Effects of Intravenous Eptinezumab vs Placebo on Headache Pain and Most Bothersome Symptom When Initiated During a Migraine Attack: A Randomized Clinical Trial

Abstract

Importance: Intravenous eptinezumab, an anti-calcitonin gene-related peptide antibody, is approved for migraine prevention in adults. It has established onset of preventive efficacy on day 1 after infusion.

Objective: To evaluate the efficacy of and adverse events related to eptinezumab when initiated during a migraine attack.

Design, setting, and participants: Phase 3, multicenter, parallel-group, double-blind, randomized, placebo-controlled trial conducted from November 4, 2019, to July 8, 2020, at 47 sites in the United States and the country of Georgia. Participants (aged 18-75 years) with a greater than 1-year history of migraine and migraine on 4 to 15 days per month in the 3 months prior to screening were treated during a moderate to severe migraine attack.

Interventions: Eptinezumab, 100 mg (n = 238), or placebo (n = 242), administered intravenously within 1 to 6 hours of onset of a qualifying moderate to severe migraine.

Main outcomes and measures: Co-primary efficacy end points were time to headache pain freedom and time to absence of most bothersome symptom (nausea, photophobia, or phonophobia). Key secondary end points were headache pain freedom and absence of most bothersome symptom at 2 hours after start of infusion. Additional secondary end points were headache pain freedom and absence of most bothersome symptom at 4 hours and use of rescue medication within 24 hours.

Results: Of 480 randomized and treated patients (mean age, 44 years; 84% female), 476 completed the study. Patients treated with eptinezumab vs placebo, respectively, achieved statistically significantly faster headache pain freedom (median, 4 hours vs 9 hours; hazard ratio, 1.54 [P < .001]) and absence of most bothersome symptom (median, 2 hours vs 3 hours; hazard ratio, 1.75 [P < .001]). At 2 hours after infusion, in the respective eptinezumab and placebo groups, headache pain freedom was achieved by 23.5% and 12.0% (between-group difference, 11.6% [95% CI, 4.78%-18.31%]; odds ratio, 2.27 [95% CI, 1.39-3.72]; P < .001) and absence of most bothersome symptom by 55.5% and 35.8% (between-group difference, 19.6% [95% CI, 10.87%-28.39%]; odds ratio, 2.25 [95% CI, 1.55-3.25]; P < .001). Results remained statistically significant at 4 hours after infusion. Statistically significantly fewer eptinezumab-treated patients used rescue medication within 24 hours than did placebo patients (31.5% vs 59.9%, respectively; between-group difference, -28.4% [95% CI, -36.95% to -19.86%]; odds ratio, 0.31 [95% CI, 0.21-0.45]; P < .001). Treatment-emergent adverse events occurred in 10.9% of the eptinezumab group and 10.3% of the placebo group; the most common was hypersensitivity (eptinezumab, 2.1%; placebo, 0%). No treatment-emergent serious adverse events occurred.

Conclusions and relevance: Among patients eligible for preventive migraine therapy experiencing a moderate to severe migraine attack, treatment with intravenous eptinezumab vs placebo shortened time to headache and symptom resolution. Feasibility of administering eptinezumab treatment during a migraine attack and comparison with alternative treatments remain to be established.

Trial registration: ClinicalTrials.gov Identifier: NCT04152083.

Figure 1.. Recruitment, Randomization, and Patient Flow in the RELIEF Trial

^aThere were 38 reasons for the 290 screening failures (patients could have >1 reason for failure); the most common (≥10 patients) were (1) not willing and/or able to receive infusion with study drug during a qualifying migraine attack within 8 weeks of screening visit (n = 153); (2) not willing and/or able to adhere to scheduled clinic visits and complete all study-related procedures (n = 29); (3) use of acetaminophen, aspirin, or nonsteroidal anti-inflammatory drugs for any indication for ≥15 days per month in each of the 3 months prior to screening (n = 13); and (4) women of childbearing potential and men with partners of childbearing potential not agreeing to use adequate contraception for the duration of the study (n = 10). ^bReasons infusion was discontinued in the eptinezumab group included adverse events (n = 3), a patient needing to use the restroom (n = 2), difficulty finding vein/infiltration/repositioning (n = 1), electronic diary issues (n = 1), and a fire alarm (n = 1). Reasons infusion was discontinued in the placebo group included adverse events (n = 2) and line occlusion/bag running dry and inability to flush (n = 2). ^cThe 2 patients with missing data for infusion completion underwent infusion for 30 and 31 minutes. ^dAdverse event was an upper respiratory tract infection that began on day 32 after the 28-day study (captured in the study completion/termination form) and was not considered related to study drug. ^eAll treated patients received the treatment to which they were randomized; therefore, the full analysis set and safety population comprise the same patients in each treatment group.

Figure 2.. Co-primary End Points: Time to Headache Pain Freedom and Absence of Most Bothersome Symptom in the Full Analysis Set

For headache pain freedom, the median observation time was 2 hours (interquartile range [IQR], 1-2.5 hours) for the eptinezumab group and 2.5 hours (IQR, 1-3 hours) for the placebo group. For absence of most bothersome symptom, the median observation time was 3 hours (IQR, 2-6 hours) for the eptinezumab group and 3 hours (IQR, 2.5-4 hours) for the placebo group. Median times to headache pain freedom were 4.0 (interquartile range [IQR], 2.5-12.0) hours in the eptinezumab group and 9.0 (IQR, 3.0-48.0) hours in the placebo group; median times to absence of most bothersome symptom were 2.0 (IQR, 1.0-3.5) hours and 3.0 (IQR, 1.5-12.0) hours, respectively. ^aAll censoring of patients was due to rescue medication use.