The relation between the placebo response, observed treatment effect, and failure to meet primary endpoint: A systematic review of clinical trials of preventative pharmacological migraine treatments

Abstract

Objective To evaluate the association between the degree of response to placebo in migraine studies and the observed difference between drug and placebo across studies of preventative treatments for migraine. Methods A systematic review was performed using MEDLINE and the Cochrane Central Register of Controlled Clinical Trials from January 1988 to June 2019. Randomized, double-blind, parallel-group, placebo-controlled trials on oral or injection preventative treatments for migraine were included. Single- and multi-variable linear regression analyses were performed on the placebo-subtracted response rate (i.e. placebo responders subtracted from active responders), and the proportion of placebo responders. Fisher’s exact tests were performed on the level of placebo response and the success in meeting the study’s primary endpoint. Results After adjusting for route of administration and number of randomized subjects, there was a statistically significant association between the proportion of patients who were placebo responders and the placebo-subtracted response rate (b = −0.27, p = 0.02). There was a statistically significant difference in trial success rate (60%) between studies with ≤20% placebo responders and studies with > 30% placebo responders ( p = 0.03). Conclusion Considering the detrimental impact that high placebo response can have on clinical trials, it is imperative to find effective solutions to decrease the placebo response and increase assay sensitivity.

The Temporal Trend of Placebo Response in Migraine Prevention from 1990 to 2021: A Systematic Literature Review and Meta-Analysis with Regression

“…Evans et al only examined the proportion of ≥ 50% responders, de ned as a ≥ 50% reduction in migraine days/month. After adjusting for a similar set of confounders as this study, they did not nd a signi cant linear relationship between year of publication in placebo response [13]. In our larger analysis of 52 studies incorporating a more diverse group of dichotomous outcomes, we also did not nd a relationship with year of publication and placebo response.…”

“…Since most trials for neurological conditions use subjective patient-reported outcomes, they are especially sensitive to placebo response [11,12]. Degree of response to placebo in migraine studies shows a signi cant association with the percent of placebo responders [13], and the route of administration and type of treatment affect placebo response. Other studies reported placebo response for speci c migraine treatments such as CGRP antibodies.…”

“…Forbes et al, evaluated contextual treatment effects of CGRP antibodies in adults with episodic migraine (EM) and chronic migraine (CM), and found that approximately 66% of the reduction in migraine days is due to contextual or placebo effects. However, there are limited comprehensive literature reviews and meta-analyses (MAs) that speci cally examined placebo response over years in migraine prevention trials, especially since e cacy outcomes reported in migraine RCT evolved over years, and these changes may have affected the temporal trends in placebo response [13,14]. Additionally, previous MAs did not adequately assess potential confounders affecting placebo response in all migraine types [13,14].…”

“…However, there are limited comprehensive literature reviews and meta-analyses (MAs) that speci cally examined placebo response over years in migraine prevention trials, especially since e cacy outcomes reported in migraine RCT evolved over years, and these changes may have affected the temporal trends in placebo response [13,14]. Additionally, previous MAs did not adequately assess potential confounders affecting placebo response in all migraine types [13,14]. Addressing these gaps may improve design of clinical trials and affect clinical practice.…”

CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs

“…In both EM and CM, the highest MMD reduction was found for the CGRP mAb. The true clinical efficacy of CGRP mAb might even be higher since overall a high placebo response was reached in most of the trials probably related to their more invasive route of administration [ 81 ]. However, whether this small difference reflects a clinically meaningful difference remains unclear, since a head-to-head statistical comparison of the studied prophylactic agents is limited by several factors.…”