A Multi-center, Randomized, Double-blind, Placebo-controlled Trial of Topical Ketotifen Fumarate 0.25% Cream for Females With Secondary Vestibulodynia
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 54
- 试验地点
- 3
- 主要终点
- Change in Dilator-Induced Pain at the Baseline Dilator Maximum Tested Size (DMTS)
研究概览
简要总结
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.
详细描述
This Phase 2 clinical trial is designed to evaluate a novel, mechanism-based topical treatment for secondary provoked vestibulodynia (PVD), a chronic pain condition affecting the vulvar vestibule. Women with PVD commonly describe burning, stinging, or sharp pain with tampon insertion, penetrative sexual activity, or light touch to the vestibular tissue. Many have lived with symptoms for years, and the condition can severely impair sexual function, intimate relationships, and overall quality of life. At present, there are no FDA-approved pharmacologic options, and the most effective intervention, vestibulectomy (surgical excision of painful vestibular tissue), is invasive and often unacceptable to patients.
Histopathologic and translational research has begun to clarify biological mechanisms that may drive PVD, particularly in women whose symptoms arise after recurrent vulvovaginal candidiasis or exposure to topical irritants. Vestibular tissue samples from patients undergoing vestibulectomy consistently show increased nerve density and clusters of activated mast cells within the mucosa. These findings support a model in which recurrent or persistent inflammation leads to mast-cell activation, release of pro-inflammatory mediators (including histamine and nerve growth factor), and pathologic neuroproliferation in the vestibular tissue. Preclinical work in rodent models has further demonstrated that repeated vulvovaginal fungal infections can induce chronic vulvar pain, even after clearance of infection, and that mast cell-derived factors are key contributors to sustained hypersensitivity and abnormal innervation.
Ketotifen fumarate is an oral and topical antihistamine with dual activity as a non-competitive H1 receptor antagonist and mast-cell stabilizer. It has decades of clinical use in allergic disorders and asthma prophylaxis and is generally well tolerated when used chronically. In a validated rat model mimicking PVD, ketotifen reduced vulvar mechanical and thermal hypersensitivity, decreased mast-cell activation and accumulation, lowered levels of nerve growth factor, and limited excessive nerve fiber growth in the vestibule. Modulation of these neuroinflammatory pathways suggests that ketotifen may attenuate the central biological processes driving pain in secondary PVD.
On the basis of this mechanistic rationale, an international vulvodynia summit of clinicians, scientists, and patient stakeholders recently reviewed potential candidates for future clinical trials in PVD. Ketotifen emerged as the highest-priority medication to move forward into human studies for neuroproliferative, inflammation-driven PVD. However, to date, no randomized, placebo-controlled clinical trial has tested topical ketotifen for this indication. This trial is designed to fill that gap by rigorously evaluating efficacy, safety, and tolerability of a 0.25% ketotifen fumarate cream applied directly to the vulvar vestibule.
Study Objectives
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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
研究组 & 干预措施
Ketotifen Fumarate 0.25% Cream
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.
干预措施: Ketotifen Fumarate 0.25% Cream (Drug)
Placebo (Vehicle Cream)
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.
干预措施: Placebo (Vehicle Cream) (Drug)
结局指标
主要结局
Change in Dilator-Induced Pain at the Baseline Dilator Maximum Tested Size (DMTS)
时间窗: Baseline to Week 15
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.
次要结局
- Change in Vulvodynia Experience Questionnaire (VEQ) Scores(Baseline, Week 3, Week 9, Week 15.)
- Patient-Reported Meaningful Benefit(Week 15)
- Change in Vestibular Pain Thresholds (Wagner Algometer)(Baseline, Week 3, Week 9, Week 15.)
研究者
Andrew T. Goldstein, MD
Medical Director, Center for Vulvovaginal Disorders
Center for Vulvovaginal Disorders