Efficacy and Safety of Oral Zavegepant in Migraine Prevention: A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study in Patients with Chronic Migraine

This study aimed to assess the efficacy and safety of once daily oral zavegepant as a preventive treatment for chronic migraine. This multicenter, randomized, double-blind, placebo-controlled phase 2/3 study consisted of a 12-week double-blind treatment (DBT) phase and a 52-week open-label extension (OLE). Adults with ≥ 1-year history of chronic migraine (with or without aura), ≥ 15 headache days/month, ≥ 8 migraine days/month, and ≥ 1 headache-free day/month during the 3 months prior to screening were randomly assigned 2:2:1:1 to zavegepant 100 mg, 200 mg, placebo for zavegepant 100 mg, or placebo for zavegepant 200 mg. Following a 28-day observation phase (OP), participants took the study treatment every calendar day. The primary endpoint was mean change from the OP in number of migraine days/month in the DBT phase. This study was stopped prematurely due to recruitment challenges. Of 1753 screened participants, 522 were treated and 411 completed the DBT phase. Participants were predominantly female (n = 391, 79.5%) and mean (SD) age of chronic migraine onset was 26.5 (11.7) years. The mean (97.5% CI) changes from the OP in number of migraine days/month in the DBT phase were – 7.0 (– 8.10, – 5.92), – 6.3 (– 7.45, – 5.10), and – 5.6 (– 6.80, – 4.37) for zavegepant 100 mg, 200 mg, and placebo groups, respectively. The corresponding least squares (LS) mean change differences (zavegepant–placebo pooled; 97.5% CI) were – 1.4 (– 2.72, – 0.12) and – 0.7 (– 2.07, 0.69) for zavegepant 100 mg and zavegepant 200 mg groups, respectively. During DBT, 21 (12.1%) and 14 (8.0%) participants had at least one adverse event considered zavegepant-related in the zavegepant 100 mg and 200 mg groups, respectively, with corresponding rates of nine (5.8%) and nine (6.3%) participants during the OLE. Oral zavegepant had a favorable safety and tolerability profile for up to 200 mg daily. Additional research is needed to determine the effectiveness of oral zavegepant as a preventive migraine treatment. ClinicalTrials.gov number: NCT04804033. Migraine is a long-term condition that causes repeated headaches called migraine attacks. Migraine preventive treatments are taken regularly to help prevent future migraine attacks. The aim of this study was to test zavegepant soft capsules for the preventive treatment of migraine. In this study, adults with migraine were assigned to one of four study treatments for 12 weeks: zavegepant 100 mg, zavegepant 200 mg, placebo for zavegepant 100 mg, or placebo for zavegepant 200 mg. People took the study treatment every calendar day. Researchers looked at changes in the number of days when a person has migraine symptoms (called migraine days). Researchers also looked at the side effects people had. This study was stopped early as it was challenging to find enough people to take part. A total of 411 people completed all 12 weeks of treatment. People taking zavegepant 100 mg had an average of seven fewer migraine days each month. People taking zavegepant 200 mg had an average of six fewer migraine days per month. People taking any dose of placebo had an average of almost six fewer migraine days per month. During the 12 weeks, 21 out of 173 people taking zavegepant 100 mg, and 14 out of 175 people taking zavegepant 200 mg, had a side effect that may have been caused by the treatment. Researchers concluded that further study is needed to tell if zavegepant soft capsules are effective as a preventive treatment for migraine.