This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of topical ketotifen fumarate 0.25% cream in adult women with secondary provoked vestibulodynia (PVD). Secondary PVD is a chronic vulvar pain condition characterized by burning or sharp pain with vaginal penetration (e.g., intercourse, tampon use) and touch of the vulvar vestibule, often following recurrent infections or topical irritant exposures. Preclinical studies suggest that ketotifen, a mast-cell stabilizer and histamine H1 antagonist, may reduce neuroinflammation and abnormal nerve growth in the vulvar vestibule, offering a mechanism-based, non-surgical treatment option.
Approximately 54 women aged 18 years and older who meet ISSVD/ISSWSH/IPPS criteria for secondary PVD without vulvovaginal atrophy will be enrolled. After a 1-week screening period, all participants will complete a 2-week single-blind placebo run-in; those with a strong placebo response or intolerance to vehicle cream will not be randomized. Eligible participants will then be randomized 1:1 to receive ketotifen fumarate 0.25% cream or matching placebo cream applied twice daily to the vulvar vestibule for 12 weeks.
The primary outcome is change from baseline to Week 15 in pain intensity with the baseline dilator maximum tested size (DMTS), measured on an 11-point numeric rating scale. Secondary outcomes include changes in Vulvodynia Experience Questionnaire (VEQ) scores, vestibular pain thresholds measured by Wagner algometry, and participant-reported meaningful benefit at the end of treatment. Safety assessments will include adverse events, application-site reactions, physical examinations, vital signs, and pregnancy testing. This study will provide the first controlled clinical data on topical ketotifen for secondary PVD and inform the feasibility of larger registration trials.
Female participants ≥18 years of age
Able to provide signed and dated informed consent
Able to read, write, understand, and complete English-language study-related forms and communicate in English
Has a stable address and is available for the duration of the study
Pregnancy or lactation
Unable to tolerate the smallest dilator during baseline dilator assessment
Active vaginal infection (Candida, BV, trichomonas, HSV)
May re-screen after treatment and documented cure
Parallel
Ketotifen Fumarate 0.25% Cream
DrugParticipants apply topical ketotifen fumarate 0.25% cream as a thin layer to the vulvar vestibule twice daily (approximately every 8-12 hours) for 12 weeks after completing the 2-week placebo run-in period. The cream is provided in pre-weighed tubes and used throughout the randomized treatment phase.
Placebo (Vehicle Cream)
DrugParticipants apply the matching vehicle cream as a thin layer to the vulvar vestibule twice daily (approximately every 8-12 hours) for 12 weeks following completion of the 2-week placebo run-in period. The placebo cream is identical in appearance and packaging to the ketotifen cream and is provided in pre-weighed tubes for use throughout the randomized treatment phase.
Change in Dilator-Induced Pain at the Baseline Dilator Maximum Tested Size (DMTS)
Pain intensity is measured using the 11-point Numeric Rating Scale (0-10) at the participant's baseline dilator maximum tested size during standardized dilator testing. This assesses change in insertional pain from baseline over the randomized treatment period.
Change in Vulvodynia Experience Questionnaire (VEQ) Scores
Change from baseline in patient-reported symptoms, function, and quality of life using the validated VEQ instrument administered at each study visit.
Change in Vestibular Pain Thresholds (Wagner Algometer)
Mechanical pain thresholds measured at six standardized vestibular sites using a Wagner algometer applying force at 0.5 N/s. Threshold recorded when the participant first reports pain.
Patient-Reported Meaningful Benefit
Participant-reported global assessment asking whether the treatment provided meaningful benefit.
Incidence of Adverse Events (AEs)
Frequency and type of treatment-emergency adverse events
Incidence of Serious Adverse Events (SAEs)
Number of serious adverse events meeting regulatory criteria
Local Application Site Reactions
Incidence of stinging, burning, pruritis, erythema, or related reactions at applications site
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Center for Vulvovaginal Disorders
Lead sponsor
National Vulvodynia Association
Collaborator
