DISCUSSION
The results of this analysis show that the placebo response in migraine
clinical studies may vary according to the route of administration, the
type of migraine being investigated (episodic vs chronic), and prior
treatment failures. Importantly, even after accounting for migraine type
and clinical history, patients who received IV placebo had a greater
response (-1.34 MMDs) than those who received SC placebo. Therefore, the
efficacy of eptinezumab, which is administered via the IV route, is
likely to be underestimated in comparisons that assume a common placebo
effect. Notably, our study likely underestimates the IV placebo effect,
which may be even greater, given the conservative estimates made
regarding the number of patients with ≥2 prior treatment failures in
PROMISE-1 and PROMISE-2 (i.e., if the true percentage of patients with
≥2 prior treatment failures was greater than 0, then the IV coefficient
would increase in the meta-regression). Overall, the finding that
intravenous administration was associated with larger placebo response
is consistent with a previous meta-analysis .
Additional sources contributing to the placebo effect included the
frequency of migraine (i.e., episodic vs chronic migraine) and the
number of prior treatment failures. Analysis of eptinezumab studies
where placebo was administered IV found differences between migraine
types, with a higher incremental placebo response in patients with
chronic migraine (2.0 MMDs) compared to patients with episodic migraine
(1.0 MMD); however, the P -value for the interaction variable was
above 0.05 (P =0.07), possibly because of the very low number of
trials with IV placebo administration, or a ceiling effect due to the
definition of episodic migraine. This is in alignment with another
systematic review and meta-analysis which found differences of 1.5 MMDs
in studies of episodic migraine and 2.23 MMDs in studies of chronic
migraine . The review also found that 67% of interventional benefit was
due to contextual effects (including placebo effect) rather than direct
effect of anti-CGRP action; however, the analysis did not account for
administration (IV vs SC) . We also found that the IV effect was
numerically lessened for patients with ≥2 prior treatment failures (0.47
fewer MMDs gained vs treatment-naïve patients), butP >0.05. This is in alignment with previous research
describing that the proportion contextual effect (i.e., ratio of mean
MMD change in control group to experimental group) was lower in
anti-CGRP studies in episodic migraine including patients with ≥3 prior
treatment failures . Interestingly, the relationship between percentage
of treatment failure and geographic location was high (correlation
between percentage of 2+ treatment failures and percentage of North
American patients was -0.91 in EM). Therefore, we cannot rule out that
patient continent of origin rather than percentage of ≥2 prior treatment
failures was the driver of different placebo responses.
Further research is needed to definitively determine the causes
underlying the greater placebo response associated with IV
administration. One possible explanation is that increased healthcare
contact at the point of administration may contribute to the observed
higher placebo effect in IV trials. The number of clinic visits, the
time taken to administer the IV infusion (30–60 minutes), and the
extended period of post-infusion monitoring (2–4 hours) in the PROMISE
trials allowed the opportunity for greater interaction with clinicians
and nurses, which may impact the subsequent treatment response. Prior
studies of patients with other medical conditions indicate that among
individuals who prefer IV treatment administration, presence of
healthcare professionals and the feeling of greater procedural safety
are important , along with the belief that IV treatment has greater
efficacy than SC .
A myriad of contextual effects—that are rarely measured in randomized
clinical trials—can impact placebo response and explain our results,
including (but not limited to) interactions between the patient and
investigator , patient expectations of treatment and treatment regimen .
There is evidence to suggest that verbal suggestion from investigators
during explanation of clinical trial procedures can influence placebo
response based on patients’ expectations and desire for positive
outcomes . In a randomized, balanced placebo design study of rizatriptan
vs placebo for acute migraine treatment, investigators found that drug
labeling influenced patient outcomes, that increasing the likelihood of
receiving active treatment increased the likelihood of pain relief, and
that presenting negative vs neutral vs positive information may have
influenced placebo outcomes . In addition, more frequent interactions
between the patient and investigator may heighten expectations and
response. Time between dosing may influence placebo response, with lower
frequency of dosing possibly linked to a higher expectation of strength
and duration of effect. Patient expectations in those who have failed
several preventive therapies may be lower due to negative conditioning
with previous treatments, which was observed in lower placebo rates in
studies and subgroups of patients with evidence of ≥2 prior failures.