Estriol and Trimegestone Dose-response Trial With Single Dose Application of Vaginal Rings

Study Overview
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Brief Summary
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This clinical trial is performed as proof of pharmacological action investigation by demonstration of ovulation inhibition (dose-response study) under treatment with three Test vaginal rings releasing varying doses of estriol (E3) and trimegestone (TMG). Blood samples for determination of estradiol (E2) and progesterone (PG) levels will serve as pharmacodynamic surrogate parameters for characterization of the treatment effect on the endogenous hormones. Blood samples for determination of E3 and TMG in plasma will be collected in order to characterize pharmacokinetic parameters. Additionally, local tolerability characterized by gynecological inspection of the vaginal mucosa prior to and after insertion of the Investigational Medicinal Product (IMPs) is planned to be assessed

Detailed Description
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The IMPs, releasing either 0.400 mg E3 and 0.06 mg TMG, or 0.300 mg E3 and 0.12 mg TMG, or 0.200 mg E3 and 0.18 mg TMG per 24 h, will be applied intravaginally and remain in the vagina for the subsequent 21 days (single dose, 1 treatment cycle). A total of 36 female subjects, 12 per treatment group, are intended to be randomized. Blood samples for determination of E2 and PG levels will be collected during treatment and until 20 days after removal of the ring. Blood samples for determination of E3 and TMG in plasma will be collected over the treatment period and until 48 h after removal of the ring. Bleeding intensity will also be documented during treatment and until 20 days after removal of the vaginal ring in a diary to characterize the effects of the different treatments.

Official Title
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Dose-response Study With Three Vaginal Rings With Different Doses of Estriol and Trimegestone: Effect on Progesterone and Estradiol Levels in Healthy Females With Childbearing Potential

Conditions
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Pregnancy

Intervention / Treatment
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* Drug: Estriol 0.400 mg/day and Trimegestone 0.06 mg/day
* Drug: Estriol 0.300 mg/day and Trimegestone 0.12 mg/day
* Drug: Estriol 0.200 mg/day and Trimegestone 0.18 mg/day


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Under treatment with a commercially available combined oral contraceptive containing 30 µg ethinylestradiol (EE) and 150 µg levonorgestrel (LVN) for the last 3 months prior to enrolment Body-mass index (BMI): ≥ 18.5 kg/m² and ≤ 30.0 kg/m² Good state of health Non-smoker, ex-smoker for at least 3 months Regular menstrual cycle with a length between 21 and 35 days Written informed consent, after having been informed about benefits and potential risks of the clinical trial Exclusion Criteria: Existing diseases or pathological findings, which might interfere with the safety or tolerability, and/or pharmacokinetics of the IMPs Subjects with severe allergies or multiple drug allergies Positive anti human immunodeficiency virus (anti-HIV) test, hepatitis B surface antigen (HBs-AG) test or anti hepatitis C virus (anti-HCV) test Presence or history of venous or arterial thrombosis, cerebrovascular accident, or increased risk of thrombosis Diabetes mellitus Unclarified vaginal bleeding or frequent infections of the urogenital tract Severe or chronic constipation Presence or history of migraine Drug or alcohol dependence Blood donation or other blood loss of more than 400 ml within the last 3 months Participation in a clinical trial during the last 6 months Pregnant or lactating women Subjects who do not agree to apply a barrier method for contraception

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single centre, open-label, randomized (assignment to treatment group), parallel-group, three-arm single-dose clinical trial with application performed over 1 treatment cycle of 21 days.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test 1 vaginal ring<br>Single intravaginal application of 1 vaginal ring of Estriol 0.400 mg/day and Trimegestone 0.06 mg/day (Test 1) over 21 days | Drug: Estriol 0.400 mg/day and Trimegestone 0.06 mg/day<br>* Vaginal ring with a nominal delivery rate of 0.400 mg/d estriol (E3) and 0.06 mg/d trimegestone (TMG), vaginal application<br>|
| Experimental: Test 2 vaginal ring<br>Single intravaginal application of 1 vaginal ring of Estriol 0.300 mg/day and Trimegestone 0.12 mg/day (Test 2) over 21 days | Drug: Estriol 0.300 mg/day and Trimegestone 0.12 mg/day<br>* Vaginal ring with a nominal delivery rate of 0.300 mg/d estriol (E3) and 0.12 mg/d trimegestone (TMG), vaginal application<br>|
| Experimental: Test 3 vaginal ring<br>Single intravaginal application of 1 vaginal ring of Estriol 0.200 mg/day and Trimegestone 0.18 mg/day (Test 3) over 21 days | Drug: Estriol 0.200 mg/day and Trimegestone 0.18 mg/day<br>* Vaginal ring with a nominal delivery rate of 0.200 mg/d estriol (E3) and 0.18 mg/d trimegestone (TMG), vaginal application<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of E2 and PG plasma levels | Blood sampling for the determination of plasma levels of E2 and PG, in participants of each treatment group, as surrogate variables for treatment response. | 0 - 41 days | 
| Measurement of E3 and TMG plasma levels | Blood sampling for the determination of plasma levels of E3 and TMG, in participants of each treatment group. | 0 - 23 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bleeding intensity | Bleeding intensity, graded as no bleeding, spotting or bleeding as recorded in diary by the subject on a daily basis | start of treatment until 42 days after treatment | 
| Number of adverse events per participant | Number of adverse events, in each treatment group, including clinically relevant alterations of vital signs and laboratory tests results | up to 42 days after treatment | 
| Maximum Plasma Concentration (Cmax) of E3 and TMG | Determination of Cmax for E3 and for TMG, based on plasma concentrations of samples obtained. | 0 - 23 days | 
| Area Under the Curve (AUC) for E3 and TMG | Calculation of the AUC for E3 and for TMG, based on plasma concentrations of samples obtained | 0 - 23 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Estriol, Trimegestone, Vaginal Ring