Clinical trial NCT03353857: Drug-drug Interaction Between Rifampicin and Progestins/Ethinylestradiol and Midazolam
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Biological Availability
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2017-11-27
Enrollment: 68
Sex: FEMALE
Minimum age (years): 45
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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


Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
measure: 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
timeFrame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
measure: 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
timeFrame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
measure: 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
timeFrame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
measure: 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
timeFrame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
measure: 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
timeFrame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
measure: 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
timeFrame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
measure: 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
timeFrame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
measure: 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
timeFrame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
measure: 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
timeFrame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
measure: 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
timeFrame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
measure: 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
timeFrame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
measure: 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
timeFrame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
measure: 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
timeFrame: Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3
Secondary outcomes:
Other outcomes:
Locations:
city: Mannheim
country: Germany
facility: CRS Clinical-Research-Services Mannheim GmbH
state: Baden-Württemberg
city: Mönchengladbach
country: Germany
facility: CRS Clinical-Research-Services Mönchengladbach GmbH
state: Nordrhein-Westfalen
Study officials:
References: