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

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

Tracking Information
First Submitted Date  ICMJE November 20, 2017
First Posted Date  ICMJE November 27, 2017
Last Update Posted Date February 28, 2019
Actual Study Start Date  ICMJE November 29, 2017
Actual Primary Completion Date July 4, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 23, 2017)
  • 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
  • Maximum plasma concentration (Cmax) of levonorgestrel alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
  • 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
  • Maximum plasma concentration (Cmax) of norethindrone alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
  • 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
  • Maximum plasma concentration (Cmax) of etonogestrel alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
  • 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
  • Maximum plasma concentration (Cmax) of dienogest alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
  • 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
  • Maximum plasma concentration (Cmax) of drospirenone and ethinylestradiol alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
  • 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
  • Maximum plasma concentration (Cmax) of midazolam alone and in the presents of rifampicin [ Time Frame: Day 1, Day 15 and Day 26 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Drug-drug Interaction Between Rifampicin and Progestins/Ethinylestradiol and Midazolam
Official Title  ICMJE 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
Brief Summary Quantify the effect of a probe CYP3A4 inducer (Rifampicin) on the pharmacokinetics of levonorgestrel, norethindrone, desogestrel, dienogest, drospirenone,estradiol and midazolam
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Biological Availability
Intervention  ICMJE
  • 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: 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: 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: 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: 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
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: levonorgestrel/ Microlut
    • Drug: Midazolam/ Midazolam-ratiopharm
    • Drug: Rifampicin
  • 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.
    Interventions:
    • Drug: Norethindrone/ Noriday
    • Drug: Midazolam/ Midazolam-ratiopharm
    • Drug: Rifampicin
  • 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.
    Interventions:
    • Drug: Desogestrel/ Cerazette
    • Drug: Midazolam/ Midazolam-ratiopharm
    • Drug: Rifampicin
  • 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.
    Interventions:
    • Drug: Dienogest/ Visanne
    • Drug: Midazolam/ Midazolam-ratiopharm
    • Drug: Rifampicin
  • 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.

    Interventions:
    • Drug: Drospirenone, Ethinylestradiol/ Yasmin
    • Drug: Midazolam/ Midazolam-ratiopharm
    • Drug: Rifampicin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 27, 2019)
68
Original Estimated Enrollment  ICMJE
 (submitted: November 23, 2017)
70
Actual Study Completion Date  ICMJE February 19, 2019
Actual Primary Completion Date July 4, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 45 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03353857
Other Study ID Numbers  ICMJE 19604
2017-002792-26 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Bayer
Study Sponsor  ICMJE Bayer
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Bayer
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP