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

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

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.

Study Overview

• Status: Completed
• Conditions: Menopause
• Intervention / Treatment: Drug: Estriol 0.125 mg/day; Drug: Estriol 0.250 mg/day; Drug: Estriol 0.500 mg/day

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.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Contacts and Locations

Study Locations

• Brazil
  • SP
    • Campinas, SP, Brazil
      • Galeno Desenvolvimento de Pesquisas Clinicas Ltda. - ME

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Test 1 vaginal ring; 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; Application of one vaginal ring
EXPERIMENTAL: Test 2 vaginal ring; 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; Application of one vaginal ring
EXPERIMENTAL: Test 3 vaginal ring; 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; Application of one vaginal ring

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Galeno Desenvolvimento de Pesquisas Clínicas
• Collaborators: SocraTec R&D GmbH
• Investigators: Principal Investigator: Gilberto De Nucci, MD, Galeno Desenvolvimento de Pesquisas Clinicas Ltda

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 23, 2016
• Primary Completion (ACTUAL): December 15, 2016
• Study Completion (ACTUAL): June 6, 2017

Study Registration Dates

• First Submitted: November 27, 2017
• First Submitted That Met QC Criteria: November 30, 2017
• First Posted (ACTUAL): December 6, 2017

Study Record Updates

• Last Update Posted (ACTUAL): December 6, 2017
• Last Update Submitted That Met QC Criteria: November 30, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: pharmacokinetic; pharmacodynamic; hormone replacement therapy; estriol; vaginal ring administration
• Other Study ID Numbers: GDN 005/16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No