| アブストラクト | BACKGROUND: Neurite outgrowth inhibitor A (Nogo-A) is thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). A monoclonal antibody against Nogo-A showed a positive effect in the SOD1(G93A) mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. Therefore, we aimed to assess the safety and efficacy of ozanezumab in patients with ALS. METHODS: This randomised, double-blind, placebo-controlled, phase 2 trial was done in 34 centres in 11 countries. Patients aged 18-80 years with a diagnosis of familial or sporadic ALS were randomly assigned (1:1), centrally according to a computer-generated allocation schedule, to receive ozanezumab (15 mg/kg) or placebo as intravenous infusions over 1 h every 2 weeks for 46 weeks, followed by assessments at week 48 and week 60. Patients and study personnel were masked to treatment assignment. The primary outcome was a joint-rank analysis of function (ALS Functional Rating Scale-Revised) and overall survival, analysed at 48 weeks in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01753076, and with GSK-ClinicalStudyRegister.com, NOG112264, and is completed. FINDINGS: Between Dec 20, 2012, and Nov 1, 2013, we recruited 307 patients, of whom 303 were randomly assigned to receive placebo (n=151) or ozanezumab (n=152). The adjusted mean of the joint-rank score was -14.9 (SE 13.5) for the ozanezumab group and 15.0 (13.6) for the placebo group, with a least squares mean difference of -30.0 (95% CI -67.9 to 7.9; p=0.12). Overall, reported adverse events, serious adverse events, and adverse events leading to permanent discontinuation of study drug or withdrawal from study were similar between the treatment groups, except for dyspepsia (ten [7%] in the ozanezumab group vs four [3%] in the placebo group), depression (11 [7%] vs five [3%]), and diarrhoea (25 [16%] vs 12 [8%]). Respiratory failure was the most common serious adverse event (12 [8%] vs seven [5%]). At week 60, the number of deaths was higher in the ozanezumab group (20 [13%]) than in the placebo group (16 [11%]), mainly as a result of respiratory failure (ten [7%] vs five [3%]). Two deaths were considered related to the study drug (bladder transitional cell carcinoma in the ozanezumab group and cerebrovascular accident in the placebo group). INTERPRETATION: Ozanezumab did not show efficacy compared with placebo in patients with ALS. Therefore, Nogo-A does not seem to be an effective therapeutic target in ALS. FUNDING: GlaxoSmithKline. |
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| 投稿者 | Meininger, Vincent; Genge, Angela; van den Berg, Leonard H; Robberecht, Wim; Ludolph, Albert; Chio, Adriano; Kim, Seung H; Leigh, P Nigel; Kiernan, Matthew C; Shefner, Jeremy M; Desnuelle, Claude; Morrison, Karen E; Petri, Susanne; Boswell, Diane; Temple, Jane; Mohindra, Rajat; Davies, Matt; Bullman, Jonathan; Rees, Paul; Lavrov, Arseniy |
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| 組織名 | Ramsay Generale de Sante Hopital Prive Peupliers, Paris, France.;Department of Neurology and Neurosurgery, Montreal Neurological Institute and;Hospital, Montreal, QC, Canada.;Department of Neurology, Brain Centre Rudolf Magnus, University Medical Center;Utrecht, Utrecht, Netherlands.;KU Leuven, Department of Neurosciences, Experimental Neurology University;Hospitals Leuven, Department of Neurology, Leuven, Belgium.;Department of Neurology, University of Ulm, Ulm, Germany.;Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin,;Italy.;Department of Neurology, Hanyang University Medical Center, Seoul, South Korea.;Division of Medicine (Neurology), Trafford Centre for Biomedical Research,;Brighton and Sussex Medical School, University of Sussex, East Sussex, UK.;Brain & Mind Centre, Sydney Medical School, the University of Sydney, Sydney,;NSW, Australia.;Barrow Neurological Institute, Phoenix, AZ, USA.;Department of Neurology, University Hospital of Nice, Nice, France.;Institute of Clinical Sciences, University of Birmingham, Edgbaston, Birmingham,;UK; Faculty of Medicine, University of Southampton, University Hospital;Southampton, Southampton, UK.;Department of Neurology, Hannover Medical School, Hannover, Germany.;Neurosciences Therapy Area Unit, GlaxoSmithKline, Uxbridge, UK.;R&D Projects Clinical Platforms and Sciences, Quantitative Sciences, Clinical;Statistics, GlaxoSmithKline, Uxbridge, UK.;Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Uxbridge, UK.;Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stevenage, UK.;Neurosciences Therapy Area Unit, GlaxoSmithKline, Uxbridge, UK. Electronic;address: arseniy.j.lavrov@gsk.com. |
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