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Strong nocebo effect in amyotrophic lateral sclerosis trials might mask conclusions

2018; Elsevier BV; Volume: 17; Issue: 10 Linguagem: Inglês

10.1016/s1474-4422(18)30310-7

1474-4465

Miguel Leal Rato, Gonçalo S. Duarte, Tiago Mestre, Mamede de Carvalho, Joaquim J. Ferreira,

Parkinson's Disease Mechanisms and Treatments

Reported in The Lancet Neurology, Albert Ludolph and colleagues1Ludolph AC Schuster J Dorst J et al.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: 681-688Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar did a randomised placebo-controlled trial of rasagiline as an add-on therapy to riluzole for the treatment of amyotrophic lateral sclerosis. We congratulate the authors for their continuing effort to identify better pharmacological treatments for this condition, and we appreciate the promising positive results. However, we notice the report of a high incidence of adverse events; a total of 331 events in 251 participants. Furthermore, none of the reported adverse events differed significantly between the rasagiline and placebo groups. Ludolph and colleagues conclude that this finding means rasagiline is safe and that adverse events are mainly attributable to disease progression.1Ludolph AC Schuster J Dorst J et al.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: 681-688Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar We challenge this conclusion on safety and reinforce the notion that randomised controlled trials are not the ideal study design to draw conclusions about safety. A placebo group is used in randomised controlled trials to control for the placebo effect and more accurately determine the efficacy of a new treatment. It is also well known that a placebo might also be associated with negative effects (the nocebo effect).2Silva MA Duarte GS Camara R et al.Placebo and nocebo responses in restless legs syndrome: a systematic review and meta-analysis.Neurology. 2017; 88: 2216-2224Crossref PubMed Scopus (34) Google Scholar A strong nocebo effect in trials of amyotrophic lateral sclerosis has been reported for those evaluating riluzole3Miller RG Mitchell JD Moore DH Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).Cochrane Database Syst Rev. 2012; 3 (CD001447.)Google Scholar and edaravone,4Abe K Aoki M Tsuji S et al.Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial.Lancet Neurol. 2017; 16: 505-512Summary Full Text Full Text PDF PubMed Scopus (514) Google Scholar in which only small differences in adverse events were found between study groups. For unknown reasons, the nocebo effect seems to be stronger in patients with amyotrophic lateral sclerosis than in other neurological disorders. Although some adverse events might be explained by disease-related features and disease progression, it does not account for all adverse events. In fact, falls, headache, depression, vertigo, and back pain correspond to 29% of the adverse events reported by Ludolph and colleagues1Ludolph AC Schuster J Dorst J et al.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: 681-688Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar and are among the most frequent events reported in trials of rasagiline in Parkinson's disease.5European Medicines AgencyEMEA/H/C/000574-N/0078—summary of product characteristics Azilect.http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000574/WC500030048.pdfDate: 2018Date accessed: June 27, 2018Google Scholar Consequently, the frequency and type of adverse events reported might be suggestive of a substantial nocebo effect. We conclude that patients' negative expectations related with the occurrence of adverse events might have been enough to overlap the report of adverse events directly attributable to rasagiline's mechanism of action. We hypothesise that—similar to the situations in which the presence of a large placebo-associated response makes demonstration of efficacy difficult—a strong nocebo effect can challenge the interpretation of safety in clinical trials. We suggest these concerns should be considered on the critical appraisal of safety data from amyotrophic lateral sclerosis trials and for the design of future studies. JJF has received speaker and consultant fees from Novartis, TEVA, Lundbeck, Solvay, Abbott, BIAL, Merck-Serono, Grunenthal, Merck Sharp & Dohme, Biogen, Sunovion Pharmaceuticals, and Medtronic. All other authors declare no competing interests. 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 trialRasagiline was safe in patients with amyotrophic lateral sclerosis. There was no difference between groups in the primary outcome of survival, although post-hoc analysis suggested that rasagiline might modify disease progression in patients with an initial slope of Amyotrophic Lateral Sclerosis Functional Rating Scale Revised greater than 0·5 points per month at baseline. This should be confirmed in another clinical trial. Full-Text PDF