Topical Ketotifen 0.25% for Secondary Vestibulodynia

Summary

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.

Timeline

Start

2026-01-02

Primary completion

2026-08-01

Completion

2027-01-01

Publications

• Background Tympanidis P, Terenghi G, Dowd P. Increased innervation of the vulval vestibule in patients with vulvodynia. Br J Dermatol. 2003 May;148(5):1021-7. doi: 10.1046/j.1365-2133.2003.05308.x.
• Background Gagnon C, Minton J, Goldstein I. Vestibular anesthesia test for neuroproliferative vestibulodynia. J Sex Med. 2014 Aug;11(8):1888-91. doi: 10.1111/jsm.12630. No abstract available.
• Background Goldstein AT, Pukall CF, Brown C, Bergeron S, Stein A, Kellogg-Spadt S. Vulvodynia: Assessment and Treatment. J Sex Med. 2016 Apr;13(4):572-90. doi: 10.1016/j.jsxm.2016.01.020. Epub 2016 Mar 25.
• Background Awad-Igbaria Y, Edelman D, Ianshin E, Abu-Ata S, Shamir A, Bornstein J, Palzur E. Inflammation-induced mast cell-derived nerve growth factor: a key player in chronic vulvar pain? Brain. 2025 Jan 7;148(1):331-346. doi: 10.1093/brain/awae228.
• Background Awad-Igbaria Y, Dadon S, Shamir A, Livoff A, Shlapobersky M, Bornstein J, Palzur E. Characterization of Early Inflammatory Events Leading to Provoked Vulvodynia Development in Rats. J Inflamm Res. 2022 Jul 11;15:3901-3923. doi: 10.2147/JIR.S367193. eCollection 2022.
• Background Drian A, Goldstein SW, Kim NN, Goldstein AS, Hartzell-Cushanick R, Yee A, Goldstein I. Immunohistochemical staining with CD117 and PGP9.5 of excised vestibular tissue from patients with neuroproliferative vestibulodynia. J Sex Med. 2024 Apr 30;21(5):479-493. doi: 10.1093/jsxmed/qdae030.
• Background Bornstein J, Bogliatto F, Haefner HK, Stockdale CK, Preti M, Bohl TG, Reutter J; ISSVD Terminology Committee. The 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar Squamous Intraepithelial Lesions. Obstet Gynecol. 2016 Feb;127(2):264-8. doi: 10.1097/AOG.0000000000001285.

Drugs

Indications