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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03363997
Recruitment Status : Completed
First Posted : December 6, 2017
Last Update Posted : December 6, 2017
Sponsor:
Collaborator:
SocraTec R&D GmbH
Information provided by (Responsible Party):
Gilberto De Nucci, Galeno Desenvolvimento de Pesquisas Clínicas

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.

Condition or disease Intervention/treatment Phase
Menopause Drug: Estriol 0.125 mg/day Drug: Estriol 0.250 mg/day Drug: Estriol 0.500 mg/day Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 31 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : September 23, 2016
Actual Primary Completion Date : December 15, 2016
Actual Study Completion Date : June 6, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Menopause
Drug Information available for: Estriol

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




Primary Outcome Measures :
  1. Measurement of estriol plasma levels [ Time Frame: 0-22 days ]
    Blood sampling for the determination of plasma levels of estriol in participants of each treatment group.


Secondary Outcome Measures :
  1. Maximum Plasma Concentration (Cmax) of estriol [ Time Frame: 0-22 days ]
    Determination of Cmax for estriol based on plasma concentrations of samples obtained.

  2. Area Under the Curve (AUC) for estriol [ Time Frame: 0-22 days ]
    Calculation of the AUC for estriol based on plasma concentrations of samples obtained.

  3. Characterisation of follicle stimulating hormone (FSH) [ Time Frame: 0-22 days ]
    Determination of serum concentrations of FSH under the three treatments

  4. Characterisation of luteinising hormone (LH) [ Time Frame: 0-22 days ]
    Determination of serum concentrations of LH under the three treatments

  5. Characterisation of sex hormone binding globulin (SHBG) [ Time Frame: 0-22 days ]
    Determination of serum concentrations of SHBG under the three treatments

  6. Characterisation of cytology of vaginal smear [ Time Frame: 0-22 days ]
    Characterisation of cytology of vaginal smear (parabasal, intermediate and superficial cells) under the three treatments

  7. Calculation of maturation index [ Time Frame: 0-22 days ]
    Calculation of maturation index under the three treatments

  8. Determination of vaginal pH [ Time Frame: 0-22 days ]
    Determination of vaginal pH under the three treatments

  9. Number of adverse events per participant [ Time Frame: up to 22days after treatment ]
    Number of adverse events, in each treatment group, including clinically relevant alterations of vital signs and laboratory tests results.



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Ages Eligible for Study:   45 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03363997


Locations
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Brazil
Galeno Desenvolvimento de Pesquisas Clinicas Ltda. - ME
Campinas, SP, Brazil
Sponsors and Collaborators
Galeno Desenvolvimento de Pesquisas Clínicas
SocraTec R&D GmbH
Investigators
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Principal Investigator: Gilberto De Nucci, MD Galeno Desenvolvimento de Pesquisas Clinicas Ltda
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Responsible Party: Gilberto De Nucci, Doctor, Galeno Desenvolvimento de Pesquisas Clínicas
ClinicalTrials.gov Identifier: NCT03363997    
Other Study ID Numbers: GDN 005/16
First Posted: December 6, 2017    Key Record Dates
Last Update Posted: December 6, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Gilberto De Nucci, Galeno Desenvolvimento de Pesquisas Clínicas:
estriol
pharmacokinetic
pharmacodynamic
hormone replacement therapy
vaginal ring administration