Clinical trial NCT01253187: 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)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Contraception
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2010-12-03
Enrollment: 44
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 38
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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


Eligibility 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

Primary outcomes:
measure: Mean Maximum Concentration (Cmax) of EE Incl. Bioequivalence (BE) Evaluation
timeFrame: up to 96 hours after administration
measure: Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of EE Incl. Bioequivalence (BE) Evaluation
timeFrame: up to 96 hours after administration
measure: Mean Maximum Concentration (Cmax) of DRSP Incl. Bioequivalence (BE) Evaluation
timeFrame: up to 168 hours after administration
measure: Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of DRSP Incl. Bioequivalence (BE) Evaluation
timeFrame: up to 168 hours after administration
measure: Mean Maximum Concentration (Cmax) of L-5-methyl-THF (Baseline Corrected) Incl. Bioequivalence (BE) Evaluation
timeFrame: up to 12 hours after administration
measure: 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
timeFrame: up to 12 hours after administration
measure: Mean Maximum Concentration (Cmax) of L-5-methyl-THF (Baseline Uncorrected) Incl. Bioequivalence (BE) Evaluation
timeFrame: up to 12 hours after administration
measure: 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
timeFrame: up to 12 hours after administration
Secondary outcomes:
measure: Time to Reach Maximum Concentration (Tmax) of EE
timeFrame: up to 96 hours after administration
measure: Mean Area Under the Concentration-time Curve From Administration up to 72h AUC(0-72h) of DRSP
timeFrame: up to 72 hours after administration
measure: Time to Reach Maximum Concentration (Tmax) of DRSP
timeFrame: up to 168 hours after administration
measure: Time to Reach Maximum Concentration (Tmax) of L-5-methyl-THF
timeFrame: up to 12 hours after administration
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: Dinox B.V.
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: Blode H, Klipping C, Richard F, Trummer D, Rohde B, Diefenbach K. Bioequivalence study of an oral contraceptive containing ethinylestradiol/drospirenone/levomefolate calcium relative to ethinylestradiol/drospirenone and to levomefolate calcium alone. Contraception. 2012 Feb;85(2):177-84. doi: 10.1016/j.contraception.2011.05.015. Epub 2011 Jul 19.