(007) Topical Ketotifen Fumarate 0.25% Cream for Secondary Provoked Vestibulodynia: Protocol for a Randomized, Double-blind, Placebo-controlled Phase 2 Trial

Abstract Introduction Provoked vestibulodynia (PVD) is one of the most common causes of insertional dyspareunia, yet there are no FDA-approved pharmacologic treatments. Many patients experience years of persistent pain despite topical hormones, neuromodulators, or pelvic floor therapy, and although vestibulectomy can be curative for patients, it is highly invasive. Increasing histopathologic and mechanistic evidence supports a neuro-inflammatory model of PVD in which mast-cell activation, histamine release, and downstream nociceptor hyperinnervation drive localized hypersensitivity in the vulvar vestibule. These pathways frequently appear following immune-inflammatory triggers such as recurrent candidal infections or chronic exposure to irritants or allergens, consistent with the clinical history of many patients with secondary PVD. Ketotifen fumarate (KF) is a mast-cell stabilizer and histamine H1 receptor antagonist with a long-standing safety profile in allergic conditions. Preclinical models of vulvodynia demonstrate that ketotifen reduces mast-cell recruitment, nerve growth factor signaling, and abnormal neuronal sprouting, leading to meaningful reductions in mechanical and thermal hypersensitivity. A recent international consensus of vulvodynia experts identified ketotifen as the highest-priority candidate for clinical testing among novel, mechanism-based therapies. However, no controlled human trial has evaluated topical KF for PVD. Objective To determine the efficacy, safety, and tolerability of topical KF 0.25% cream in females with secondary PVD using a placebo-controlled design that mitigates nonspecific response. Methods This is a multicenter, randomized, double-blind, placebo-controlled Phase 2 trial with a single-blind 2-week placebo run-in followed by 12 weeks of twice-daily (BID) blinded treatment. Approximately 54 women ≥18 years who meet ISSVD/ISSWSH/IPPS criteria for secondary PVD (≥6 months insertional pain, localized vestibular tenderness, no vulvovaginal atrophy) will be randomized 1:1 to KF 0.25% cream or vehicle. Exclusion before randomization occurs for placebo response (≥2-size increase on the standardized dilator test) or vehicle intolerance. Clinic visits occur at Weeks 0 (screening/baseline), 3 (randomization), 9, and 15. Assessments include Dilator Maximum Tested Size (DMTS) with 11-point pain NRS, the Vulvodynia Experience Questionnaire (VEQ), vestibular pain thresholds by Wagner algometry at six sites (0.5 N/s), adverse events, vitals, and pregnancy testing. Primary endpoint is change from baseline to Week 15 in dilator-induced pain (NRS) at the baseline DMTS; key secondary endpoints include change in DMTS, VEQ domains, algometry thresholds, and patient-reported meaningful benefit at Week 15. Analyses use mixed models for repeated measures (intent-to-treat), with site and visit as fixed effects and baseline values as covariates; logistic regression will compare meaningful-benefit proportions. Sample size (n = 54; 27/arm) provides 80% power (α = 0.05) to detect a clinically important between-arm difference allowing for 10% attrition. Results Trial initiation and enrollment are underway; no outcomes are available at submission. Screening metrics, run-in exclusion rates, adherence, and baseline characteristics will be summarized to demonstrate feasibility and fidelity to standardized procedures. Conclusions This Phase 2 RCT tests a non-surgical, mechanism-based therapy targeting mast-cell-mediated neuroinflammation in secondary PVD while prospectively addressing possible placebo response via a run-in. The multidimensional endpoint set captures pain intensity, penetrative function, and quantitative sensory thresholds. If efficacious and well-tolerated, topical KF 0.25% could advance to larger trials as the first locally applied, mechanism-guided pharmacotherapy for PVD. Disclosure No.