E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
In postmenopausal hormone receptor positive breast cancer, treatment with aromatase inhibitors is the most effective and well-studied therapy. Lack of adherence is common due to the side-effects; vaginal dryness and vaginal atrophy. The study will explore the safety of 0.005% estriol vaginal gel in the oncological context, to demostrate that the gel is a safe option to treat the vaginal atrophy caused by AIs, without a significant decline in gonadotropin or increase in systemic estrogen levels |
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E.1.1.1 | Medical condition in easily understood language |
Postmenopausal woman with breast cancer are treated with aromatase inhibitors. The problem is that causes many vaginal adverse events that may be treated safely with 0.005% estriol vaginal gel |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the levels of FSH after treatment with 0.005% estriol vaginal gel in hormone receptor-positive postmenopausal women with early stage breast cancer in treatment with NSAIs in the adjuvant setting and symptoms of vaginal atrophy |
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E.2.2 | Secondary objectives of the trial |
To evaluate the levels of estriol, estradiol, estrone, FSH and LH after treatment with 0.005% estriol vaginal gel in hormone receptor-positive postmenopausal women with early stage breast cancer in treatment with NSAIs in the adjuvant setting and symptoms of vaginal atrophy. To assess the safety and tolerability of 0.005% estriol vaginal gel in hormone receptor-positive postmenopausal women with early stage breast cancer in treatment with NSAIs in the adjuvant setting and symptoms of vaginal atrophy. To assess the efficacy of 0.005% estriol vaginal gel in the treatment of symptoms and signs of vaginal atrophy in hormone receptor-positive postmenopausal women with early stage breast cancer in treatment with NSAIs and symptoms of vaginal atrophy. To measure the impact of treatment with 0.005% estriol vaginal gel in sexual function of hormone receptor-positive postmenopausal women with early stage breast cancer in treatment with NSAIs and symptoms of vaginal atrophy |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent prior to beginning specific protocol procedures. 2. Patients must have histological confirmation of breast adenocarcinoma with stage I-IIIA, documented at a local pathology department. 3. The breast tumors must be estrogen-receptor positive and/or progesterone receptor positive (≥1% of stained tumor cells by IHC as determined by the local laboratory) with any HER2 status. 4. Postmenopausal status defined as: 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/ml or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy. 5. Patient must be receiving the non-steroidal aromatase inhibitors anastrozole or letrozole as breast cancer treatment in the adjuvant setting for a minimum of 6 months. 6. Women suffering from moderate to severe vaginal dryness according to the FDA guidelines for drug development in postmenopausal women (Center for Drug Evaluation and Research, CDER Jan 2003). A moderate symptom will be considered if the symptom is present, bothersome and annoying, and a severe symptom will be considered if the symptom is present, bothersome and annoying, and interferes with the normal patient activity. 7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. 8. Adequate bone marrow as defined by the following laboratory values: a. Absolute Neutrophil Count (ANC) ≥1.5 x 109/L. b. Platelets (plt) ≥100 x 109/L. c. Hemoglobin (Hgb) ≥ 10 g/dl. 9. Patient has adequate organ function as defined by the following laboratory values: d. Serum creatinine ≤ 1.5 x ULN. e. Bilirubin ≤ 1.5 × ULN. f. Alkaline phosphatase ≤ 2 × ULN. g. AST and ALT ≤ 2 × ULN. 10. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures. |
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E.4 | Principal exclusion criteria |
1. Stage IIIB-IV breast cancer or bilateral breast cancer. 2. Treatment with any other current anti-tumoral therapy (chemotherapy, anti-Her2?etc) besides the NSAI. Pamidronate or Alendronate are permitted. 3. Prior history of other malignancy within 5 years of study entry, aside from non-melanoma skin cancer or carcinoma-in-situ of the uterine cervix adequately treated. 4. Postmenopausal uterine bleeding. Vaginal bleeding of unknown etiology. 5. Patients with endometrial thickness equal to or greater than 4 mm 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. Use of any hormone, natural (phytoestrogens) or herbal products for the treatment of menopausal symptoms within the last 6 months. 8. Current or previous history of thromboembolic disease or coagulopathies. 9. Severe cardiovascular or respiratory diseases in the previous 6 months. 10. Renal Impairment. 11. Hepatitis B and/or hepatitis C carriers (unless with normal hepatic function). 12. Known human immunodeficiency virus infection. 13. Known hypersensitivity to NSAI. 14. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study. 15. Previous investigational treatment for any condition or participation in any clinical trial within 4 weeks of inclusion date. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Variation in serum levels of FSH from baseline to 12 weeks of treatment. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Variation in serum levels of FSH at different time points compared to baseline (weeks 1, 3 and 8). Variation in serum levels of LH and plasma levels of estriol, estradiol and estrone, at different time points compared to baseline (weeks 1, 3, 8 and 12). AEs according to the Medical Dictionary for Regulatory Activities (MedDRA) Changes in vaginal dryness and other symptoms and signs of vaginal atrophy; changes in vaginal maturation value and changes in vaginal pH at week 3 and week 12 vs baseline. Changes in sexual function measured by the Female Sexual Function Index (FSFI ) scale at week 3 and week 12 vs baseline. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Weeks 1, 3, 8, 12 of treatment |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 11 |