Meta-regression to explain the placebo effects in clinical trials of
anti-CGRP monoclonal antibodies for migraine prevention
Abstract
Background: Commonly used methods of comparison (e.g., network
meta-analyses) require common comparator(s) across trials, such as
placebo in placebo-controlled trials. Recent literature indicates that
route of administration differences across placebo arms of clinical
trials in pain disorders may contribute to differences in placebo
effect. Methods: We conducted a meta-regression on placebo data from
pivotal clinical trials of anti-calcitonin gene-related peptide
(anti-CGRP) monoclonal antibodies for migraine prevention to quantify
the impact of route of administration, migraine type (episodic/chronic),
and number of prior treatment failures on placebo reduction in monthly
migraine days (MMDs) across weeks 1‒12 of treatment. A systematic
literature review of Embase, MEDLINE, the Cochrane Library, and grey
literature conducted in June 2021 identified relevant 14 randomised,
placebo-controlled trials for analysis. Results: After testing models
with different covariates, a meta-regression was fitted to the extracted
placebo data with the covariates of route of administration, migraine
type, and proportion of patients with ≥2 prior preventive treatment
failures. An intravenous route of administration for the placebo arm was
a predictor for higher MMD reduction. Predictors of lower MMD reduction
were migraine type (episodic migraine) and a higher proportion of
patients having ≥2 failed preventive treatments. Conclusions: The
efficacy of intravenous anti-CGRP monoclonal antibodies are likely
underestimated, and differences in the route of administration of
placebo may necessitate use of alternative methods that do not assume
the presence of a common comparator when comparing anti-CGRP monoclonal
antibodies in migraine prevention. Further research into the contextual
effects of the placebo effect is warranted.