Topical Ketotifen 0.25% for Secondary Vestibulodynia

NCT07257029 | Recruiting Phase 2 FDA Drug

• 1 other identifier: CVVD-KF1
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Vulvary Pain Disorders; Neuroproliferative Vestibulodynia; Mast Cell-mediated Neuroinflammation; Instertional Dyspareunia; Provoked Vestibulodynia; Secondary Provoked Vestibulodynia; Vulvodynia

Keywords

ketotifen fumarate; vulvodynia; provoked vestibulodynia; secondary vestibulodynia; vulvar pain; insertional dyspareunia; mast cell stabilizer; neuroproliferative pain; topical antihistamine; vulvar vestibule; non-hormonal treatment; vestibular tenderness; female sexual pain; vestibulodynia clinical trial; vulvar pain disorder; randomized controlled trial; algometer; dilator test; vulvodynia experience questionnaire (VEQ)

Outcome Measures

Primary Outcomes (1)

• 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.

  Baseline to Week 15

Secondary Outcomes (3)

• Change in Vulvodynia Experience Questionnaire (VEQ) Scores

  Baseline, Week 3, Week 9, Week 15.

• Change in Vestibular Pain Thresholds (Wagner Algometer)

  Baseline, Week 3, Week 9, Week 15.

• Patient-Reported Meaningful Benefit

  Week 15

Other Outcomes (3)

• Incidence of Adverse Events (AEs)

  From first application through 30 days after last dose

• Incidence of Serious Adverse Events (SAEs)

  From informed consent through 30 days after last dose

• Local Application Site Reactions

  Baseline, Week 3, Week 9, Week 15

Study Arms (2)

Ketotifen Fumarate 0.25% Cream

EXPERIMENTAL

Participants receive topical ketotifen fumarate 0.25% cream applied 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 ketotifen cream is supplied in pre-weighed tubes and used for the full randomized treatment phase.

Drug: Ketotifen Fumarate 0.25% Cream

Placebo (Vehicle Cream)

PLACEBO COMPARATOR

Participants receive the matching vehicle cream applied 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 active study cream and is supplied in pre-weighed tubes for the full randomized treatment phase.

Drug: Placebo (Vehicle Cream)

Interventions

Placebo (Vehicle Cream) DRUG

Participants 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.

Placebo (Vehicle Cream)

Ketotifen Fumarate 0.25% Cream DRUG

Participants 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.

Ketotifen Fumarate 0.25% Cream

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• In good general health based on medical history
• Willing to comply with all study procedures
• Body mass index (BMI) between 18.5 kg/m² and 32.0 kg/m² (inclusive)
• Meets ISSVD/ISSWSH/IPPS criteria for secondary provoked vestibulodynia, including: 6 continuous months of vulvar symptoms (insertional dyspareunia, pain with tampon insertion, or pain to touch); moderate to severe vestibular tenderness to light touch on physical exam
• No evidence of vulvovaginal atrophy
• If atrophy is present, must complete ≥12 weeks of topical hormone therapy and be re-screened to confirm resolution before enrollment
• Negative vaginal culture for infection at randomization (participants with positive cultures at screening may be treated and retested)

You may not qualify if:

• 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
• Active cutaneous disease of the vestibule
• Current presentation of other painful vulvar conditions, including:
• Pudendal neuralgia Lichen sclerosus Lichen planus Plasma cell vulvitis Vulvar intraepithelial neoplasia Sjögren's disease Desquamative inflammatory vaginitis
• Hypoestrogenic states (e.g., vulvar atrophy due to menopause or medications)
• History of significant vestibular or vaginal surgery, including:
• Vestibulectomy Perineoplasty Bladder neck suspension Anterior/posterior colporrhaphy Pudendal nerve neurolysis Ablative or fractional laser procedures
• Initiation or planned change in any of the following within 30 days before screening or during the study:
• Gabapentinoids Tricyclic antidepressants SSRIs or SNRIs Hormone replacement therapy Systemic or local muscle relaxants (benzodiazepines, baclofen, botulinum toxin, cyclobenzaprine, CBD suppositories) Pelvic floor physical therapy
• Use of another investigational drug or intervention within the past 3 months
• Positive vaginal culture during the study requiring two or more treatments (per protocol, second infection leads to termination)
• Any condition or factor that, in the opinion of the investigator, would interfere with study participation or safety

Sponsors & Collaborators

• National Vulvodynia Association: collaborator
• Center for Vulvovaginal Disorders: lead

Study Sites (3)

The Center for Vulvovaginal Disorders - Washington, DC

Washington D.C., District of Columbia, 20037, United States

RECRUITING

The Center for Vulvovaginal Disorders

Tampa, Florida, 33609, United States

RECRUITING

The Center for Vulvovaginal Disorders - New York

New York, New York, 10036, United States

RECRUITING

Related Publications (7)

• 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.

  PMID: 12786836 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.

  PMID: 25066059 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.

  PMID: 27045258 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.

  PMID: 39001871 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.

  PMID: 35845089 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.

  PMID: 38521973 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.

  PMID: 26942352 BACKGROUND

MeSH Terms

Conditions

Vulvodynia

Interventions

Ketotifen

Condition Hierarchy (Ancestors)

Vulvar Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Andrew T Goldstein, MD

  Center for Vulvovaginal Disorders

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Andrew T Goldstein, MD

CONTACT

410-279-0209; obstetrics@yahoo.com

Kate L Tolleson, MS

CONTACT

903-424-1410; kate@vulvodynia.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Director, Center for Vulvovaginal Disorders

Model Details: This is a multi-center, randomized, double-blind, placebo-controlled, parallel-assignment Phase 2 trial. After a 2-week single-blind placebo run-in, eligible participants are randomized 1:1 to receive topical ketotifen fumarate 0.25% cream or matching vehicle cream. Participants apply their assigned treatment twice daily for 12 weeks, with no crossover between study arms. All investigators, participants, and study staff remain blinded to assignment until database lock.

Study Record Dates

• First Submitted: November 21, 2025
• First Posted: December 2, 2025
• Study Start: January 2, 2026
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): January 1, 2027
• Last Updated: March 18, 2026

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)