Evaluation of Vaginal Tamoxifen Citrate for Improvement of Sexual Function in Women with Breast Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

The primary objective of this study is to evaluate the **efficacy** of vaginal administration of **tamoxifen** in reducing the most troublesome symptoms of **vulvovaginal atrophy** in women with breast cancer. This will be assessed using the Endocrine Subscale of the Functional Assessment of Cancer Therapy-Breast (FACT-B). The clinical relevance of this objective lies in addressing the significant impact of vulvovaginal atrophy on the quality of life and sexual function in women undergoing treatment for breast cancer. By potentially alleviating these symptoms, the study aims to improve overall patient well-being and treatment satisfaction.

The clinical trial focuses on evaluating the efficacy of vaginal tamoxifen in reducing vulvovaginal atrophy symptoms in women with breast cancer. The study population consists exclusively of **postmenopausal women** who are currently undergoing adjuvant antiestrogen treatment with aromatase inhibitors. Participants are required to be sexually active and in otherwise good health, as determined by a comprehensive medical evaluation. The age range of the participants falls within categories 3 and 4, which typically corresponds to middle-aged and older adults. The trial does not include male subjects or vulnerable populations. Participants were selected based on specific criteria, including having a vaginal pH greater than 5.0, estradiol levels below 20 pmol/l, and an endometrial thickness of less than 4 mm. Additionally, participants must have identified one moderate to severe vulvovaginal atrophy symptom as the most bothersome, as assessed by the Endocrine Subscale-FACT-B. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** longitudinal phase 3 study. The primary objective is to evaluate the efficacy of vaginal **tamoxifen citrate** in reducing the most troublesome vulvovaginal atrophy symptom in women with breast cancer, assessed using the Endocrine Subscale-FACT-B. The trial is expected to run from March 2022 to June 2025, with a maximum treatment period of 12 weeks for each participant. Participants will be postmenopausal women with breast cancer undergoing adjuvant antiestrogen treatment with aromatase inhibitors, meeting specific inclusion criteria such as a vaginal pH > 5.0 and estradiol levels below 20 pmol/l.

The study involves several key visits: an initial screening visit, multiple follow-up visits, and an end-of-study visit. During the screening visit, eligibility will be confirmed through assessments including physical and gynecological examinations, mammography, and laboratory tests. Follow-up visits will occur at regular intervals to monitor safety, adherence, and efficacy, with data collected on changes in symptoms and quality of life using validated scales such as the Female Sexual Function Index and the Female Sexual Distress Scale-revised. The end-of-study visit will involve a final evaluation of the primary and secondary endpoints.

Participant involvement is expected to last approximately 12 weeks, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with the study protocol. The primary endpoint will be measured by a modified version of the Endocrine Subscale-FACT-B, while secondary endpoints will assess changes in sexual function, distress, and quality of life from baseline to week 12. The trial aims to provide insights into the potential benefits of vaginal tamoxifen for improving sexual function in this patient population.

The clinical trial involves the administration of **tamoxifen citrate**, a selective estrogen receptor modulator, as the experimental medication. Tamoxifen citrate is provided in a pharmaceutical form identified by the code PHF00082MIG. The medication is administered via the **vaginal route**. The maximum daily dose is 20 mg, with a total maximum dose of 20 mg per day. The treatment period is set for a maximum of 12 months. The active substance, tamoxifen citrate, is of chemical origin and is classified under the ATC code L02BA01, indicating its role as an antiestrogenic agent. The primary objective of the trial is to evaluate the efficacy of vaginal tamoxifen in reducing vulvovaginal atrophy symptoms in women with breast cancer, as assessed by the Endocrine Subscale-FACT-B.

The study also includes a **placebo** as a non-experimental treatment to serve as a comparator in this randomized, double-blinded, placebo-controlled phase 3 study. The placebo is used to ensure the validity of the trial results by providing a baseline for comparison against the effects of the experimental medication. The placebo is administered in a manner consistent with the experimental treatment to maintain the study's blinding and integrity. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to accurately assess the treatment's efficacy and safety.

The efficacy of vaginal **tamoxifen** in reducing vulvovaginal atrophy symptoms in women with breast cancer will be assessed using a modified version of the Endocrine Subscale-FACT-B. This validated 5-point response scale, specifically developed for breast cancer research, will serve as the primary endpoint. The scale measures symptom severity on a range from "not at all" to "severe." Secondary endpoints include changes from baseline to week 12 in all subscales of the modified Endocrine Subscale-FACT-B, as well as total scores on the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale-revised (FSDS-R). Additionally, changes in Quality of Life will be evaluated using the EORTC QLQ-C30. These assessments will be conducted at baseline and at week 12 to determine the treatment's impact over the study period.