Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial

Michael G. Hanna, Umesh A. Badrising, Olivier Benveniste, Thomas E. Lloyd, Merrilee Needham, Hector Chinoy, Masashi Aoki, Pedro M. Machado, 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, P. Van den Bergh, Jonathan BaetsJ. L. De Bleecker, Chafic Karam, William S. David, Massimiliano Mirabella, Sharon P. Nations, Hans H. Jung, E. Pegoraro, Lorenzo Maggi, Carmelo Rodolico, Massimiliano Filosto, Aziz I. Shaibani, Kumaraswamy Sivakumar, Namita A. Goyal, Madoka Mori-Yoshimura, Satoshi Yamashita, N. Suzuki, Masahisa Katsuno, K. Murata, Hiroyuki Nodera, Ichizo Nishino, Carla D. Romano, Valerie S.L. Williams, John Vissing, Lixin Zhang Auberson, Min Wu, Ana de Vera, Dimitris A. Papanicolaou, Anthony A. Amato

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)834-844
Number of pages11
JournalThe Lancet Neurology
Volume18
Issue number9
DOIs
StatePublished - Sep 2019

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Inclusion Body Myositis
Placebos
Safety
Walking
Echocardiography
bimagrumab
Electrocardiography
Research Personnel
Myositis
Urinalysis
Spasm
Muscular Diseases
Random Allocation
Natural History
Least-Squares Analysis
Hypnotics and Sedatives
Intravenous Infusions
Antidepressive Agents

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT) : a randomised, double-blind, placebo-controlled phase 2b trial. / Hanna, Michael G.; Badrising, Umesh A.; Benveniste, Olivier; Lloyd, Thomas E.; Needham, Merrilee; Chinoy, Hector; Aoki, Masashi; Machado, Pedro M.; Liang, Christina; Reardon, Katrina A.; de Visser, Marianne; Ascherman, Dana P.; Barohn, Richard J.; Dimachkie, Mazen M.; Miller, James A.L.; Kissel, John T.; Oskarsson, Björn; Joyce, Nanette C.; Van den Bergh, P.; Baets, Jonathan; De Bleecker, J. L.; Karam, Chafic; David, William S.; Mirabella, Massimiliano; Nations, Sharon P.; Jung, Hans H.; Pegoraro, E.; Maggi, Lorenzo; Rodolico, Carmelo; Filosto, Massimiliano; Shaibani, Aziz I.; Sivakumar, Kumaraswamy; Goyal, Namita A.; Mori-Yoshimura, Madoka; Yamashita, Satoshi; Suzuki, N.; Katsuno, Masahisa; Murata, K.; Nodera, Hiroyuki; Nishino, Ichizo; Romano, Carla D.; Williams, Valerie S.L.; Vissing, John; Auberson, Lixin Zhang; Wu, Min; de Vera, Ana; Papanicolaou, Dimitris A.; Amato, Anthony A.

In: The Lancet Neurology, Vol. 18, No. 9, 09.2019, p. 834-844.

Research output: Contribution to journalArticle

Hanna, MG, Badrising, UA, Benveniste, O, Lloyd, TE, Needham, M, Chinoy, H, Aoki, M, Machado, PM, Liang, C, Reardon, KA, de Visser, M, Ascherman, DP, Barohn, RJ, Dimachkie, MM, Miller, JAL, Kissel, JT, Oskarsson, B, Joyce, NC, Van den Bergh, P, Baets, J, De Bleecker, JL, Karam, C, David, WS, Mirabella, M, Nations, SP, Jung, HH, Pegoraro, E, Maggi, L, Rodolico, C, Filosto, M, Shaibani, AI, Sivakumar, K, Goyal, NA, Mori-Yoshimura, M, Yamashita, S, Suzuki, N, Katsuno, M, Murata, K, Nodera, H, Nishino, I, Romano, CD, Williams, VSL, Vissing, J, Auberson, LZ, Wu, M, de Vera, A, Papanicolaou, DA & Amato, AA 2019, 'Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial', The Lancet Neurology, vol. 18, no. 9, pp. 834-844. https://doi.org/10.1016/S1474-4422(19)30200-5
Hanna, Michael G. ; Badrising, Umesh A. ; Benveniste, Olivier ; Lloyd, Thomas E. ; Needham, Merrilee ; Chinoy, Hector ; Aoki, Masashi ; Machado, Pedro M. ; Liang, Christina ; Reardon, Katrina A. ; de Visser, Marianne ; Ascherman, Dana P. ; Barohn, Richard J. ; Dimachkie, Mazen M. ; Miller, James A.L. ; Kissel, John T. ; Oskarsson, Björn ; Joyce, Nanette C. ; Van den Bergh, P. ; Baets, Jonathan ; De Bleecker, J. L. ; Karam, Chafic ; David, William S. ; Mirabella, Massimiliano ; Nations, Sharon P. ; Jung, Hans H. ; Pegoraro, E. ; Maggi, Lorenzo ; Rodolico, Carmelo ; Filosto, Massimiliano ; Shaibani, Aziz I. ; Sivakumar, Kumaraswamy ; Goyal, Namita A. ; Mori-Yoshimura, Madoka ; Yamashita, Satoshi ; Suzuki, N. ; Katsuno, Masahisa ; Murata, K. ; Nodera, Hiroyuki ; Nishino, Ichizo ; Romano, Carla D. ; Williams, Valerie S.L. ; Vissing, John ; Auberson, Lixin Zhang ; Wu, Min ; de Vera, Ana ; Papanicolaou, Dimitris A. ; Amato, Anthony A. / Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT) : a randomised, double-blind, placebo-controlled phase 2b trial. In: The Lancet Neurology. 2019 ; Vol. 18, No. 9. pp. 834-844.
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title = "Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial",
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 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.",
author = "Hanna, {Michael G.} and Badrising, {Umesh A.} and Olivier Benveniste and Lloyd, {Thomas E.} and Merrilee Needham and Hector Chinoy and Masashi Aoki and Machado, {Pedro M.} and Christina Liang and Reardon, {Katrina A.} and {de Visser}, Marianne and Ascherman, {Dana P.} and Barohn, {Richard J.} and Dimachkie, {Mazen M.} and Miller, {James A.L.} and Kissel, {John T.} and Bj{\"o}rn Oskarsson and Joyce, {Nanette C.} and {Van den Bergh}, P. and Jonathan Baets and {De Bleecker}, {J. L.} and Chafic Karam and David, {William S.} and Massimiliano Mirabella and Nations, {Sharon P.} and Jung, {Hans H.} and E. Pegoraro and Lorenzo Maggi and Carmelo Rodolico and Massimiliano Filosto and Shaibani, {Aziz I.} and Kumaraswamy Sivakumar and Goyal, {Namita A.} and Madoka Mori-Yoshimura and Satoshi Yamashita and N. Suzuki and Masahisa Katsuno and K. Murata and Hiroyuki Nodera and Ichizo Nishino and Romano, {Carla D.} and Williams, {Valerie S.L.} and John Vissing and Auberson, {Lixin Zhang} and Min Wu and {de Vera}, Ana and Papanicolaou, {Dimitris A.} and Amato, {Anthony A.}",
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month = "9",
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language = "English (US)",
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pages = "834--844",
journal = "The Lancet Neurology",
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}

TY - JOUR

T1 - Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT)

T2 - a randomised, double-blind, placebo-controlled phase 2b trial

AU - Hanna, Michael G.

AU - Badrising, Umesh A.

AU - Benveniste, Olivier

AU - Lloyd, Thomas E.

AU - Needham, Merrilee

AU - Chinoy, Hector

AU - Aoki, Masashi

AU - Machado, Pedro M.

AU - Liang, Christina

AU - Reardon, Katrina A.

AU - de Visser, Marianne

AU - Ascherman, Dana P.

AU - Barohn, Richard J.

AU - Dimachkie, Mazen M.

AU - Miller, James A.L.

AU - Kissel, John T.

AU - Oskarsson, Björn

AU - Joyce, Nanette C.

AU - Van den Bergh, P.

AU - Baets, Jonathan

AU - De Bleecker, J. L.

AU - Karam, Chafic

AU - David, William S.

AU - Mirabella, Massimiliano

AU - Nations, Sharon P.

AU - Jung, Hans H.

AU - Pegoraro, E.

AU - Maggi, Lorenzo

AU - Rodolico, Carmelo

AU - Filosto, Massimiliano

AU - Shaibani, Aziz I.

AU - Sivakumar, Kumaraswamy

AU - Goyal, Namita A.

AU - Mori-Yoshimura, Madoka

AU - Yamashita, Satoshi

AU - Suzuki, N.

AU - Katsuno, Masahisa

AU - Murata, K.

AU - Nodera, Hiroyuki

AU - Nishino, Ichizo

AU - Romano, Carla D.

AU - Williams, Valerie S.L.

AU - Vissing, John

AU - Auberson, Lixin Zhang

AU - Wu, Min

AU - de Vera, Ana

AU - Papanicolaou, Dimitris A.

AU - Amato, Anthony A.

PY - 2019/9

Y1 - 2019/9

N2 - 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.

AB - 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.

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