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

• ClinicalTrials.gov Identifier: NCT01253174
• Recruitment Status: Completed
• First Posted: December 3, 2010
• Results First Posted: May 9, 2011
• Last Update Posted: August 7, 2013
• Sponsor: Bayer
• Information provided by: Bayer

Study Description

Brief Summary:

The purpose of this study is to examine and compare the uptake of Yasmin (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 Yasmin in the body, in healthy volunteers not using hormonal contraception.

Condition or disease	Intervention/treatment	Phase
Contraception	Drug: EE 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131); Drug: EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca); Drug: L-5-MTHF Ca 0.451 mg (Metafolin)	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-label, Randomized, Three-fold Crossover Study to Investigate the Bioequivalence of Two Different Tablet Formulations Containing 0.03 mg Ethinylestradiol (EE) and 3 mg Drospirenone (DRSP) Without [SH T470FA] and With [SH T04532A] 0.451 mg Metafolin®, and to Investigate the Bioequivalence of Two Different Tablet Formulations Containing 0.451 mg Metafolin® Without [SH T04532C] and With 0.03 mg EE/ 3 mg DRSP [SH T04532A] in 42 Healthy Young Women
• Study Start Date: August 2006
• Actual Primary Completion Date: July 2007
• Actual Study Completion Date: July 2007

Arms and Interventions

Arm	Intervention/treatment
Experimental: EE 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131); single oral administration of 1 film-coated SHT470FA tablet (Yasmin with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP)	Drug: EE 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131); single oral administration of 1 coated tablet SH T470FA (Yasmin, film-coated tablets with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP)
Experimental: EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca); single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca])	Drug: EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca); single oral administration of 1 coated tablet SH T04532A (film-coated tablet with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin
Active Comparator: L-5-MTHF Ca 0.451 mg (Metafolin); single oral administration of 1 coated tablet SHT04532C, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca])	Drug: L-5-MTHF Ca 0.451 mg (Metafolin); single oral administration of 1 coated tablet SH T04532C, containing 0.451 mg Metafolin

Outcome Measures

Primary Outcome Measures :

1. Mean Maximum Concentration (Cmax) of EE Incl. Bioequivalence (BE) Evaluation [ Time Frame: up to 96 hours after administration ]
   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.
2. 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 ]
   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
3. Mean Maximum Concentration (Cmax) of DRSP Incl. Bioequivalence (BE) Evaluation [ Time Frame: up to 168 hours after administration ]
   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.
4. Mean Area Under the Concentration-time Curve (AUC) of DRSP Incl. Bioequivalence (BE) Evaluation [ Time Frame: up to 168 hours after administration ]
   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
5. Mean Maximum Concentration (Cmax) of L-5-methyl-THF (Baseline Corrected) Incl. Bioequivalence (BE) Evaluation [ Time Frame: up to 12 hours after administration ]
   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.
6. 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 ]
   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.
7. Mean Maximum Concentration (Cmax) of L-5-methyl-THF (Baseline Uncorrected) Incl. Bioequivalence (BE) Evaluation [ Time Frame: up to 12 hours after administration ]
   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.
8. 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 ]
   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 :

1. Time to Reach Maximum Concentration (Tmax) of EE [ Time Frame: up to 96 hours after administration ]
   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
2. 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 ]
   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
3. Time to Reach Maximum Concentration (Tmax) of DRSP [ Time Frame: up to 168 hours after administration ]
   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
4. Time to Reach Maximum Concentration (Tmax) of L-5-methyl-THF [ Time Frame: up to 12 hours after administration ]
   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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 38 Years (Adult)
• Sexes 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

Locations

Germany

Scope International

Hamburg, Germany, 22525

Sponsors and Collaborators

Bayer

Investigators

• Study Director: Bayer Study Director; Bayer

More Information

Publications of Results:

Wiesinger H, Eydeler U, Richard F, Trummer D, Blode H, Rohde B, Diefenbach K. Bioequivalence evaluation of a folate-supplemented oral contraceptive containing ethinylestradiol/drospirenone/levomefolate calcium versus ethinylestradiol/drospirenone and levomefolate calcium alone. Clin Drug Investig. 2012 Oct 1;32(10):673-84. doi: 10.2165/11635280-000000000-00000.

• Responsible Party: Head Clinical Pharmacology, Bayer Healthcare AG
• ClinicalTrials.gov Identifier: NCT01253174 History of Changes
• Other Study ID Numbers: 91457; 2005-001913-16 ( EudraCT Number )
• First Posted: December 3, 2010
• Results First Posted: May 9, 2011
• Last Update Posted: August 7, 2013
• Last Verified: August 2013

Additional relevant MeSH terms:

Drospirenone; Drospirenone and ethinyl estradiol combination; Ethinyl Estradiol; Calcium, Dietary; Tetrahydrofolates; Calcium; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Bone Density Conservation Agents; Estrogens; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Hormone Antagonists; Diuretics, Potassium Sparing; Diuretics; Natriuretic Agents; Reproductive Control Agents; Vitamin B Complex; Vitamins; Micronutrients; Nutrients; Growth Substances