INTRODUCTION
Migraine, a common disorder affecting more than 1 billion people around the globe, places a substantial humanistic and socio-economic burden on affected individuals, their families, and society . For many years, the only available pharmacologic management methods included using analgesics or nonsteroidal anti-inflammatory drugs for mild attacks, and triptans for more severe attacks . More recently, the development of drugs that prevent migraine by targeting the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor have caused a seismic shift in migraine management .
To date, four anti-CGRP monoclonal antibodies have been approved in the US and elsewhere for migraine prevention (erenumab, fremanezumab, galcanezumab, and eptinezumab), along with two small-molecule inhibitors (gepants) . However, there are currently no head-to-head trials comparing the anti-CGRP monoclonal antibodies, resulting in a proliferation of indirect treatment comparisons (ITCs), such as network meta-analyses, to assess relative treatment effectiveness . At first glance, ITCs appear straightforward, since all the anti-CGRP pivotal trials used the reduction in monthly migraine days (MMDs) as the primary endpoint and all were placebo controlled. However, there is mounting evidence to suggest that simple subtraction of placebo response from active treatment response may result in highly inaccurate estimates of therapeutic efficacy . There are several contextual aspects to placebo administration that can greatly impact patient responses to medication in clinical trials of migraine, including patient expectation , route of administration , and physician demeanour .
While the use of randomised, controlled trials aims to overcome bias related to perceptions of drug efficacy, by blinding the investigators and participants to the treatment received, the issue of route of administration is less easily addressed. This is of particular interest when comparing the anti-CGRPs, since three of the available products are administered subcutaneously (SC) and one (eptinezumab) is administered intravenously (IV). A key assumption is that the common comparator (i.e., placebo) is essentially congruent across trials. However, the results of a recent meta-analysis of treatment administration for chronic migraine clearly illustrated that SC and IV placebo produce different responses and therefore cannot be assumed to be directly interchangeable across studies. As a result, the ‘true’ effect of a treatment, as measured by its efficacy relative to placebo response, might be underestimated in clinical trials if the placebo contextual effect (such as IV administration) is strong.
The objective of this analysis is to understand whether, and to what extent, the route of administration should be considered when conducting an ITC between anti-CGRP monoclonal antibodies for the preventive treatment of migraine by assessing how the placebo effect varied in trials using SC or IV administration. Given that the pivotal anti-CGRP studies also varied in terms of migraine type (episodic vs chronic) and number of prior treatment failures, we also conducted meta-regressions to control for these factors.