A Phase II Clinical Trial to Test the Efficacy of Rimegepant for Endometriosis-Associated Pain

Project Summary/Abstract Endometriosis, a chronic gynecological condition affecting 10% of reproductive-age women, causes severe pelvic pain, fuels opioid dependence, and incurs ~$280 billion in annual U.S. healthcare and indirect costs, yet no targeted non-hormonal therapies have been approved in over 50 years. Elevated calcitonin gene-related peptide (CGRP) in endometriotic tissue and a 53% migraine-endometriosis comorbidity (Hazard Ratio 2.5) implicate CGRP in endometriosis- associated pain (EAP), amplified by shared neuroinflammatory mechanisms with migraine. This Phase 2, double-blind, placebo-controlled randomized controlled trial (RCT) will evaluate the efficacy and safety of rimegepant, an FDA-approved oral calcitonin gene-related peptide (CGRP) receptor antagonist, in 132 women aged 18–45 with histologically confirmed endometriosis and moderate-to-severe endometriosis-associated pain (EAP) (EDPI/Endometriosis Daily Pain Impact ≥2). Specific aims are: (1) assess rimegepant’s efficacy (75 mg every other day) versus placebo over 12 weeks, with co-primary outcomes of reduced non-menstrual pelvic pain (NMPP) and dysmenorrhea (EDPI score changes, weeks 9–12), and secondary outcomes including reduced rescue analgesic use (with opioid-specific sub-analysis), migraine frequency, and responder rates (≥40% EDPI decrease for NMPP, ≥60% for dysmenorrhea); (2) evaluate safety through adverse event monitoring; (3) explore CGRP-based biomarkers by correlating tissue CGRP expression (via immunohistochemistry and tissue microarray) and serum CGRP, IL-6, and TNFα levels with pain reduction, using mediation analysis. The trial employs stratified randomization, electronic diaries, and intention-to-treat analyses. By repurposing rimegepant, this study addresses a critical gap in EAP management, aims to reduce opioid use, explores the potential for decreasing surgical interventions, and supports Phase 3 trials. Expected outcomes will advance precision medicine for endometriosis and migraine, align with NICHD’s mission, and promote reproductive health.