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.