Evaluation of the Performance and Safety of Hyalo Gyn® Gel Compared to Placebo in Postmenopausal Breast Cancer Survivors

A Prospective, Randomized, Controlled, 2-arms, Double-blind, Multicentre Clinical Investigation to Evaluate the Performance and Safety of Hyalo Gyn® Gel Compared to Placebo in the Management of Vulvovaginal Atrophy in Postmenopausal Breast Cancer Survivors

Eligible patients will be randomized to treatment with Hyalo Gyn® gel or placebo, at the dose regimen of 1 application deeply in the vagina every 3 days (i.e. an application is followed by 2 days without application), up to a total of 12 consecutive weeks.

After 12 weeks (i.e. at Visit 3), the following rules will apply for the second 12- week phase of the study:

• In case of resolution of the symptom (the dryness single score is equal to zero), the patient will suspend treatment and will undergo follow-up visits;
• In case of the single score is reduced but still greater than zero: the subject will receive Hyalo Gyn® open-label.
• In case the dryness gets worse the subject can choose whether receive Hyalo Gyn® gel open-label or undergo the follow-up visits. Patients will be allowed to use only water-based lubricants, not containing HA, hormones, or isoflavones, if necessary, only when engaging in sexual activity and specifying the reason for its use (multiple choice answer). The number of lubricant applications, as well as the frequency of the sexual activity, will be recorded weekly in the diary by the patient.

This will be a prospective, randomized, controlled, 2-arms, placebo-controlled, double-blind, multicentre clinical investigation. Patients with good compliance and who are voluntary to sign the informed consent will be enrolled in a period time of approximately 6 months. The screened and eligible patients will be randomly assigned in one of the two groups: Group A will receive Hyalo Gyn® and Group B will receive Placebo. Neither the Investigator nor the Patient will be aware of the assigned treatment.

Subjects of both groups will start the treatment with 1 application of Hyalo Gyn® gel or placebo gel, deeply in the vagina every 3 days (i.e. an application is followed by 2 days without application) up to a total of 12 consecutive weeks.

After 12 weeks (i.e. at Visit 3), according to the status of dryness symptom, measured with the VRS dryness score from baseline to 12 weeks, patients will undergo different procedures for the second phase of the study as reported in the brief summary.

Visits at the investigational site will be performed at screening/baseline (V0, Week 0) and every 4 weeks, alternated to telephone contacts by the clinician (V1, Week 4; T1, Week 6; V2, Week 8; T2, Week 10; V3, Week 12) up to the end of the first 12-week phase of the study. Two phone follow-up visits will be performed at Week 16 (T3) and Week 20 (T4), followed by a visit at the investigational site at the end of the second 12-week phase of the study (V4, Week 24). Visit 4 (Week 24) will represent the end of study visit. In case of premature withdrawal from the investigation for whatever reason an "Early termination Visit" will be performed, which will include all assessments foreseen for the final visit (Visit 4, Week 24 ± 5 days).

Inclusion Criteria:

1. Written informed consent prior to beginning specific protocol procedures;
2. Women between 25 and 80 years of age (inclusive);
3. Women with intention or willingness to have sex;
4. Patients with a history of breast cancer who had completed primary cancer treatment (surgery, non-endocrine chemotherapy, or radiation therapy) 3-60 months prior to enrolment;
5. Patient receiving endocrine therapy (an AI or tamoxifen or a GnRH analogue) as a breast cancer treatment in the adjuvant setting for a minimum of 3 months. The therapy program must cover the entire duration of the study (24 weeks);
6. Life expectancy of at least 12 months;
7. Postmenopausal status defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/ml or 6 weeks' postsurgical bilateral oophorectomy with or without hysterectomy;
8. Vulvovaginal dryness assessed as moderate to severe. A moderate and severe symptom (i.e. a score of 2 = moderate or 3 = severe) will be considered if the symptoms are present and could be bothersome and could interfere with the normal patient activity;
9. Vaginal Health Index ≤15;
10. Vaginal pH ≥5;
11. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1;
12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;
13. Patients legally able to give written informed consent to the trial (signed and dated by the participant) and able to understand study procedures and protocol requirements.

Exclusion Criteria:

1. Stage IIIB-IV breast cancer;
2. Treatment with any other current anti-tumoral therapy besides an AI or tamoxifen or a GnRH analogue;
3. Prior history of other malignancy other to breast cancer within 5 years of study entry, with the exception of non-melanoma skin cancer or carcinoma in-situ of the uterine cervix adequately treated;
4. Postmenopausal uterine bleeding and/or vaginal bleeding of unknown aetiology;
5. Patients with endometrial thickness equal to or greater than 4 mm for patientson AI or GnRH analogue, or equal to or greater than 9 mm for patients on tamoxifen, measured by transvaginal ultrasound;
6. Patients who have received any type of vulvovaginal treatment in the 15 days prior to the start of the study;
7. Patients that present clinical signs of vaginal infections such as trichomonas, candida, and bacterial vaginosis (BV), confirmed with a vaginal swab;
8. Patients with a history of vulvovaginal contact allergy or with a diagnosis of vulvovaginal lichen;
9. Positive history of hypersensitivity to hyaluronic acid (HA) or to any component of the medical device;
10. Use of any hormone, or any products with phytoestrogenic activity (for instance resveratrol, flax seeds, hops, isoflavones as red clover and soy) for the treatment of menopausal symptoms in the previous month (cimicifuga extract and pollen are allowed);
11. Known human immunodeficiency virus infection;
12. Other severe acute or chronic medical condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with investigation participation or product administration and investigation's procedures, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this investigation;
13. Previous investigational treatment for any condition or participation in any clinical trial in the previous month before inclusion date