Efficacy and Safety of Estriol, Prasterone, and Estriol-Lactobacillus Acidophilus Combination in Breast Cancer Patients with Vulvovaginal Atrophy on Endocrine Therapy

The primary objectives of this randomized active-controlled trial, known as the GRACE-trial, are twofold. Firstly, the study aims to assess the **efficacy** of different treatment regimens for vulvovaginal atrophy in breast cancer patients undergoing endocrine therapy. This will be evaluated through patient-reported outcome measures (PROMs) and clinical evaluations, including vaginal pH and the vaginal maturation index, which involves a direct microscopic evaluation of the vaginal epithelium. Secondly, the trial seeks to evaluate the **safety** of these treatment regimens. Although previous research suggests no increased risk of breast cancer recurrence, there is a lack of direct comparative data on the safety of different treatment regimes. This study will address this gap by measuring systemic sex hormone concentrations as a surrogate for safety evaluation. The clinical relevance of these objectives lies in improving the management of vulvovaginal atrophy in this patient population, potentially enhancing quality of life and treatment adherence. The secondary objective is to identify microbial alterations following treatment initiation. Understanding these alterations could provide insights into the pathophysiology of vulvovaginal atrophy and inform the development of new treatment strategies for patients with breast cancer on endocrine therapy.

The clinical trial involves **breast cancer** patients who are currently undergoing endocrine therapy, specifically Aromatase Inhibitors (AI) or Selective Estrogen Receptor Modulators (SERM), and are experiencing symptoms of vulvovaginal atrophy. The study population is exclusively female, with participants being postmenopausal, as defined by specific criteria such as 12 months of amenorrhea or induced postmenopause. The age range of 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. The sponsor has not provided information regarding the total number of participants. Participants were selected based on their current health status, specifically their breast cancer diagnosis and ongoing endocrine therapy, as well as the presence of symptoms related to vulvovaginal atrophy. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial aims to assess the efficacy and safety of different treatment regimens for these symptoms, with a focus on clinical evaluations and patient-reported outcomes.

The clinical trial is designed as a **randomized**, active-controlled study aimed at evaluating the efficacy and safety of different treatment regimens for **vulvovaginal atrophy** in postmenopausal breast cancer patients undergoing endocrine therapy. The trial will involve the administration of various pharmaceutical forms, including pessaries and vaginal tablets, containing active substances such as **estriol** and **prasterone**. The study will be conducted over a period of 12 weeks, with the primary endpoint being the efficacy of the treatment regimens, assessed through patient-reported outcome measurements using validated questionnaires at three time points: baseline, 6 weeks, and 12 weeks. The secondary endpoint focuses on the safety of the treatments, evaluated by measuring blood serum concentrations of sex steroid hormones at the same intervals.

Participants will be required to attend several study visits throughout the trial. The initial visit will serve as the inclusion or screening visit, where eligibility criteria will be confirmed, including postmenopausal status and the presence of symptoms of vulvovaginal atrophy. Follow-up visits will occur at 6 weeks and 12 weeks, during which efficacy and safety assessments will be conducted. The end-of-study visit will coincide with the 12-week follow-up, marking the conclusion of the participant's involvement in the trial. The expected duration of participant involvement is approximately 12 weeks, with conditions for early termination including non-compliance with the study protocol or adverse events that compromise participant safety.

The trial is expected to run from April 2022 to December 2026, with recruitment starting in April 2022. Participants will be randomly assigned to different treatment groups, ensuring a double-blind approach to minimize bias. The study will adhere to rigorous scientific and ethical standards, with all procedures conducted in accordance with regulatory guidelines. The trial's findings are anticipated to provide valuable insights into the management of vulvovaginal atrophy in this specific patient population, potentially influencing future therapeutic strategies.

The clinical trial involves the administration of several experimental medications, each with specific characteristics and administration protocols. The first experimental medication is **Oekolp 0.03 mg**, formulated as ovules for vaginal use. The active substance in this medication is **estriol**, a chemical compound. The maximum daily dose is 0.03 mg, with a total maximum dose of 1.17 mg over a treatment period of up to 12 weeks. The administration route is strictly vaginal, and the medication is produced by DR. KADE PHARMAZEUTISCHE FABRIK GMBH.

Another experimental medication used in the trial is **Intrarosa 6.5 mg pessary**, which contains the active substance **prasterone**. This medication is also administered vaginally, with a maximum daily dose of 6.5 mg and a total maximum dose of 546 mg over a 12-week period. The pharmaceutical form is a pessary, and it is manufactured by ENDOCEUTICS S.A. The medication is classified as a biosynthetic product.

The trial also includes the use of **Gynoflor vaginal tablets**, which contain a combination of **estriol** and **lactobacillus acidophilus, lyophilized**. These tablets are administered vaginally, with a maximum daily dose of 900 mg and a total maximum dose of 28,800 mg over a 12-week period. The product is manufactured by GEDEON RICHTER PLC and is classified as a biosynthetic product. The administration route is vaginal, and the formulation is designed to support the vaginal microbiome alongside hormonal treatment.

All medications in the trial are administered via the vaginal route, and participant compliance is monitored throughout the study. The trial aims to assess the efficacy and safety of these treatments in patients with vulvovaginal atrophy, particularly those undergoing endocrine therapy for breast cancer. The study does not include any non-experimental treatments such as placebos or standard-of-care therapies, focusing solely on the experimental medications described.

The efficacy of the treatment regimens in the clinical trial for **vulvovaginal atrophy** in breast cancer patients on endocrine therapy will be assessed using patient-reported outcome measurements (PROMs) and clinical evaluations. The primary endpoint focuses on the efficacy of the treatment, which will be evaluated through two validated questionnaires: the EQ5D-questionnaire and the FACT-ES questionnaire. These assessments will occur at three specific time points: at the start of the trial, after 6 weeks, and at the end of the trial (after 12 weeks).

Clinical evaluations will include the measurement of vaginal pH and the vaginal maturation index, which involves a direct microscopic evaluation of the vaginal epithelium. These parameters will provide additional insights into the treatment's efficacy. The trial is designed to ensure a comprehensive assessment of the treatment's impact on the symptoms of vulvovaginal atrophy, with a structured schedule for data collection and analysis.