NOCEBO IN MULTIPLE SCLEROSIS TRIALS: A META-ANALYSIS ON ORAL AND NEWER INJECTABLE DISEASE-MODIFYING TREATMENTS

Abstract Background Nocebo phenomena are linked to decreased adherence to treatments in clinical practice as well as difficulty in assessing the adverse effect profile in clinical trials. Objective To estimate the incidence and severity of nocebo responses in clinical trials of oral and newer injectable disease-modifying treatments (DMTs) for relapsing multiple sclerosis (MS). Methods Meta-analysis of the incidence of nocebo responses was performed by pooling the percentage of placebo-treated patients that exhibited adverse events (AEs) in randomized, placebo-controlled MS trials published between 2005 and 2018. Nocebo severity was estimated as a percentage of placebo-treated patients who discontinued the treatment due to drug-related AEs. Results The pooled incidence of nocebo was 89% (95% CI: 88%- 90%) in trials for oral DMTs (cladribine, fingolimod, teriflunomide and dimethyl fumarate) and 66% (95% CI: 51%- 80%) in trials of newer injectable DMTs (biosimilar glatiramer acetate 20mg, innovator glatiramer acetate 40mg and pegylated interferon beta). The pooled nocebo severity was 8% (95% CI: 5% – 12%) for oral treatments and 2% (95% CI: 0 – 2%) for newer injectable DMTs. Conclusions Oral DMTs may be associated with a higher incidence and greater nocebo severity than newer injectables.