1. Patients with chronic migraine receiving fremanezumab had significantly fewer migraines and headaches than those receiving placebo after 12 weeks of treatment.
2. Injection-site reactions, including pain and induration, were the most frequently reported adverse event in both fremanezumab and placebo treated patients.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Migraine is a common neurological cause of morbidity and disability. Current preventative treatment options are often ineffective or associated with prominent side effects. Investigations into the pathophysiology of migraine have yielded calcitonin gene-related peptide (CGRP) as a possible drug target. Fremanezumab is a humanized monoclonal antibody targeting CGRP, and has previously shown efficacy in reducing migraines and headaches in persons with chronic migraines in a phase 2 trial. This phase 3 randomized controlled trial compared two dosing regimens of fremanezumab to placebo in reduction of headache and migraine days for patients with chronic migraine. The primary study endpoint was the mean change in the average number of headache days. Compared to those taking placebo, participants in the active treatment arms had a significantly greater reduction in migraine and headache days. Significantly greater reductions in headache-related disability were seen in the treatment arm relative to the placebo arm.
Strengths of this study include its multinational phase 3 design and numerous secondary endpoints. Limitations of this study are the short duration of treatment and exclusion of patients with refractory migraines. Notably, analysis of trial results was performed by the company producing the study drug.
In-Depth [randomized controlled trial]: This phase 3, multinational, randomized controlled trial enrolled 1130 patients from March 2016 to January 2017. Eligible adult patients had a history of chronic migraine for at least twelve months and were excluded if they had recently used migraine treatments such as onabotulinumtoxinA, opioids, or nerve blocks. Participants were randomized to receive quarterly fremanezumab (n = 376), monthly fremanezumab (n = 379), or placebo (n = 375). The primary endpoint was the mean change in the average number of headache days after 12 weeks of treatment.
The mean (±SE) reduction in headache days in the quarterly (4.3±0.3 days) and monthly (4.6±0.3 days) treatment arms were greater than the placebo arm (2.5±0.3 days) (p < 0.001 for both comparisons vs placebo). The mean (±SE) reduction in migraine days in the quarterly (4.9±0.4 days) and monthly (5.0±0.4 days) treatment arms were also greater than the placebo arm (3.2±0.4 days) (p < 0.001 for both comparisons). Other secondary endpoints, including reduction in disability and reduction of at least 50% in the average number of headache days per month, were also significantly improved in both treatment arms compared to placebo. Overall adverse events were more common in those receiving monthly fremanezumab (71%) compared to the placebo arm (64%) (p = 0.03), but no significant difference was seen between quarterly fremanezumab (70%) and placebo (p = 0.06). The most common adverse events were injection-site reactions, occurring in the monthly fremanezumab arm significantly more than the placebo arm (47% vs 40%, p = 0.03). Serious adverse events were rare in all study groups. There was no evidence that liver injury was more common in the treatment arm (p = 0.56 for combined groups vs. placebo).
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