Clinical Study of Vaginal Lactobacilli and Estriol (Gynoflor®) for Atrophic Vaginitis in Breast Cancer Patients (Gynoflor)

A Clinical Study of Pharmacokinetics, Efficacy and Safety of Vaginal Application of Lyophilised Lactobacilli and 0.03 mg Estriol (Gynoflor®) on Atrophic Vaginitis in Postmenopausal Breast Cancer Patients Treated With Aromatase Inhibitors

The purpose of this study is to assess the long term safety and efficacy of the vaginal application of Gynoflor®, an extremely low dosed estrogen therapy with lactobacilli, on atrophic vaginitis in postmenopausal breast cancer patients who have been treated with aromatase inhibitors.

Study Overview

• Status: Completed
• Conditions: Atrophic Vaginitis
• Intervention / Treatment: Drug: Estriol 0.03 mg, lyophylized lactobacillus

Detailed Description

Two center phase I pharmacokinetic study assessed circulating estrogens in breast cancer patients on a non-steroidal aromatase inhibitor (NSAI) with vaginal atrophy using vaginal ultra-low-dose 0.03 mg estriol (E3) and Lactobacillus combination vaginal tablets (Gynoflor). 16 women on nonsteroidal aromatase inhibitor with severe vaginal atrophy applied a daily vaginal tablet of Gynoflor for 28 days followed by a maintenance therapy of 3 tablets weekly for 8 weeks.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium
    • University Hospital Leuven
• Germany
  • Regensburg, Germany
    • Department of Obstetrics and Gynaecology, University of Regensburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 52 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with breast cancer on non-steroidal AI therapy (AI therapy start at least 6 months ago, and are scheduled to receive them during the study)
2. Postmenopausal and age ≥52 with cessation of menses for at least 12 months
3. Age 52 - 75 years
4. Clinical symptoms of vaginal atrophy
5. Vaginal pH > 5.0
6. Karnofsky score ≥80%
7. Signed Informed Consent Form together with contractual capability

Exclusion Criteria:

1. Local or systemic use of any other sexual hormones (estrogens, progestins, androgens), 6 months before and during study
2. Local or systemic use of phytoestrogens or products known for or taken to improve vaginal mucosal function, risk of vaginal infections, or vulvovaginal symptoms, 4 weeks before and during study
3. Local or systemic use of any other anti-infectives, 2 weeks before and during study
4. Use of any other vaginal medication, vaginal rinses and/or moisturizers, gels containing xylocain or other analgesic products to decrease pain during intercourse, 1 week before and during study
5. Known or suspected hypersensitivity or intolerance to the study medications, inclusive their excipients
6. Suspicion of or clinically manifest sexually transmitted infections (infections with Neisseria gonorrhoea, Chlamydia trachomatis, Treponema pallidum, genital herpes, Trichomonas vaginalis, genital condylomata, HIV)
7. Clinical evidence of vaginal infections requiring extra treatment
8. Any infections of the upper genital tract
9. Hysterectomy
10. Genital haemorrhage of unknown origin
11. Malignant or pre-cancerous conditions of the uterus, vulva and/or vagina (PAP smear less than 3 years ago)
12. Acute thrombophlebitis, thromboembolic disorders or a history of these disorders in association with previous use of oestrogen preparations
13. Abuse of alcohol or drugs
14. All chronic illnesses which could influence the absorption, distribution, biotransformation or elimination of the test preparation
15. Patient has a condition or is in a situation which, in the investigator's opinion, may put the patient in significant risk, may confound the study result, or may interfere significantly with the patient's participation in the study
16. BMI lower than 18.5 or higher than 30
17. Patient on steroidal AIs (aromasin)
18. Vulvo-dermatological conditions (like Lichen sclerosus, Lichen rubrus, Psoriasis)
19. Genital prolapses
20. Endometriosis
21. Use of antibiotics or chemotherapeuticals which are harmful to lactobacilli
22. Participation of patient in another investigational drug study, with the exception of treatment optimisation studies with non-steroidal aromatase inhibitors (AI)s
23. Previous participation in this study
24. Patient is a relative of, or staff directly reporting to the investigator
25. Patient is an employee of the sponsor

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Gynoflor; Gynoflor vaginal tablets 1/day x 4 weeks, then 3/week for 8 weeks	Drug: Estriol 0.03 mg, lyophylized lactobacillus; Vaginal tablet with lyophilised lactobacilli and 0.03 mg estriol; Once daily for 28 days then 3 times per week for 8 weeks; Other Names: Gynoflor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Concentrations of Estriol (E3)	Estrogens were analyzed using a highly sensitive gas chromatography-mass spectrometry (GC/MS) method. The lower limits of quantitation (LLOQ) were 10.00 pg/ml for E3, 1.The coefficient of variation (CV, intra-assay variation) was 2.0 % for E3 (calibration range (CR) 10.00-500.00 pg/). The lower limits of quantitation (LLOQ) were 1.00 pg/ml for E2, and 2.00 pg/ml for E1.The coefficient of variation (CV, intra-assay variation) was 4.2 % for E2 (CR 1.00-150.00 pg/ml), and 3.4 % for E1 (CR 2.00-300.00 pg/ml).	-0.5, 0.5, 1, 2, 3, 4, 6, 8, 24 hours on days 0 and 28
Calculation of Pharmacokinetic Parameters Estriol: Cmax	Cmax is the highest measured concentration	Days 0 and 28
Calculation of Pharmacokinetic Parameters Estriol: Tmax	Tmax is the peak time at which the Cmax (maximum concentration) was measured	Days 0 and 28
Calculation of Pharmacokinetic Parameters Estriol: Area Under the Curve (AUC)	Area under the curve from administration to the last measured concentration (AUC0-24)	Days 0 and 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline / Trough Serum Concentrations of Estriol		Days 0, 14, 28, 56 and 84
Vaginal pH	The normal vaginal pH is 3.8-5.0 pH is a logarithmic scale used to specify the acidity or basicity of aqueous solutions. The scale has values ranging from zero (the most acidic) to 14 (the most basic). Pure water has a pH value of 7. This value is considered neutral-neither acidic or basic.	at all visits during 12 weeks
Baseline / Trough Serum Concentrations of Luteinizing Hormone (LH)		Days 0, 14, 28, 56 and 84
Baseline / Trough Serum Concentrations of Sex Hormone Binding Globulin (SHBG)		Days 0, 14, 28, 56 and 84
Baseline / Trough Serum Concentrations of Follicule Stimulating Hormone (FSH)		Days 0, 14, 28, 56 and 84

Collaborators and Investigators

• Sponsor: Medinova AG
• Investigators: Principal Investigator: Patrick Neven, Prof. Dr., University Hospital Leuven, Belgium; Principal Investigator: Stefan Buchholz, PD Dr., Department of Obstetrics and Gynaecology, University of Regensburg, Germany; Principal Investigator: Gilbert Donders, Prof. Dr., Femicare, University Hospital, Leuven, Belgium

Publications and helpful links

General Publications

• Donders G, Neven P, Moegele M, Lintermans A, Bellen G, Prasauskas V, Grob P, Ortmann O, Buchholz S. Ultra-low-dose estriol and Lactobacillus acidophilus vaginal tablets (Gynoflor((R))) for vaginal atrophy in postmenopausal breast cancer patients on aromatase inhibitors: pharmacokinetic, safety, and efficacy phase I clinical study. Breast Cancer Res Treat. 2014 Jun;145(2):371-9. doi: 10.1007/s10549-014-2930-x. Epub 2014 Apr 10.
• Buchholz S, Mogele M, Lintermans A, Bellen G, Prasauskas V, Ortmann O, Grob P, Neven P, Donders G. Vaginal estriol-lactobacilli combination and quality of life in endocrine-treated breast cancer. Climacteric. 2015 Apr;18(2):252-9. doi: 10.3109/13697137.2014.991301. Epub 2015 Jan 20.
• Donders G, Bellen G, Neven P, Grob P, Prasauskas V, Buchholz S, Ortmann O. Effect of ultra-low-dose estriol and lactobacilli vaginal tablets (Gynoflor(R)) on inflammatory and infectious markers of the vaginal ecosystem in postmenopausal women with breast cancer on aromatase inhibitors. Eur J Clin Microbiol Infect Dis. 2015 Oct;34(10):2023-8. doi: 10.1007/s10096-015-2447-1. Epub 2015 Jul 30.

Helpful Links

• Publication of main results

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: May 10, 2011
• First Submitted That Met QC Criteria: June 8, 2011
• First Posted (Estimated): June 10, 2011

Study Record Updates

• Last Update Posted (Actual): October 15, 2024
• Last Update Submitted That Met QC Criteria: October 10, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathological Conditions, Anatomical; Vaginal Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Vaginitis; Atrophic Vaginitis; Atrophy
• Other Study ID Numbers: 806109