Rasagiline is a monoamine oxidase B inhibitor that appears to be safe for use in combination with riluzole in patients with amyotrophic lateral sclerosis (ALS), according to results from a phase 2 trial published in Lancet Neurology. Rasagiline as add-on therapy was also shown to have an effect on survival within 6 months of treatment, but these findings require more rigorous study for validation, the researchers report.
Study investigators enrolled 273 patients with possible, probable, or definite ALS from 15 centers. Patients had onset of progressive weakness <36 months prior to study enrollment and a disease duration of >6 months and <3 years. Investigators randomly assigned patients to either 1 mg/day rasagiline (n=127) or placebo (n=125), and all patients received 100 mg/day riluzole. Follow-up occurred at 2 months, 6 months, 12 months, and 18 months. Survival time (ie, time to death or time to study cut-off date) comprised the primary end point. The intention-to-treat population, consisting of patients receiving ≥1 treatment dose, were analyzed with regard to the primary end point and additional safety measures. In terms of survival probability, there were no differences between the rasagiline (0.43; 95% CI, 0.25-0.59) or placebo (0.53; 95% CI, 0.43-0.62) groups (hazard ratio 0.91; P =.31).
No differences were observed between rasagiline or placebo with regard to secondary efficacy end points, including change of total score of the revised ALS Functional Rating Scale (0.95; 95% CI, 0.41-1.28 vs 1.02; 95% CI, 0.48-1.53, respectively; P =.32), change in slow vital capacity (2.07; 95% CI, 0.65-4.08 vs 1.78; 95% CI, 0.49-4.23, respectively; P =.82), change in the Schedule for the Evaluation of Individual Quality of Life sum score (0.03; 95% CI, -0.67 to 0.95 vs 0.24; 95% CI, -0.27 to 1.22, respectively; P =.20), and time until tracheostomy or death (probability 0.37; 95% CI, 0.20-0.55 vs 0.48; 95% CI, 0.38-0.58, respectively; P =.65).
Rasagiline was associated with a significant effect on survival within 6 months of treatment in an exploratory analysis (hazard ratio -1.16; 95% CI, -2.17 to -0.15; log-rank P =.0178); however, this finding was not replicated at the 12- and 18-month follow-ups. Adverse events were few, and the majority of adverse events were found to be related to ALS progression and not to the study drug.
The lack of information on dose-response associations as well as the small number of patients included in the overall cohort represent the trial’s primary limitations.
Findings from this analysis demonstrate the importance “for a stratification of future trials according to fast and slow progressors to identify subgroups most likely to benefit from a treatment.”
Ludolph AC, Schuster J, Dorst J, et al; for the RAS-ALS Study Group. Safety and efficacy of rasagiline as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomised, double-blind, parallel-group, placebo-controlled, phase 2 trial. Lancet Neurol. 2018;17:681-688.