Anna IR - Mayhew A FIR - Mazzone, Elena S IR - Mazzone ES FIR - Nelson, Leslie IR - Nelson L FIR - Rose, Kristy J IR - Rose KJ FIR - Abdel-Hamid, Hoda Z IR - Abdel-Hamid HZ FIR - Apkon, Susan D IR - Apkon SD FIR - Barohn, Richard J IR - Barohn RJ FIR - Bertini, Enrico IR - Bertini E FIR - Bloetzer, Clemens IR - Bloetzer C FIR - de Vaud, Lausanne Canton IR - de Vaud LC FIR - Butterfield, Russell J IR - Butterfield RJ FIR - Chabrol, Brigitte IR - Chabrol B FIR - Chae, Jong-Hee IR - Chae JH FIR - Jongno-Gu, Daehak-Ro IR - Jongno-Gu DR FIR - Comi, Giacomi Pietro IR - Comi GP FIR - Darras, Basil T IR - Darras BT FIR - Dastgir, Jahannaz IR - Dastgir J FIR - Desguerre, Isabelle IR - Desguerre I FIR - Escobar, Raul G IR - Escobar RG FIR - Finanger, Erika IR - Finanger E FIR - Guglieri, Michela IR - Guglieri M FIR - Hughes, Imelda IR - Hughes I FIR - Iannaccone, Susan T IR - Iannaccone ST FIR - Jones, Kristi J IR - Jones KJ FIR - Karachunski, Peter IR - Karachunski P FIR - Kudr, Martin IR - Kudr M FIR - Lotze, Timothy IR - Lotze T FIR - Mah, Jean K IR - Mah JK FIR - Mathews, Katherine IR - Mathews K FIR - Nevo, Yoram IR - Nevo Y FIR - Parsons, Julie IR - Parsons J FIR - Pereon, Yann IR - Pereon Y FIR - de Queiroz Campos Araujo, Alexandra Prufer IR - de Queiroz Campos Araujo AP FIR - Renfroe, J Ben IR - Renfroe JB FIR - de Resende, Maria Bernadete Dutra IR - de Resende MBD FIR - Ryan, Monique IR - Ryan M FIR - Selby, Kathryn IR - Selby K FIR - Tennekoon, Gihan IR - Tennekoon G FIR - Vita, Giuseppe IR - Vita G EDAT- 2017/07/22 06:00 MHDA- 2018/09/28 06:00 CRDT- 2017/07/22 06:00 PHST- 2016/12/19 00:00 [received] PHST- 2017/05/09 00:00 [revised] PHST- 2017/05/11 00:00 [accepted] PHST- 2017/07/22 06:00 [pubmed] PHST- 2018/09/28 06:00 [medline] PHST- 2017/07/22 06:00 [entrez] AID - S0140-6736(17)31611-2 [pii] AID - 10.1016/S0140-6736(17)31611-2 [doi] PST - ppublish SO - Lancet. 2017 Sep 23;390(10101):1489-1498. doi: 10.1016/S0140-6736(17)31611-2. Epub 2017 Jul 17.