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

Sponsor

Bayer (Industry)

Overall Status

Completed

CT.gov ID

NCT03353857

Collaborator

(none)

Enrollment

Locations

Arms

14.7

Actual Duration (Months)

Patients Per Site

2.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Biological Availability	Drug: levonorgestrel/ Microlut Drug: Norethindrone/ Noriday Drug: Desogestrel/ Cerazette Drug: Dienogest/ Visanne Drug: Drospirenone, Ethinylestradiol/ Yasmin Drug: Midazolam/ Midazolam-ratiopharm Drug: Rifampicin	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

68 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

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

Actual Study Start Date :

Nov 29, 2017

Actual Primary Completion Date :

Jul 4, 2018

Actual Study Completion Date :

Feb 19, 2019

Arms and Interventions

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: 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 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: 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: 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 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: 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: 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 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: 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: 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, 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

Outcome Measures

Primary Outcome Measures

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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3]

Eligibility Criteria

Criteria

Ages Eligible for Study:

45 Years to 70 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CRS Clinical-Research-Services Mannheim GmbH	Mannheim	Baden-Württemberg	Germany	68167
2	CRS Clinical-Research-Services Mönchengladbach GmbH	Mönchengladbach	Nordrhein-Westfalen	Germany	41061