Placebo and Nocebo Responses in Multiple System Atrophy - a systematic review and meta-analysis of clinical trials

BACKGROUND Multiple System Atrophy (MSA) is a rapidly progressive and fatal neurodegenerative disease, with no effective treatment. Estimating the placebo and nocebo responses will help better design and interpret clinical trials. Objective To estimate the placebo and nocebo responses in MSA and explore their determinants. METHODS Electronic databases were searched up to November 2020. Randomized, blinded, placebo- or sham-controlled trials of patients with MSA were included if quantitative data were extractable on the placebo arm. The primary outcomes were: placebo response, defined as the within-group change from baseline, using any scale measuring motor outcomes; and nocebo response, defined as the proportion of patients experiencing adverse effects in the placebo arm. Random-effects meta-analyses were used to pool data. Several predetermined subgroup analyses and metaregressions were performed. PROSPERO registration number: CRD42021222915. RESULTS We included 21 randomized controlled trials (614 participants). Pooled placebo response was an increase in the Unified MSA Rating Scale (UMSARS) parts I and II of 9.09 points (95% CI 7.78 to 10.31, I 2 =94.00%, 9 studies, 304 participants). Pooled nocebo response was 63,88% (CI 95% 41.15 to 84.05, I 2 =93.03%, 13 studies, 331 participants). Both placebo and nocebo responses were greater in trials with longer duration, whereas nocebo response was also higher in studies testing pharmacological interventions when compared with non-pharmacological interventions. CONCLUSIONS There may be a favorable response associated with the placebo, but this data needs to be compared with a “no treatment group” in order to validate its real impact. The nocebo response is high and should be considered in future clinical trial design and interpretation.