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 SOD1G93A 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.