Pharmacokinetics and Pharmacodynamics of 3 Dosages of Estriol After Continuous Vaginal Administration for 21 Days

Study Overview
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Brief Summary
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This clinical trial evaluated the pharmacokinetics and pharmacodynamics of estriol in healthy post-menopausal women after the application of one vaginal ring containing one of three different dosages of estriol (100 mg (Test 1), 300 mg (Test 2) or 600 mg (Test 3)) with continuous delivery (0.125, 0.250 or 0.500 mg/day) for 21 days. And also, characterized its safety and tolerability.

Detailed Description
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This phase I, single center, open-label, randomised (allocation to treatment), balanced, single dose trial was performed in a parallel-group design. The subjects were randomly assigned to one of the 3 possible treatments (single vaginal application of 1 vaginal ring containing 100, 300 or 600 mg estriol, with delivery rate of 0.125, 0.250 or 0.500 mg/day over 21 days. Blood samples were collected at 0.5 h prior to drug application, 1, 2, 4, 6, 12, 24, 48, 96, 144, 216, 288, 360, 432 h after application; 5 min prior to removal, i.e., 21 d after application (study day 22), as well as 6, 12 and 24 h after removal to characterise pharmacokinetic parameters of estriol in plasma. Serum concentrations of follicle stimulating hormone (FSH), luteinising hormone (LH) and sex hormone binding globulin (SHBG) and gynaecological parameters (cytology of vaginal smear, the maturation index and the vaginal pH) were evaluated as pharmacodynamic parameters. The safety and tolerability was assessed by endometrial thickness and documentation of adverse events.

Official Title
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A Randomized, Open-label Trial to Evaluate the Pharmacokinetics and Pharmacodynamics of 3 Dosages of Estriol After Continuous Vaginal Administration for 21 Days in Healthy, Post-menopausal Women

Conditions
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Menopause

Intervention / Treatment
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* Drug: Estriol 0.125 mg/day
* Drug: Estriol 0.250 mg/day
* Drug: Estriol 0.500 mg/day


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body-mass index (BMI) ≥18.5 kg/m² and ≤ 30.0 kg/m² Postmenopausal state: FSH (plasma) ≥ 40 IU/l, estradiol (serum) ≤ 20 pg/ml last spontaneous menstruation at least 12 months ago Normal transvaginal endometrial scan (endometrial thickness < 5 mm) Good state of health Non-smoker or ex-smoker for at least 6 month Written informed consent, after having been informed about benefits and potential risks of the clinical trial, as well as details of the insurance taken out to cover the subjects participating in the clinical trial Exclusion Criteria: Existing cardiac, hepatic and/or haematological diseases or pathological findings, which might interfere with the safety or tolerability and/or pharmacokinetics and/or pharmacodynamics of the active ingredient History of relevant central nervous system (CNS) and/or psychiatric disorders and/or currently treated CNS and/or psychiatric disorders Known allergic reactions to the active ingredients used or to constituents of the pharmaceutical preparations Subjects with severe allergies or multiple drug allergies, unless it is judged as not relevant for the clinical trial by the investigator Positive anti-HIV-test (if positive to be verified by western blot), HBs-AG-test (if positive to be verified by test for HBc-IgM) or anti-HCV-test Presence or history of venous or arterial thrombosis (e.g. deep venous thrombosis, pulmonary embolism) Known, past or suspected breast cancer or increased familiar risk for development Known or suspected estrogen-dependent malignant tumours (e.g. endometrial or breast cancer) Undiagnosed genital bleeding Acute vaginal infection or other diseases prohibiting the placement of vaginal ring History of endometrial hyperplasia Migraine or frequent episodes of severe headache History of or current drug or alcohol dependence Subjects who are on a diet which could affect the pharmacokinetics of the active ingredient Regular intake of caffeine containing food or beverages of ≥ 500 mg caffeine per day Blood donation or other blood loss of more than 400 ml within the last 3 months prior to individual enrolment of the subject Participation in a clinical trial during the last 6 months prior to individual enrolment of the subject Concomitant systemic therapy with antibiotics, which might interfere with enterohepatic recirculation (e.g. cephalosporines, neomycin, ampicillin or tetracyclines) Use of sex hormones within 6 months (oral, transdermal, vaginal) or 8 months (intramuscular administered depot preparations used once per month) or 12 months (intramuscular administered depot preparations used once per 3 months) before screening Use of systemic or topical medications or substances which oppose the study objectives or which might influence them within 8 weeks before screening examination Subjects who are unable to understand the written and verbal instructions, in particular regarding the risks and inconveniences they will be exposed to during their participation in the clinical trial

Ages Eligible for Study
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Minimum Age: 45 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test 1 vaginal ring<br>Single vaginal application of 1 vaginal ring containing 100 mg estriol, with delivery rate of 0.125 mg/day over 21 days | Drug: Estriol 0.125 mg/day<br>* Application of one vaginal ring<br>|
| Experimental: Test 2 vaginal ring<br>Single vaginal application of 1 vaginal ring containing 300 mg estriol, with delivery rate of 0.250 mg/day over 21 days | Drug: Estriol 0.250 mg/day<br>* Application of one vaginal ring<br>|
| Experimental: Test 3 vaginal ring<br>Single vaginal application of 1 vaginal ring containing 600 mg estriol, with delivery rate of 0.500 mg/day over 21 days | Drug: Estriol 0.500 mg/day<br>* Application of one vaginal ring<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of estriol plasma levels | Blood sampling for the determination of plasma levels of estriol in participants of each treatment group. | 0-22 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of estriol | Determination of Cmax for estriol based on plasma concentrations of samples obtained. | 0-22 days | 
| Area Under the Curve (AUC) for estriol | Calculation of the AUC for estriol based on plasma concentrations of samples obtained. | 0-22 days | 
| Characterisation of follicle stimulating hormone (FSH) | Determination of serum concentrations of FSH under the three treatments | 0-22 days | 
| Characterisation of luteinising hormone (LH) | Determination of serum concentrations of LH under the three treatments | 0-22 days | 
| Characterisation of sex hormone binding globulin (SHBG) | Determination of serum concentrations of SHBG under the three treatments | 0-22 days | 
| Characterisation of cytology of vaginal smear | Characterisation of cytology of vaginal smear (parabasal, intermediate and superficial cells) under the three treatments | 0-22 days | 
| Calculation of maturation index | Calculation of maturation index under the three treatments | 0-22 days | 
| Determination of vaginal pH | Determination of vaginal pH under the three treatments | 0-22 days | 
| 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 22days after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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estriol, pharmacokinetic, pharmacodynamic, hormone replacement therapy, vaginal ring administration