Atrophic Vaginitis
Conditions
Brief summary
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.
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.
Interventions
DRUGEstriol 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;
Sponsors
Medinova AG
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
52 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum Concentrations of Estriol (E3) | -0.5, 0.5, 1, 2, 3, 4, 6, 8, 24 hours on days 0 and 28 | 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). |
| Calculation of Pharmacokinetic Parameters Estriol: Cmax | Days 0 and 28 | Cmax is the highest measured concentration |
| Calculation of Pharmacokinetic Parameters Estriol: Tmax | Days 0 and 28 | Tmax is the peak time at which the Cmax (maximum concentration) was measured |
| Calculation of Pharmacokinetic Parameters Estriol: Area Under the Curve (AUC) | Days 0 and 28 | Area under the curve from administration to the last measured concentration (AUC0-24) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline / Trough Serum Concentrations of Estriol | Days 0, 14, 28, 56 and 84 | — |
| Baseline / Trough Serum Concentrations of Follicule Stimulating Hormone (FSH) | Days 0, 14, 28, 56 and 84 | — |
| Vaginal pH | at all visits during 12 weeks | 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. |
| 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 | — |
Countries
Belgium, Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Gynoflor Gynoflor vaginal tablet with lyophilised lactobacilli and 0.03 mg estriol: 1 x 28 days, then 3x per week x 8 weeks | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | Gynoflor |
|---|---|
| Age, Continuous | 57 years |
| Bacterial vaginosis (BV) score | 0.1 units on a scale STANDARD_DEVIATION 0.4 |
| Estriol | 104.5 pg/ml STANDARD_DEVIATION 40.9 |
| Follicule Stimulating Hormone (FSH) | 107.88 mIU/ml STANDARD_DEVIATION 48.62 |
| Lactobacillary grade (LBG) | 3.9 units on a scale STANDARD_DEVIATION 0.3 |
| Luteinizing hormone (LH) | 36.46 mIU/ml STANDARD_DEVIATION 11.05 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Region of Enrollment Belgium | 8 participants |
| Region of Enrollment Germany | 8 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 0 Participants |
| Sex hormone binding globulin (SHBG) | 73.04 nmol/l STANDARD_DEVIATION 29.66 |
| Vaginal maturation index (VMI) | 31.2 % STANDARD_DEVIATION 19.4 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 16 |
| other Total, other adverse events | 14 / 16 |
| serious Total, serious adverse events | 0 / 16 |
Outcome results
Primary
Calculation of Pharmacokinetic Parameters Estriol: Area Under the Curve (AUC)
Area under the curve from administration to the last measured concentration (AUC0-24)
Time frame: Days 0 and 28
Population: PP
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gynoflor | Calculation of Pharmacokinetic Parameters Estriol: Area Under the Curve (AUC) | AUC (0-24h) (Day 0) | 212 hours * pg/ml | Standard Deviation 93.2 |
| Gynoflor | Calculation of Pharmacokinetic Parameters Estriol: Area Under the Curve (AUC) | AUC (0-24h) (Day 28) | 130.7 hours * pg/ml | Standard Deviation 147.2 |
Primary
Calculation of Pharmacokinetic Parameters Estriol: Cmax
Cmax is the highest measured concentration
Time frame: Days 0 and 28
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gynoflor | Calculation of Pharmacokinetic Parameters Estriol: Cmax | Cmax (Day 0) | 104.5 pg/ml | Standard Deviation 40.9 |
| Gynoflor | Calculation of Pharmacokinetic Parameters Estriol: Cmax | Cmax (Day 28) | 15.8 pg/ml | Standard Deviation 13.9 |
Primary
Calculation of Pharmacokinetic Parameters Estriol: Tmax
Tmax is the peak time at which the Cmax (maximum concentration) was measured
Time frame: Days 0 and 28
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gynoflor | Calculation of Pharmacokinetic Parameters Estriol: Tmax | Tmax (Day 0) | 2.5 hours | Standard Deviation 0.5 |
| Gynoflor | Calculation of Pharmacokinetic Parameters Estriol: Tmax | Tmax (Day 28) | 7.2 hours | Standard Deviation 1.5 |
Primary
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).
Time frame: -0.5, 0.5, 1, 2, 3, 4, 6, 8, 24 hours on days 0 and 28
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Gynoflor | Serum Concentrations of Estriol (E3) | -0.5 h (Day 28) | 0.91 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | 3 h (Day 0) | 84.35 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | 3 h (Day 28) | 2.48 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | 24 h (Day 28) | 0.00 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | 24 h (Day 0) | 0.00 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | -0.5 h (Day 0) | 0 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | 0.5 h (Day 0) | 3.83 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | 0.5 h (Day 28) | 1.58 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | 1 h (Day 0) | 11.04 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | 1 h (Day 28) | 1.55 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | 2 h (Day 0) | 72.73 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | 2 h (Day 28) | 1.96 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | 4 h (Day 0) | 28.29 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | 4 h (Day 28) | 3.12 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | 6 h (Day 0) | 0.00 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | 6 h (Day 28) | 7.33 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | 8 h (Day 0) | 0.00 pg/ml |
| Gynoflor | Serum Concentrations of Estriol (E3) | 8 h (Day 28) | 10.23 pg/ml |
Secondary
Baseline / Trough Serum Concentrations of Estriol
Time frame: Days 0, 14, 28, 56 and 84
Population: PP
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gynoflor | Baseline / Trough Serum Concentrations of Estriol | Estriol (Day 0) | 0.00 pg/ml | Standard Deviation 0 |
| Gynoflor | Baseline / Trough Serum Concentrations of Estriol | Estriol (Day 14) | 5.11 pg/ml | Standard Deviation 14.01 |
| Gynoflor | Baseline / Trough Serum Concentrations of Estriol | Estriol (Day 28) | 0.91 pg/ml | Standard Deviation 3.63 |
| Gynoflor | Baseline / Trough Serum Concentrations of Estriol | Estriol (Day 56) | 0.00 pg/ml | Standard Deviation 0 |
| Gynoflor | Baseline / Trough Serum Concentrations of Estriol | Estriol (Day 84) | 0.00 pg/ml | Standard Deviation 0 |
Secondary
Baseline / Trough Serum Concentrations of Follicule Stimulating Hormone (FSH)
Time frame: Days 0, 14, 28, 56 and 84
Population: PP
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gynoflor | Baseline / Trough Serum Concentrations of Follicule Stimulating Hormone (FSH) | FSH (Day 0) | 107.88 mIU/ml | Standard Deviation 48.62 |
| Gynoflor | Baseline / Trough Serum Concentrations of Follicule Stimulating Hormone (FSH) | FSH (Day 14) | 103.71 mIU/ml | Standard Deviation 39.76 |
| Gynoflor | Baseline / Trough Serum Concentrations of Follicule Stimulating Hormone (FSH) | FSH (Day 28) | 98.94 mIU/ml | Standard Deviation 34.95 |
| Gynoflor | Baseline / Trough Serum Concentrations of Follicule Stimulating Hormone (FSH) | FSH (Day 56) | 103.55 mIU/ml | Standard Deviation 37.53 |
| Gynoflor | Baseline / Trough Serum Concentrations of Follicule Stimulating Hormone (FSH) | FSH (Day 84) | 105.93 mIU/ml | Standard Deviation 43.69 |
Secondary
Baseline / Trough Serum Concentrations of Luteinizing Hormone (LH)
Time frame: Days 0, 14, 28, 56 and 84
Population: PP
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gynoflor | Baseline / Trough Serum Concentrations of Luteinizing Hormone (LH) | LH (Day 56) | 34.2 mIU/ml | Standard Deviation 49.87 |
| Gynoflor | Baseline / Trough Serum Concentrations of Luteinizing Hormone (LH) | LH (Day 0) | 36.46 mIU/ml | Standard Deviation 11.05 |
| Gynoflor | Baseline / Trough Serum Concentrations of Luteinizing Hormone (LH) | LH (Day 14) | 34.52 mIU/ml | Standard Deviation 12.18 |
| Gynoflor | Baseline / Trough Serum Concentrations of Luteinizing Hormone (LH) | LH (Day 28) | 34.02 mIU/ml | Standard Deviation 12.68 |
| Gynoflor | Baseline / Trough Serum Concentrations of Luteinizing Hormone (LH) | LH (Day 84) | 35.13 mIU/ml | Standard Deviation 10.34 |
Secondary
Baseline / Trough Serum Concentrations of Sex Hormone Binding Globulin (SHBG)
Time frame: Days 0, 14, 28, 56 and 84
Population: PP
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gynoflor | Baseline / Trough Serum Concentrations of Sex Hormone Binding Globulin (SHBG) | SHBG (Day 0) | 73.04 nmol/ml | Standard Deviation 29.66 |
| Gynoflor | Baseline / Trough Serum Concentrations of Sex Hormone Binding Globulin (SHBG) | SHBG (Day 14) | 74.24 nmol/ml | Standard Deviation 35.35 |
| Gynoflor | Baseline / Trough Serum Concentrations of Sex Hormone Binding Globulin (SHBG) | SHBG (Day 28) | 71.29 nmol/ml | Standard Deviation 31.88 |
| Gynoflor | Baseline / Trough Serum Concentrations of Sex Hormone Binding Globulin (SHBG) | SHBG (Day 56) | 73.35 nmol/ml | Standard Deviation 32.76 |
| Gynoflor | Baseline / Trough Serum Concentrations of Sex Hormone Binding Globulin (SHBG) | SHBG (Day 84) | 72.43 nmol/ml | Standard Deviation 34.57 |
Secondary
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.
Time frame: at all visits during 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gynoflor | Vaginal pH | C1 (Day 14) | 4.6 pH | Standard Deviation 0.5 |
| Gynoflor | Vaginal pH | C2 (Day 28) | 4.4 pH | Standard Deviation 0.4 |
| Gynoflor | Vaginal pH | C3 (Day 56) | 4.6 pH | Standard Deviation 0.5 |
| Gynoflor | Vaginal pH | C4 (Day 84) | 4.5 pH | Standard Deviation 0.5 |
| Gynoflor | Vaginal pH | Entry (Day 0) | 6.0 pH | Standard Deviation 0.3 |