Investigation of Bioequivalence of Ethinylestradiol (EE) and Drospirenone (DRSP) in Two Different Tablet Formulations: YAZ and YAZ + Levomefolate Calcium (Metafolin) & L-5-MTHF in Two Different Tablet Formulations: Levomefolate Calcium (Metafolin) and YAZ + Levomefolate Calcium (Metafolin)

This study has been completed.
Sponsor:
Information provided by:
Bayer
ClinicalTrials.gov Identifier:
NCT01253187
First received: December 2, 2010
Last updated: August 1, 2013
Last verified: August 2013
  Purpose

The purpose of this study is examine and compare the uptake of YAZ (oral contraceptive containing drospirenone and ethinylestradiol) with or without levomefolate calcium (Metafolin, a registered vitamin supplement) in the body and to examine and compare the uptake of levomefolate calcium with or without YAZ in the body, in healthy volunteers not using hormonal contraception


Condition Intervention Phase
Contraception
Drug: EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300)
Drug: EE 0.02 mg/DRSP 3 mg/L-5-MTHF Ca 0.451 mg (EE20/DRSP/L-5-MTHF Ca)
Drug: L-5-MTHF 0.451mg (Metafolin)
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-equivalence Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Open-label, Randomized, Three-fold Crossover Study to Investigate the Bioequivalence of Two Different Tablet Formulations Containing 0.02 mg Ethinylestradiol (EE) and 3 mg Drospirenone (DRSP) Without [SH T00186D] and With [SH T04532B] 0.451 mg L-mefolinate (Metafolin), and to Investigate the Bioequivalence of Two Different Tablet Formulations Containing 0.451 mg L-mefolinate (Metafolin) Without [SH T04532C] and With 0.02 mg EE/ 3 mg DRSP [SH T04532B] in 42 Healthy Young Women

Resource links provided by NLM:


Further study details as provided by Bayer:

Primary Outcome Measures:
  • Mean Maximum Concentration (Cmax) of EE Incl. Bioequivalence (BE) Evaluation [ Time Frame: up to 96 hours after administration ] [ Designated as safety issue: No ]
    Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample

  • Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of EE Incl. Bioequivalence (BE) Evaluation [ Time Frame: up to 96 hours after administration ] [ Designated as safety issue: No ]
    The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample

  • Mean Maximum Concentration (Cmax) of DRSP Incl. Bioequivalence (BE) Evaluation [ Time Frame: up to 168 hours after administration ] [ Designated as safety issue: No ]
    Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample

  • Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of DRSP Incl. Bioequivalence (BE) Evaluation [ Time Frame: up to 168 hours after administration ] [ Designated as safety issue: No ]
    The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample

  • Mean Maximum Concentration (Cmax) of L-5-methyl-THF (Baseline Corrected) Incl. Bioequivalence (BE) Evaluation [ Time Frame: up to 12 hours after administration ] [ Designated as safety issue: No ]
    The baseline corrected Cmax is a measure of the highest measured drug concentration provided solely by the treatment after subtracting endogenous L-5-methyl-THF level. It is obtained by collecting a series of blood samples, measuring the concentrations of L-5-methyl-THF in each sample and by subtracting the pre-treatment concentration.

  • Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of L-5-methyl-THF (Baseline Corrected) Incl. Bioequivalence (BE) Evaluation [ Time Frame: up to 12 hours after administration ] [ Designated as safety issue: No ]
    The baseline corrected AUC is a measure of the systemic drug exposure provided by the treatment excluding the endogenous L-5-methyl-THF level. It is obtained by collecting a series of blood samples, measuring the concentrations of L-5-methyl-THF in each sample and by subtracting the pre-treatment concentration.

  • Mean Maximum Concentration (Cmax) of L-5-methyl-THF (Baseline Uncorrected) Incl. Bioequivalence (BE) Evaluation [ Time Frame: up to 12 hours after administration ] [ Designated as safety issue: No ]
    The baseline uncorrected Cmax is a measure of the highest measured drug concentration including the endogenous L-5-methyl-THF level. It is obtained by collecting a series of blood samples and measuring the concentrations of L-5-methyl-THF in each sample.

  • Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of L-5-methyl-THF (Baseline Uncorrected) Incl. Bioequivalence (BE) Evaluation [ Time Frame: up to 12 hours after administration ] [ Designated as safety issue: No ]
    The baseline uncorrected AUC is a measure of the systemic drug exposure provided by the treatment including the endogenous L-5-methyl-THF level. It is obtained by collecting a series of blood samples and measuring the concentrations of L-5-methyl-THF in each sample.


Secondary Outcome Measures:
  • Time to Reach Maximum Concentration (Tmax) of EE [ Time Frame: up to 96 hours after administration ] [ Designated as safety issue: No ]
    Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content

  • Mean Area Under the Concentration-time Curve From Administration up to 72h AUC(0-72h) of DRSP [ Time Frame: up to 72 hours after administration ] [ Designated as safety issue: No ]
    The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample

  • Time to Reach Maximum Concentration (Tmax) of DRSP [ Time Frame: up to 168 hours after administration ] [ Designated as safety issue: No ]
    Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content

  • Time to Reach Maximum Concentration (Tmax) of L-5-methyl-THF [ Time Frame: up to 12 hours after administration ] [ Designated as safety issue: No ]
    Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content


Enrollment: 44
Study Start Date: October 2006
Study Completion Date: September 2007
Primary Completion Date: September 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300)
single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP)
Drug: EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300)
Treatment group A: Single 1 film-coated tablet (Ethinylestradiol [EE] 0.02mg / Drospirenone [DRSP] 3mg) taken orally under fasting condition at intervals of at least one menstrual cycle.
Experimental: EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca)
single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca])
Drug: EE 0.02 mg/DRSP 3 mg/L-5-MTHF Ca 0.451 mg (EE20/DRSP/L-5-MTHF Ca)
Treatment group B: Single 1 film-coated tablet (Ethinylestradiol [EE] 0.02mg / Drospirenone [DRSP] 3mg / L-5-methyltetrahydrofolate [L-5-MTHF] 0.451mg) taken orally under fasting condition at intervals of at least one menstrual cycle.
Experimental: L-5-MTHF Ca 0.451 mg (Metafolin)
single oral administration of 1 coated SHT04532C tablet, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca])
Drug: L-5-MTHF 0.451mg (Metafolin)
Treatment group C: Single 1 coated tablet (L-5-methyltetrahydrofolate [L-5-MTHF] 0.451mg) taken orally under fasting condition at intervals of at least one menstrual cycle.

  Eligibility

Ages Eligible for Study:   18 Years to 38 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy female volunteer
  • Age: 18 - 38 years inclusive
  • Body mass index (BMI)1: ≥ 19 and < 28 kg/m²
  • Regular cyclic menstrual periods at screening OR when using combined oral contraceptives during the recruitment period reporting of natural cyclic menstrual periods prior to their use
  • Willingness to use non-hormonal methods of contraception during the complete trial OR previous tubal ligation

Exclusion Criteria:

  • incompletely cured pre-existing diseases for which it can be assumed that the absorption, distribution, metabolism, excretion and effect of the study drugs will not be normal
  • known or suspected sex-steroid influenced malignancies
  • endometrial hyperplasia; genital bleeding of unknown origin; uterus myomatosus
  • known or suspected tumors of the liver and pituitary
  • presence or history of severe hepatic disease as long as liver function values have not returned to normal
  • severe renal insufficiency or acute renal failure
  • thrombophlebitis, venous / arterial thromboembolic diseases; presence or history of prodromi of a thrombosis
  • other conditions that increase susceptibility to thromboembolic diseases
  • known neuropsychiatric diseases, especially known or suspected epilepsy, and/ or deficient status of folate or vitamin B12
  • use of any other medication within 2 cycles before first study drug administration which could affect the study aim
  • use of potassium sparing drugs; use of folic acid containing supplements or medicines or use of any medication within 2 cycles before first study drug administration known to interfere with folate metabolism
  • inadequate folate and/or Vitamin B12 status, clinically relevant deviations in red cell folate concentrations
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01253187

Locations
Netherlands
Dinox B.V.
Groningen, Netherlands, 9713GZ
Sponsors and Collaborators
Bayer
Investigators
Study Director: Bayer Study Director Bayer
  More Information

Additional Information:
Publications:
Responsible Party: Head Clinical Pharmacology, Bayer Healthcare AG
ClinicalTrials.gov Identifier: NCT01253187     History of Changes
Other Study ID Numbers: 91460, 2005-003049-15, 309664
Study First Received: December 2, 2010
Results First Received: December 9, 2010
Last Updated: August 1, 2013
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Drospirenone
Ethinyl Estradiol
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents
Cardiovascular Agents
Therapeutic Uses
Estrogens
Hormones

ClinicalTrials.gov processed this record on September 30, 2014