Journal ArticleDOI
Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial
Koji Abe,Masashi Aoki,Shoji Tsuji,Yasuto Itoyama,Gen Sobue,Masanori Togo,Chikuma Hamada,Masahiko Tanaka,Makoto Akimoto,Kazue Nakamura,Fumihiro Takahashi,Kazuoki Kondo,Hiide Yoshino,Hidenao Sasaki,Ichiro Yabe,Shizuki Doi,Hitoshi Warita,Takashi Imai,Hiroaki Ito,Mitsumasa Fukuchi,Etsuko Osumi,Manabu Wada,Imaharu Nakano,Mitsuya Morita,Katsuhisa Ogata,Yuichi Maruki,Kimiko Ito,Osamu Kano,Mineo Yamazaki,Yuji Takahashi,Hiroyuki Ishiura,Mieko Ogino,Ryoko Koike,Chiho Ishida,Tsuyoshi Uchiyama,Kouichi Mizoguchi,Tomokazu Obi,Hirohisa Watanabe,Naoki Atsuta,Ikuko Aiba,Akira Taniguchi,Hideyuki Sawada,Takanori Hazama,Harutoshi Fujimura,Hirofumi Kusaka,Takenobu Kunieda,Hitoshi Kikuchi,Hidenori Matsuo,Hidetsugu Ueyama,Kazutoshi Uekawa,Masaki Ueda,Aiko Murakami,Rie Sumii,Takuya Kudou,Kazunori Morimoto,Takatomo Yoneoka,Manabu Hirai,Kouichi Sasaki,Hidetomo Terai,Tomoko Natori,Hiroshi Matsui,Kuniko Kotani,Kaori Yoshida,Tomohisa Iwasaki +63 more
TLDR
The primary efficacy outcome was the change in ALSFRS-R score from the baseline to 24 weeks (or at discontinuation if this was after the third cycle) after randomisation and the least-squares mean difference between groups was 2·49 (SE 0·76, 95% CI 0·99-3·98) in favour of edaravone.Abstract:
Summary Background In a previous phase 3 study in patients with amyotrophic lateral sclerosis (ALS), edaravone did not show a significant difference in the Revised ALS Functional Rating Scale (ALSFRS-R) score compared with placebo Post-hoc analysis of these data revealed that patients in an early stage with definite or probable diagnosis of ALS, defined by the revised El Escorial criteria, who met a select set of inclusion criteria showed a greater magnitude of effect than did the full study population We aimed to substantiate this post-hoc result and assess safety and efficacy of edaravone in a phase 3 trial that focused on patients with early stage ALS who met the post-hoc analysis inclusion criteria Methods In this phase 3, randomised, double-blind, parallel-group study, patients aged 20–75 years with ALS of grade 1 or 2 in the Japan ALS Severity Classification, scores of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of 80% or more, definite or probable ALS according to the revised El Escorial criteria, and disease duration of 2 years or less were recruited from 31 hospitals in Japan Eligible patients also had a decrease of 1–4 points in the ALSFRS-R score during a 12-week observation period before randomisation Patients meeting all criteria were then randomly assigned 1:1 to receive 60 mg intravenous edaravone or intravenous saline placebo for 6 cycles (4 weeks per cycle with 2 weeks on, 2 weeks off) for a total treatment duration of 24 weeks In cycle 1, the study drug or placebo was administered once per day for 14 days within a 14 day period, followed by the drug-free period In cycle 2 and thereafter, the study drug or placebo was administered for 10 days within a 14 day period, followed by a 2 week drug-free period Participants and investigators, including those assessing outcomes, were masked to treatment allocation The primary efficacy outcome was the change in ALSFRS-R score from the baseline to 24 weeks (or at discontinuation if this was after the third cycle) after randomisation The primary outcome was assessed in all patients who had received at least one treatment infusion, had at least one assessment post-baseline, and reached the end of cycle 3 For patients with missing values at the end of cycle 6, data were imputed by the last observation carried forward (LOCF) method, provided the patients had completed at least cycle 3 Safety was assessed in all patients who had received at least one treatment infusion and had at least one assessment post-baseline This trial is registered with ClinicalTrialsgov, NCT01492686 Findings Between Nov 28, 2011, and Sept 3, 2014, we screened 213 patients, and enrolled 192 as potential participants Of these, 137 patients completed the observation period: 69 were randomly assigned to receive edaravone, and 68 were randomly assigned to receive placebo 68 patients taking edaravone and 66 taking placebo were included in the primary efficacy analysis For the primary outcome, the change in ALSFRS-R score was −5·01 (SE 0·64) in the edavarone group and −7·50 (0·66) in the placebo group The least-squares mean difference between groups was 2·49 (SE 0·76, 95% CI 0·99–3·98; p=0·0013) in favour of edaravone Treatment-emergent adverse events were reported in 58 (84%) patients receiving edaravone and 57 (84%) patients receiving placebo 11 (16%) patients taking edaravone and 16 (24%) taking placebo had serious adverse events, and one (1%) patient receiving edaravone and four (6%) patients receiving placebo had adverse events (one dysphagia in edaravone group and one dyspnoea, two respiratory disorder, and one rash in the placebo group) that led to withdrawal Interpretation Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo There is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria Funding Mitsubishi Tanabe Pharma Corporationread more
Citations
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Journal ArticleDOI
Amyotrophic lateral sclerosis
Eva L. Feldman,Stephen A. Goutman,Susanne Petri,Letizia Mazzini,Masha G. Savelieff,Pamela J. Shaw,Gen Sobue +6 more
TL;DR: Two possible disease-modifying therapies that can slow disease progression are available for ALS, but patient management is largely mediated by symptomatic therapies, such as the use of muscle relaxants for spasticity and speech therapy for dysarthria.
Journal ArticleDOI
Potential roles of gut microbiome and metabolites in modulating ALS in mice
Eran Blacher,Stavros Bashiardes,Hagit Shapiro,Daphna Rothschild,Uria Mor,Mally Dori-Bachash,Christian Kleimeyer,Claudia Moresi,Yotam Harnik,Maya Zur,Michal Zabari,Rotem Ben-Zeev Brik,Denise Kviatcovsky,Niv Zmora,Yotam Cohen,Noam Bar,Izhak Levi,Nira Amar,Tevie Mehlman,Alexander Brandis,Inbal E. Biton,Yael Kuperman,Michael Tsoory,Leenor Alfahel,Alon Harmelin,Michal Schwartz,Adrian Israelson,Liisa Arike,Malin E. V. Johansson,Gunnar C. Hansson,Marc Gotkine,Eran Segal,Eran Elinav +32 more
TL;DR: It is demonstrated that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS, and it is suggested that environmentally driven microbiome–brain interactions may modulate ALS in mice.
Journal ArticleDOI
Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications.
TL;DR: The identification of these seven novel genes has been important in unravelling the molecular mechanisms underlying ALS, and therapeutics targeting these pathways could be useful for a broad group of patients stratified by genotype.
Journal ArticleDOI
Amyotrophic lateral sclerosis: a clinical review
TL;DR: Different aspects of ALS are discussed, including epidemiology, aetiology, pathogenesis, clinical features, differential diagnosis, investigations, treatment and future prospects.
Journal ArticleDOI
Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing
Barry Boland,Wai Haung Yu,Olga Corti,Bertrand Mollereau,Alexandre Henriques,Erwan Bezard,Greg M. Pastores,David C. Rubinsztein,Ralph A. Nixon,Michael R. Duchen,Giovanna R. Mallucci,Guido Kroemer,Beth Levine,Eeva-Liisa Eskelinen,Fanny Mochel,Michael Spedding,Caroline Louis,Olivier R. Martin,Millan Mark +18 more
TL;DR: This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs.
References
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Journal ArticleDOI
Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis
TL;DR: Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.
Journal ArticleDOI
El Escorial revisited : revised criteria for the diagnosis of amyotrophic lateral sclerosis
TL;DR: The criteria described below represent the result of a three-day workshop, convened at Airlie Conference Center, Warrenton, Virginia on 2–4 April, 1998 by the World Federation of Neurology Research Committee on Motor Neuron Diseases, and are placed on the WFN ALS website.
Journal ArticleDOI
Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
Mariely DeJesus-Hernandez,Ian R. A. Mackenzie,Bradley F. Boeve,Adam L. Boxer,Matt Baker,Nicola J. Rutherford,Alexandra M. Nicholson,Ni Cole A. Finch,Heather C. Flynn,Jennifer Adamson,Naomi Kouri,Aleksandra Wojtas,Pheth Sengdy,Ging-Yuek Robin Hsiung,Anna Karydas,William W. Seeley,Keith A. Josephs,Giovanni Coppola,Daniel H. Geschwind,Zbigniew K. Wszolek,Howard Feldman,Howard Feldman,David S. Knopman,Ronald C. Petersen,Bruce L. Miller,Dennis W. Dickson,Kevin B. Boylan,Neill R. Graff-Radford,Rosa Rademakers +28 more
TL;DR: It is found that repeat expansion in C9ORF72 is a major cause of both FTD and ALS, suggesting multiple disease mechanisms.
Journal ArticleDOI
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
Alan E. Renton,Elisa Majounie,Adrian James Waite,Javier Simón-Sánchez,Javier Simón-Sánchez,Sara Rollinson,J. Raphael Gibbs,J. Raphael Gibbs,Jennifer C. Schymick,Hannu Laaksovirta,John C. van Swieten,John C. van Swieten,Liisa Myllykangas,Hannu Kalimo,Anders Paetau,Yevgeniya Abramzon,Anne M. Remes,Alice Kaganovich,Sonja W. Scholz,Sonja W. Scholz,Sonja W. Scholz,Jamie Duckworth,Jinhui Ding,Daniel W. Harmer,Dena G. Hernandez,Dena G. Hernandez,Janel O. Johnson,Janel O. Johnson,Kin Y. Mok,Mina Ryten,Danyah Trabzuni,Rita Guerreiro,Richard W. Orrell,James Neal,Alexandra Murray,J. P. Pearson,Iris E. Jansen,David Sondervan,Harro Seelaar,Derek J. Blake,Kate Young,Nicola Halliwell,Janis Bennion Callister,Greg Toulson,Anna Richardson,Alexander Gerhard,Julie S. Snowden,David M. A. Mann,David Neary,Mike A. Nalls,Terhi Peuralinna,Lilja Jansson,Veli-Matti Isoviita,Anna-Lotta Kaivorinne,Maarit Hölttä-Vuori,Elina Ikonen,Raimo Sulkava,Michael Benatar,Joanne Wuu,Adriano Chiò,Gabriella Restagno,Giuseppe Borghero,Mario Sabatelli,David Heckerman,Ekaterina Rogaeva,Lorne Zinman,Jeffrey D. Rothstein,Michael Sendtner,Carsten Drepper,Evan E. Eichler,Can Alkan,Ziedulla Abdullaev,Svetlana Pack,Amalia Dutra,Evgenia Pak,John Hardy,Andrew B. Singleton,Nigel Williams,Peter Heutink,Stuart Pickering-Brown,Huw R. Morris,Huw R. Morris,Huw R. Morris,Pentti J. Tienari,Bryan J. Traynor,Bryan J. Traynor +85 more
TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
Journal ArticleDOI
The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function
Jesse M. Cedarbaum,Nancy Stambler,Errol Malta,Cynthia Fuller,Dana Hilt,Barbara Thurmond,Arline Nakanishi +6 more
TL;DR: A revised version of the ALSFRS, which incorporates additional assessments of dyspnea, orthopnea, and the need for ventilatory support is validated, indicating that the quality of function is a strong determinant of quality of life in ALS.
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