Drug-drug Interaction Between Rifampicin and Progestins/Ethinylestradiol and Midazolam

April 14, 2020 updated by: Bayer

Open-label, Randomized, Fixed Sequence Cross-over Study With Five Parallel Treatment Arms and Three Treatment Periods to Quantify the Drug-drug Interactions of Two Rifampicin Dose Strengths on Four Progestins and a Fixed Progestin-ethinylestradiol Combination Compared With Midazolam in Healthy Post-menopausal Women

Quantify the effect of a probe CYP3A4 inducer (Rifampicin) on the pharmacokinetics of levonorgestrel, norethindrone, desogestrel, dienogest, drospirenone,estradiol and midazolam

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

68

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
    • Baden-Württemberg
      • Mannheim, Baden-Württemberg, Germany, 68167
        • CRS Clinical-Research-Services Mannheim GmbH
    • Nordrhein-Westfalen
      • Mönchengladbach, Nordrhein-Westfalen, Germany, 41061
        • CRS Clinical-Research-Services Mönchengladbach GmbH

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

43 years to 68 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Healthy female subject based on a complete medical history, physical examination, ECG, and clinical laboratory tests
  • Age: 45 to 70 years (inclusive) at the first screening visit
  • Minimum body weight 50 kg with Body mass index (BMI) above or equal to 18.5 kg/m², and below or equal to 30 kg/m² at the first screening visit

  • Postmenopausal state, revealed indicated by either:

    • medical history, if applicable (natural menopause at least 12 months prior to first study drug administration, for women younger than 60 years confirmed by follicle stimulating hormone (FSH) >40 IU/L AND estradiol ≤ 20 pg/mL; or
    • surgical menopause by bilateral ovariectomy at least 3 months prior to first study drug administration)

Exclusion Criteria:

  • Relevant diseases within the last 4 weeks prior to the first study drug administration, i.e. any disease requiring treatment by a health-care provider
  • Febrile illness within 1 week before the first study drug administration
  • Known severe allergies, non-allergic drug reactions, or multiple drug allergies
  • Presence or history of thrombosis, thrombophlebitis, thromboembolic diseases of veins and/or arteries, e.g. deep vein thrombosis, stroke, myocardial infarction, pulmonary embolism, transient ischemic attack, angina pectoris
  • Presence or history of conditions that increase the risk of thromboembolic diseases, e.g. disturbances of the coagulation system, thromboembolic diseases in close relatives at age ≤50 years], valvular heart disease, atrial fibrillation, cardiac dysfunction)
  • Presence, history, or suspected presence of malignant tumors or tumors of the liver and pituitary
  • Presence or history of liver disease e.g. disturbances of the bilirubin excretion (Dubin-Johnson and Rotor syndromes), cholecystectomy ; cholestasis, idiopathic icterus or pruritus during a previous pregnancy or estrogen-progestogen treatment
  • Relevant kidney diseases or renal injury associated with multisystem diseases/disorders, e.g. glomerulonephritis systemic lupus erythematous, diabetic nephropathy. A history of a single episode of uncomplicated nephrolithiasis does not prevent participation
  • Known metabolic disorder, e.g. diabetes mellitus, severe hypertriglyceridemia
  • Migraine with neurologic symptoms
  • Clinically significant depression, current or in the last year
  • Known current thyroid disorders which require treatment. Subjects with an euthyroid struma who do not need any treatment can participate.
  • Chronic respiratory insufficiency
  • History of porphyria
  • Contraindications for midazolam, e.g. myasthenia gravis, and sleep apnea

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: levonorgestrel
levonorgestrel and midazolam will be administered on Day 1, Day 15 and Day 26. rifampicin (10 mg/day) will be administered on Day 8 to Day 18 and rifampicin (600 mg/day) on Day 19 to Day 29.
Drug: levonorgestrel/ Microlut
In Period 1, 0.03 mg single dose administered as 1x0.03 mg tablet on Study Day 1, In Period 2, 0.03 mg single dose administered as 1x0.03 mg tablet on Study Day 15 In Period 3, 0.03 mg single dose administered as 1x0.03 mg tablet at Study Day 26
Drug: Midazolam/ Midazolam-ratiopharm
In Period 1, 1 mg single dose administered as 1x0.5 ml oral solution on Study Day 1, In Period 2, 1 mg single dose administered as 1x0.5 ml oral solution on Study Day 15 In Period 3, 1 mg single dose administered as 1x0.5 ml oral solution at Study Day 26
Drug: Rifampicin
In period 2, 10 mg (suspension, 0.5 ml) for 11 days at 10 mg/day In period 3, 600 mg (film-coated tablets) for 11 days at 600 mg/day
Experimental: norethindrone
norethindrone and midazolam will be administered on Day 1, Day 15 and Day 26. rifampicin (10 mg/day) will be administered on Day 8 to Day 18 and rifampicin (600 mg/day) on Day 19 to Day 29.
Drug: Midazolam/ Midazolam-ratiopharm
In Period 1, 1 mg single dose administered as 1x0.5 ml oral solution on Study Day 1, In Period 2, 1 mg single dose administered as 1x0.5 ml oral solution on Study Day 15 In Period 3, 1 mg single dose administered as 1x0.5 ml oral solution at Study Day 26
Drug: Rifampicin
In period 2, 10 mg (suspension, 0.5 ml) for 11 days at 10 mg/day In period 3, 600 mg (film-coated tablets) for 11 days at 600 mg/day
Drug: Norethindrone/ Noriday
In Period 1, 0.35 mg single dose administered as 1x0.35 mg tablet on Study Day 1, In Period 2, 0.35 mg single dose administered as 1x0.35 mg tablet on Study Day 15 In Period 3, 0.35 mg single dose administered as 1x0.35 mg tablet at Study Day 26
Experimental: desogestrel
desogestrel and midazolam will be administered on Day 1, Day 15 and Day 26. rifampicin (10 mg/day) will be administered on Day 8 to Day 18 and rifampicin (600 mg/day) on Day 19 to Day 29.
Drug: Midazolam/ Midazolam-ratiopharm
In Period 1, 1 mg single dose administered as 1x0.5 ml oral solution on Study Day 1, In Period 2, 1 mg single dose administered as 1x0.5 ml oral solution on Study Day 15 In Period 3, 1 mg single dose administered as 1x0.5 ml oral solution at Study Day 26
Drug: Rifampicin
In period 2, 10 mg (suspension, 0.5 ml) for 11 days at 10 mg/day In period 3, 600 mg (film-coated tablets) for 11 days at 600 mg/day
Drug: Desogestrel/ Cerazette
In Period 1, 0.075 mg single dose administered as 1x0.075 mg tablet on Study Day 1, In Period 2, 0.075 mg single dose administered as 1x0.075 mg tablet on Study Day 15 In Period 3, 0.075 mg single dose administered as 1x0.075 mg tablet at Study Day 26
Experimental: dienogest
dienogest and midazolam will be administered on Day 1, Day 15 and Day 26. rifampicin (10 mg/day) will be administered on Day 8 to Day 18 and rifampicin (600 mg/day) on Day 19 to Day 29.
Drug: Midazolam/ Midazolam-ratiopharm
In Period 1, 1 mg single dose administered as 1x0.5 ml oral solution on Study Day 1, In Period 2, 1 mg single dose administered as 1x0.5 ml oral solution on Study Day 15 In Period 3, 1 mg single dose administered as 1x0.5 ml oral solution at Study Day 26
Drug: Rifampicin
In period 2, 10 mg (suspension, 0.5 ml) for 11 days at 10 mg/day In period 3, 600 mg (film-coated tablets) for 11 days at 600 mg/day
Drug: Dienogest/ Visanne
In Period 1, 2 mg single dose administered as 1x2 mg tablet on Study Day 1, In Period 2, 2 mg single dose administered as 1x2 mg tablet on Study Day 15 In Period 3, 2 mg single dose administered as 1x2 mg tablet at Study Day 26
Experimental: Drospirenone/ ethinylestradiol

drospirenone/ethinylestradiol and midazolam will be administered on Day 1, Day 15 and Day 26.

rifampicin (10 mg/day) will be administered on Day 8 to Day 18 and rifampicin (600 mg/day) on Day 19 to Day 29.
Drug: Midazolam/ Midazolam-ratiopharm
In Period 1, 1 mg single dose administered as 1x0.5 ml oral solution on Study Day 1, In Period 2, 1 mg single dose administered as 1x0.5 ml oral solution on Study Day 15 In Period 3, 1 mg single dose administered as 1x0.5 ml oral solution at Study Day 26
Drug: Rifampicin
In period 2, 10 mg (suspension, 0.5 ml) for 11 days at 10 mg/day In period 3, 600 mg (film-coated tablets) for 11 days at 600 mg/day
Drug: Drospirenone, Ethinylestradiol/ Yasmin
In Period 1, 3 mg drospirenone, 0.03 mg ethinylestradiol single dose administered as 1x3mg drospirenone, 0.03 mg ethinylestradiol tablet on Study Day 1, In Period 2, 3 mg drospirenone, 0.03 mg ethinylestradiol single dose administered as 1x3mg drospirenone, 0.03 mg ethinylestradiol tablet on Study Day 15, In Period 3, 3 mg drospirenone, 0.03 mg ethinylestradiol single dose administered as 1x3mg drospirenone, 0.03 mg ethinylestradiol tablet on Study Day 26,

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Area under the plasma concentration time curve from zero to infinity (AUC) of levonorgestrel in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF
Time Frame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Maximum plasma concentration (Cmax) of levonorgestrel in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF
Time Frame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Area under the plasma concentration time curve from zero to infinity (AUC) of norethindrone in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF
Time Frame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Maximum plasma concentration (Cmax) of norethindrone in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF
Time Frame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Area under the plasma concentration time curve from zero to infinity (AUC) of etonogestrel in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF
Time Frame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Maximum plasma concentration (Cmax) of etonogestrel in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF
Time Frame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Area under the plasma concentration time curve from zero to infinity (AUC) of dienogest in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF
Time Frame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Maximum plasma concentration (Cmax) of dienogest in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF
Time Frame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Area under the plasma concentration time curve from zero to infinity (AUC) of drospirenone (+EE) in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF
Time Frame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Maximum plasma concentration (Cmax) of drospirenone (+EE) in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF
Time Frame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Area under the plasma concentration time curve from zero to infinity (AUC) of ethinylestradiol (+DRSP) in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF
Time Frame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Maximum plasma concentration (Cmax) of ethinylestradiol (+DRSP) in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF
Time Frame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Area under the plasma concentration time curve from zero to infinity (AUC) of midazolam in combination with the hormonal contraceptive only (without RIF) and in combination with 10 mg/d and 600 mg/d RIF
Time Frame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Maximum plasma concentration (Cmax) of midazolam in combination with the hormonal contraceptive only (without RIF) and in combination with 10 mg/d and 600 mg/d RIF
Time Frame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Bayer

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 29, 2017

Primary Completion (Actual)

July 4, 2018

Study Completion (Actual)

February 19, 2019

Study Registration Dates

First Submitted

November 20, 2017

First Submitted That Met QC Criteria

November 23, 2017

First Posted (Actual)

November 27, 2017

Study Record Updates

Last Update Posted (Actual)

April 15, 2020

Last Update Submitted That Met QC Criteria

April 14, 2020

Last Verified

April 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 19604
  • 2017-002792-26 (EudraCT Number)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Biological Availability

Clinical Trials on levonorgestrel/ Microlut

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Burkina Faso

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe