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 20 mg, innovator glatiramer acetate 40 mg 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.

Keywords: Clinical trials; Disease-modifying treatments (DMTs); Meta-analysis; Multiple sclerosis; Nocebo; Placebo.