Placebo response with subcutaneous injections in calcitonin gene-related peptide receptor monoclonal antibody migraine preventative trials – A systematic review and meta-analysis

Background: The majority of CGRP monoclonal antibodies for migraine prevention are administered subcutaneously. Therefore, we attempted to calculate the pooled placebo response with subcutaneous placebo injections in this systematic review and meta-analysis. Methods: We identified 16 randomized controlled trials that met our inclusion and exclusion criteria through a comprehensive search in five electronic databases (PubMed Central, EMBASE, MEDLINE, Cochrane library and clinicaltrials.gov). The risk of bias was assessed for all included studies. Random effects model was used to calculate pooled mean monthly migraine days and 50% response rates. Results: A total of 4240 subjects were included from 16 studies in this meta-analysis. The pooled mean monthly migraine day reduction with subcutaneous placebo injections was 2.15 (95% CI: 1.60–2.69). The pooled proportion of patients achieving a 50% reduction in mean monthly headache days was 26% (95% CI: 20%–31%). Placebo response accounted for more than 50% of therapeutic gain in our study. Conclusion: A substantial placebo response was noted with subcutaneous injections in migraine CGRP monoclonal antibody clinical trials. This meta-analysis may serve as a reference point to calculate sample size in clinical trials using subcutaneous interventions for migraine prevention. We registered our study at PROSPERO (CRD42020185300).