Michael G Hanna1, Umesh A Badrising2, Olivier Benveniste3, Thomas E Lloyd4, Merrilee Needham5, Hector Chinoy6, Masashi Aoki7, Pedro M Machado8, Christina Liang9, Katrina A Reardon10, Marianne de Visser11, Dana P Ascherman12, Richard J Barohn13, Mazen M Dimachkie13, James A L Miller14, John T Kissel15, Björn Oskarsson16, Nanette C Joyce16, Peter Van den Bergh17, Jonathan Baets18, Jan L De Bleecker19, Chafic Karam20, William S David21, Massimiliano Mirabella22, Sharon P Nations23, Hans H Jung24, Elena Pegoraro25, Lorenzo Maggi26, Carmelo Rodolico27, Massimiliano Filosto28, Aziz I Shaibani29, Kumaraswamy Sivakumar30, Namita A Goyal31, Madoka Mori-Yoshimura32, Satoshi Yamashita33, Naoki Suzuki34, Masahisa Katsuno35, Kenya Murata36, Hiroyuki Nodera37, Ichizo Nishino38, Carla D Romano39, Valerie S L Williams39, John Vissing40, Lixin Zhang Auberson41, Min Wu42, Ana de Vera41, Dimitris A Papanicolaou42, Anthony A Amato43. 1. Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, London, UK. Electronic address: m.hanna@ucl.ac.uk. 2. Department of Neurology, Leiden University Medical Center, Leiden, Netherlands. 3. Department of Internal Medicine and Clinical Immunology, Pitié-Salpêtrière Hospital, Sorbonne Université, Paris, France. 4. Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. 5. Fiona Stanley Hospital, Institute for Immunology & Infectious Diseases Murdoch University and Notre Dame University, Perth, WA, Australia. 6. National Institute for Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. 7. Department of Neurology, Tohoku University School of Medicine, Sendai, Japan. 8. Medical Research Council (MRC) Centre for Neuromuscular Diseases, University College London (UCL) Institute of Neurology, London, UK; Centre for Rheumatology, Division of Medicine, UCL, London, UK. 9. Department of Neurology, Royal North Shore Hospital, Sydney, NSW, Australia. 10. Calvary Health Care Bethlehem, Caulfield South, VIC, Australia. 11. Department of Neurology, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands. 12. Department of Medicine, University of Miami, Miami, FL, USA. 13. Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA. 14. Department of Neurology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. 15. Department of Neurology, Ohio State University Wexner Medical Center, Columbus, OH, USA. 16. UC Davis School of Medicine, Neuromuscular Research Center, Sacramento, CA, USA. 17. Department of Neurology, University Hospital Saint-Luc, University of Louvain, Brussels, Belgium. 18. Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, and the Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. 19. Department of Neurology, Ghent University Hospital, Ghent, Belgium. 20. Department of Neurology, Oregon Health & Science University, Portland, OR, USA. 21. Department of Neurology, Massachusetts General Hospital, Neuromuscular Diagnostic Center and Electromyography Laboratory, Boston, MA, USA. 22. Department of Neurology, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Universitá Cattolica del Sacro Cuore, Rome, Italy. 23. Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 24. Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland. 25. Department of Neurosciences, University of Padua School of Medicine, Padua, Italy. 26. Neuroimmunology and Neuromuscular Diseases Unit, Foundation IRCCS Neurological Institute Carlo Besta, Milan, Italy. 27. Unit of Neurology and Neuromuscular Disorders, Azienda Ospedaliera Universitaria Policlinico G Martino, University of Messina, Messina, Italy. 28. Center for Neuromuscular Diseases, Unit of Neurology, Azienda Socio Sanitaria Territoriale Spedali Civili and University of Brescia, Brescia, Italy. 29. Nerve and Muscle Center of Texas, Houston, TX, USA. 30. Neuromuscular Research Center, Phoenix, AZ, USA. 31. Department of Neurology, University of California Irvine, Amyotrophic Lateral Sclerosis & Neuromuscular Center, Orange, CA, USA. 32. Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan. 33. Department of Neurology, Kumamoto University Hospital, Kumamoto, Japan. 34. Department of Neurology, Tohoku University Hospital, Miyagi, Japan. 35. Department of Neurology, Nagoya University Hospital, Aichi, Japan. 36. Wakayama Medical University Hospital, Wakayama, Japan. 37. Tokushima University Hospital, Tokushima, Japan. 38. Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. 39. RTI Health Solutions, Research Triangle Park, NC, USA. 40. Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 41. Novartis Pharma, Basel, Switzerland. 42. Novartis Pharmaceuticals, East Hanover, NJ, USA. 43. Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Abstract
BACKGROUND: Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis. METHODS: We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis. FINDINGS:Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to theplacebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab. INTERPRETATION:Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months. FUNDING: Novartis Pharma.
RCT Entities:
BACKGROUND: Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis. METHODS: We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis. FINDINGS: Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab. INTERPRETATION:Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months. FUNDING: Novartis Pharma.
Authors: Anthony A Amato; Michael G Hanna; Pedro M Machado; Umesh A Badrising; Hector Chinoy; Olivier Benveniste; Ananda Krishna Karanam; Min Wu; László B Tankó; Agnes Annette Schubert-Tennigkeit; Dimitris A Papanicolaou; Thomas E Lloyd; Merrilee Needham; Christina Liang; Katrina A Reardon; Marianne de Visser; Dana P Ascherman; Richard J Barohn; Mazen M Dimachkie; James A L Miller; John T Kissel; Björn Oskarsson; Nanette C Joyce; Peter Van den Bergh; Jonathan Baets; Jan L De Bleecker; Chafic Karam; William S David; Massimiliano Mirabella; Sharon P Nations; Hans H Jung; Elena Pegoraro; Lorenzo Maggi; Carmelo Rodolico; Massimiliano Filosto; Aziz I Shaibani; Kumaraswamy Sivakumar; Namita A Goyal; Madoka Mori-Yoshimura; Satoshi Yamashita; Naoki Suzuki; Masashi Aoki; Masahisa Katsuno; Hirokazu Morihata; Kenya Murata; Hiroyuki Nodera; Ichizo Nishino; Carla D Romano; Valerie S L Williams; John Vissing; Lixin Zhang Auberson Journal: Neurology Date: 2021-02-17 Impact factor: 9.910
Authors: Mohamed A Alfaleh; Hashem O Alsaab; Ahmad Bakur Mahmoud; Almohanad A Alkayyal; Martina L Jones; Stephen M Mahler; Anwar M Hashem Journal: Front Immunol Date: 2020-08-28 Impact factor: 7.561