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Trial record 33 of 100 for:    DROSPIRENONE AND ETHINYL ESTRADIOL

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

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ClinicalTrials.gov Identifier: NCT03353857
Recruitment Status : Completed
First Posted : November 27, 2017
Last Update Posted : February 28, 2019
Sponsor:
Information provided by (Responsible Party):
Bayer

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

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Study Type : Interventional  (Clinical Trial)
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 : November 29, 2017
Actual Primary Completion Date : July 4, 2018
Actual Study Completion Date : February 19, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Drug Reactions

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




Primary Outcome Measures :
  1. Area under the plasma concentration time curve from zero to infinity (AUC) of levonorgestrel alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
    If AUC cannot be calculated, AUC(0-tlast) will be used instead as primary variable

  2. Maximum plasma concentration (Cmax) of levonorgestrel alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
  3. Area under the plasma concentration time curve from zero to infinity (AUC) of norethindrone alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
    If AUC cannot be calculated, AUC(0-tlast) will be used instead as primary variable

  4. Maximum plasma concentration (Cmax) of norethindrone alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
  5. Area under the plasma concentration time curve from zero to infinity (AUC) of etonogestrel alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
    If AUC cannot be calculated, AUC(0-tlast) will be used instead as primary variable

  6. Maximum plasma concentration (Cmax) of etonogestrel alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
  7. Area under the plasma concentration time curve from zero to infinity (AUC) of dienogest alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
    If AUC cannot be calculated, AUC(0-tlast) will be used instead as primary variable

  8. Maximum plasma concentration (Cmax) of dienogest alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
  9. Area under the plasma concentration time curve from zero to infinity (AUC) of drospirenone and ethinylestradiol alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
    If AUC cannot be calculated, AUC(0-tlast) will be used instead as primary variable

  10. Maximum plasma concentration (Cmax) of drospirenone and ethinylestradiol alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
  11. Area under the plasma concentration time curve from zero to infinity (AUC) of midazolam alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
    If AUC cannot be calculated, AUC(0-tlast) will be used instead as primary variable

  12. Maximum plasma concentration (Cmax) of midazolam alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   45 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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

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): NCT03353857


Locations
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Germany
CRS Clinical-Research-Services Mannheim GmbH
Mannheim, Baden-Württemberg, Germany, 68167
CRS Clinical-Research-Services Mönchengladbach GmbH
Mönchengladbach, Nordrhein-Westfalen, Germany, 41061
Sponsors and Collaborators
Bayer

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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT03353857     History of Changes
Other Study ID Numbers: 19604
2017-002792-26 ( EudraCT Number )
First Posted: November 27, 2017    Key Record Dates
Last Update Posted: February 28, 2019
Last Verified: February 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Drospirenone and ethinyl estradiol combination
Ethinyl Estradiol
Drospirenone
Midazolam
Levonorgestrel
Norethindrone
Norethindrone Acetate
Dienogest
Desogestrel
Rifampin
Progestins
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Contraceptives, Oral, Synthetic
Contraceptives, Oral