Clinical trial NCT03363997: Pharmacokinetics and Pharmacodynamics of 3 Dosages of Estriol After Continuous Vaginal Administration for 21 Days
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Menopause
Keywords: estriol
pharmacokinetic
pharmacodynamic
hormone replacement therapy
vaginal ring administration
Lead sponsor: Galeno Desenvolvimento de Pesquisas Clínicas
Sponsor class: OTHER_GOV
Collaborators: name: SocraTec R&D GmbH
First posted: 2017-12-06
Enrollment: 31
Sex: FEMALE
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Measurement of estriol plasma levels
timeFrame: 0-22 days
Secondary outcomes:
measure: Maximum Plasma Concentration (Cmax) of estriol
timeFrame: 0-22 days
measure: Area Under the Curve (AUC) for estriol
timeFrame: 0-22 days
measure: Characterisation of follicle stimulating hormone (FSH)
timeFrame: 0-22 days
measure: Characterisation of luteinising hormone (LH)
timeFrame: 0-22 days
measure: Characterisation of sex hormone binding globulin (SHBG)
timeFrame: 0-22 days
measure: Characterisation of cytology of vaginal smear
timeFrame: 0-22 days
measure: Calculation of maturation index
timeFrame: 0-22 days
measure: Determination of vaginal pH
timeFrame: 0-22 days
measure: Number of adverse events per participant
timeFrame: up to 22days after treatment
Other outcomes:
Locations:
city: Campinas
country: Brazil
facility: Galeno Desenvolvimento de Pesquisas Clinicas Ltda. - ME
state: SP
Study officials:
affiliation: Galeno Desenvolvimento de Pesquisas Clinicas Ltda
name: Gilberto De Nucci, MD
role: PRINCIPAL_INVESTIGATOR
References: