Meta-regression to explain the placebo effects in clinical trials of anti-CGRP monoclonal antibodies for migraine prevention

Figures & data

Figure 1. PRISMA diagram for the literature review.

*Number of studies included from the original SLR does not align with the original SLR report because pooled studies excluded in the original SLR were re-reviewed, and those reporting novel data in prior treatment failure subgroups have now been included in the SLR.

PRISMA, Preferred reporting items for systematic reviews and meta-analyses; TLR, Targeted literature review

Table 1. Placebo response in clinical trials of anti-CGRPs.

Study	Migraine type	Anti-CGRP	IV flag	Patients in the placebo arm, n	MMD reduction in the placebo arm, mean	SE	≥2 Treatment failures
ARISE [19]	Episodic	Erenumab	0	288	−1.52	0.20	0.17
LIBERTY [27]	Episodic	Erenumab	0	124	0.02	0.41	1.00
STRIVE [28]	Episodic	Erenumab	0	316	−1.33	0.21	0.17
STRIVE [39]^a	Episodic	Erenumab	0	54	−0.53	0.89	1.00
FOCUS [33]^b	Episodic	Fremanezumab	0	112	−0.70	0.43	1.00
HALO-EM [29]	Episodic	Fremanezumab	0	290	−2.20	0.24	0.00
CONQUER [34]^b	Episodic	Galcanezumab	0	132	−0.31	0.34	1.00
EVOLVE-1 [25]	Episodic	Galcanezumab	0	425	−2.43	0.27	0.05
EVOLVE-2 [26]	Episodic	Galcanezumab	0	450	−1.83	0.22	0.14
EVOLVE-1 + 2 [38]^a	Episodic	Galcanezumab	0	90	−0.21	0.73	1.00
DELIVER [35]^b	Episodic	Eptinezumab	1	164	−1.00	0.40	1.00
PROMISE-1 [20]	Episodic	Eptinezumab	1	222	−3.20	0.21	0.00
NCT02066415 [31]	Chronic	Erenumab	0	281	−3.50	0.40	0.50
NCT02066415 [36]^a	Chronic	Erenumab	0	142	−2.40	0.49	1.00
FOCUS [33]^c	Chronic	Fremanezumab	0	167	−0.70	0.47	1.00
HALO-CM [30]	Chronic	Fremanezumab	0	371	−3.20	0.40	0.00
CONQUER [34]^c	Chronic	Galcanezumab	0	98	−2.20	0.60	1.00
REGAIN [32]	Chronic	Galcanezumab	0	538	−2.70	0.40	0.29
REGAIN [37]^a	Chronic	Galcanezumab	0	174	−1.01	0.54	1.00
DELIVER [35]^c	Chronic	Eptinezumab	1	134	−3.30	0.66	1.00
PROMISE-2 [21]	Chronic	Eptinezumab	1	366	−5.60	0.33	0.00

^aSubgroup analysis of patients with ≥2 prior treatment failures.

^b Study included both episodic and chronic migraine; analysis population includes patients with episodic migraine only.

^c Study included both episodic and chronic migraine; analysis population includes patients with chronic migraine only.

CGRP, Calcitonin gene-related peptide; IV, Intravenous; MMDs, Monthly migraine days; SE, Standard error.

Figure 2. Relationship between MMDs reduction and subcutaneous treatment failures for (A) episodic migraine and (B) chronic migraine.

MMDs, Monthly migraine days.

Table 2. Relationship between MMDs reduction and subcutaneous treatment failures (3592 total patients, EM and CM trials).

Migraine type (data points)	Coefficient estimate	SE	95% CI	p-value
Episodic migraine (8 studies, n = 2137)
Intercept	−2.04	0.16	−2.34, −1.73	<0.001
Patients with ≥2 prior treatment failures, %	1.78	0.32	1.15, 2.41	<0.001
Chronic migraine (5 studies, n = 1455)
Intercept	−3.49	0.65	−4.76, −2.23	<0.001
Patients with ≥2 prior treatment failures, %	1.87	0.98	−0.06, 3.80	0.057

CI, Confidence interval; CM, Chronic migraine; EM, Episodic migraine; MMDs, Monthly migraine days; SE, Standard error.

Table 3. Placebo reduction in MMDs with administration route, migraine type, and percentage of patients as covariates.

	Coefficient estimate	SE	95% CI	p-value
Meta-regression
Intercept	−3.71	0.24	−4.18, −3.23	<0.001
Patients with ≥2 prior treatment failures, %	1.95	0.25	1.46, 2.43	<0.001
Episodic migraine^a	1.65	0.23	1.20, 2.10	<0.001
IV effect	−1.34	0.27	−1.86, −0.81	<0.001
Meta-regression with interaction
Intercept	−3.53	0.25	−4.02, −3.04	<0.001
Patients with ≥2 prior treatment failures, %	1.89	0.24	1.42, 2.36	<0.001
Episodic migraine^a	1.44	0.25	0.96, 1.93	<0.001
IV effect	−1.96	0.43	−2.80, −1.12	<0.001
Interaction: IV and migraine type	0.95	0.53	−0.08, 1.98	0.071

^a Chronic migraine was used as the reference value. CI, Confidence interval; IV, Intravenous; MMDs, Monthly migraine days; SE, Standard error.