Summary 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.
Abstract Background Lung volume recruitment (LVR) is a cough assistance technique used in persons with neuromuscular disorders (NMDs), most typically in those requiring noninvasive ventilation (NIV). ...Whether it may be useful in persons with NMDs who have milder respiratory impairment is unknown. Objective To assess the feasibility, impact on quality of life (QOL), and preliminary physiological effects of daily LVR in different categories of persons with NMDs who have an early stage of respiratory impairment. Design Feasibility study. Setting Academic tertiary care center. Participants Outpatients diagnosed with amyotrophic lateral sclerosis (n = 8), postpolio syndrome (n = 10), and myotonic dystrophy (n = 6) who had restrictive respiratory defects but were not yet using NIV. Methods Participants were asked to perform LVR up to 4 times daily and log their LVR use in a diary. Physiological measurements and questionnaires were completed at baseline and after 3 months. Main Outcome Measurements Compliance with LVR use was assessed, along with QOL and willingness to continue the treatment. Physiological measurements included forced vital capacity (FVC), lung insufflation capacity (LIC), and the LIC minus FVC difference. Results Of the 24 recruited subjects, 7 with amyotrophic lateral sclerosis, 7 with postpolio syndrome, and 5 with myotonic dystrophy completed the study (n = 19). At baseline, mean values for FVC and spontaneous peak cough flow were 59.9% predicted and 373.1 L/min, respectively. For subjects completing the study, 74% were willing to continue long-term LVR use, and QOL scores were not adversely affected by LVR in any NMD subgroup. The LIC-FVC difference increased from baseline to follow-up by a mean of 0.243 L ( P = .006) in all subjects (n = 19), suggesting a possible improvement in respiratory system mechanics. Conclusions In patients with NMDs who have early restrictive respiratory defects but do not yet require NIV, regular use of LVR is feasible with no negative impact on QOL over a 3-month period and may have physiological benefits. Further work is needed to determine whether early institution of LVR can improve respiratory system mechanics and help delay ventilatory failure in persons with NMDs.