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

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.

• Estriol 0.400 mg/day and Trimegestone 0.06 mg/day (Drug): Vaginal ring with a nominal delivery rate of 0.400 mg/d estriol (E3) and 0.06 mg/d trimegestone (TMG), vaginal application
• Estriol 0.300 mg/day and Trimegestone 0.12 mg/day (Drug): Vaginal ring with a nominal delivery rate of 0.300 mg/d estriol (E3) and 0.12 mg/d trimegestone (TMG), vaginal application
• Estriol 0.200 mg/day and Trimegestone 0.18 mg/day (Drug): Vaginal ring with a nominal delivery rate of 0.200 mg/d estriol (E3) and 0.18 mg/d trimegestone (TMG), vaginal application

Primary outcomes

• Measurement of E2 and PG plasma levels [0 - 41 days]: Blood sampling for the determination of plasma levels of E2 and PG, in participants of each treatment group, as surrogate variables for treatment response.
• Measurement of E3 and TMG plasma levels [0 - 23 days]: Blood sampling for the determination of plasma levels of E3 and TMG, in participants of each treatment group.

Secondary outcomes

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

Sex: Female, ages: 18 Years to 35 Years, accepts healthy volunteers

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

• Gilberto De Nucci, MD, Principal investigator, Galeno Desenvolvimento de Pesquisas Clinicas Ltda. - ME