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.