Background: Nogo-A is a neurite outgrowth inhibitor protein that 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 SOD1G93A mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. We therefore assessed the safety and efficacy of ozanezumab in patients with ALS.Methods: In a phase 2, double-blind study, patients with ALS were randomised in a 1:1 ratio with a computer-generated allocation schedule to receive ozanezumab (15 mg/kg) or placebo as intravenous infusions every 2 weeks for 46 weeks, followed by a week 48 assessment and a 12-week follow-up. Patients and study personnel were blinded to treatment assignment. The primary endpoint was a joint-rank analysis of function (ALSFRS-R) and survival. Analysis was by modified intent to treat. Trial Registration: ClinicalTrials.gov NCT01753076 GSK-ClinicalStudyRegister.com GSK ID 1223249Findings: The first patient was enrolled into the study on Dec 20, 2012, and the last patient visit was on Jan 22, 2015. 303 patients were randomly assigned to the placebo group (n=151) or ozanezumab (n=152). The joint-rank score indicated a non-significant difference in favour of placebo (adjusted placebo mean 15·0[SE 13·58] vs ozanezumab mean –14·9 [SE 13·54], with least squares mean difference –30·0 [95% CI –67·9 to 7·9]; p=0·120). The incidences of dyspepsia (7% vs 3%), depression (7% vs 3%), and diarrhoea (16% vs 8%) in the ozanezumab group were almost twice those in the placebo group. A numerically higher incidence of fatal SAEs was observed with ozanezumab versus placebo (18 [12%] vs 13 [9%] deaths), driven mainly by respiratory failure events (ten [7%] vs five [3%]). Respiratory failure was the most common SAE, reported in 12 (8%) and seven (5%) patients in the ozanezumab and placebo arms, respectively. Interpretation: Ozanezumab did not demonstrate efficacy compared with placebo in patients with ALS. Therefore, Nogo-A does not seem to be an effective therapeutic target in ALS.Funding: GlaxoSmithKline.