OBJECTIVES: Migraine, a common disabling neurovascular disorder, disproportionately affects women. Newer treatments target calcitonin gene-related peptide (CGRP) pathway; however, studies indicate interaction between this pathway and sex hormones (e.g., ovarian hormone fluctuations). Therefore, novel migraine treatment clinical trials should incorporate sex/gender considerations. Previous reviews have examined how trials have done so in their design, conduct, analysis, and reporting. This review evaluates sex/gender equity considerations in published trials of second-generation CGRP antagonists (gepants) for migraine.

METHODS: We conducted systematic review of primary trial publications reporting efficacy/safety of gepants for migraine. We searched EMBASE (03 May 2024) for randomized controlled trials involving chronic/episodic migraine patients. We assessed sex/gender equity considerations in each trial by examining recruitment (proportion of women participants), eligibility (inclusion/exclusion of pregnancy, contraception), data analysis (disaggregation of primary/secondary outcomes by sex, effect of hormone replacement therapy (HRT) and menstrual cycle), and discussion of sex/gender implications. Post-hoc analyses including sex/gender perspective were reviewed separately.

RESULTS: We identified 17 unique trials of the following: rimegepant (6 RCTs), atogepant (5 RCTs), ubrogepant (4 RCTs), and zavegepant (2 RCTs). Most trials (16/17) recruited >80% women participants. Pregnancy was an exclusion criterion in 13/17 trials; contraceptive use was explicitly mandated in 6/17 trials. No trial disaggregated primary and secondary outcomes by sex. Drug-drug interactions with HRT or contraceptives and impact of menstrual cycle on outcomes were not considered in any trial. Potential implications on fertility intentions due to short half-life were mentioned in only 3/17 trials . Only one post-hoc study reported safety profile by sex.

CONCLUSIONS: Despite the well-established gendered nature of disease and high proportions of women recruited, gepants trials for migraine did not appear to fulfil sex/gender health equity considerations in study design, conduct, analysis, and reporting. This oversight may affect the health technology assessment process leading to potential biases and inequities in healthcare recommendations and policies.