Assessment of the Pharmacodynamic Effect on Plasma Folate and Red Blood Cell Folate and Comparison of the Folate Metabolites During the 24 Weeks of Treatment (Yasmin + Metafolin Versus Yasmin + Folic Acid) Followed by a 20 Week Elimination Phase of Folate

Bayer172 enrolled

Overview

The purpose of this study is to examine and compare the uptake of levomefolate calcium (Metafolin, a registered vitamin supplement) and folic acid in the body during 24 weeks of treatment with a following folate elimination phase of 20 weeks in healthy volunteers seeking contraception. Yasmin (oral contraceptive containing drospirenone and ethinylestradiol) was co-administered over the entire period of 44 weeks.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

172

Conditions

Contraception

Interventions

EE 0.03 mg/DRSP 3 mg/Metafolin + folic acid placebo

Combination EE/DRSP/ Metafolin \[0.030 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin\] given orally in a cyclic regimen for 24 weeks (6 cycles) in combination with folic acid placebo tablets (encapsulated). Each treatment cycle consisting of once daily hormone and Metafolin treatment for 21-days followed by once daily hormone free, Metafolin only regimen for 7 days. This phase was followed by 20 weeks (5 cycles) folate elimination phase consisting of oral administration of Yasmin alone.

EE 0.03 mg/DRSP 3 mg (Yasmin) + folic acidDRUG

Yasmin \[0.030 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP)\] in combination with folic acid tablets 0.4 mg (encapsulated), given orally in a cyclic regimen for 24 weeks (6 cycles). Each treatment cycle providing once daily hormone and folic acid treatment for 21 days followed by once daily hormone free, folic acid only regimen for 7 days (encapsulated). This phase was followed by 20 weeks (5 cycles) folate elimination phase consisting of oral administration of Yasmin alone.

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 40 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Age 18-40 years. * RBC folate \> 317 nmol/L and \< 906 nmol/L. * At least 1 menstruation during the last 3 months before screening with the exception of women using progestin-only methods (injection, implant) or progestin-releasing intrauterine system (IUS). * Negative pregnancy test at screening and at admission into the study. * Healthy as confirmed by medical history and physical examination. * Body mass index (BMI) of 18.5-30.0 kg/m2 . * Volunteers that smoke less than 10 cigarettes per day can be included up to the age of 30 years. * Adequate vitamin B12 status defined as plasma B12 concentrations ≥ 110 pmol/L. Exclusion Criteria: * Regular intake of folic acid defined as \> 100 μg folic acid/day in vitamin supplements or fortified food during the last 4 months. * Treatment with the following medications, which has the potential of interfering with folate metabolism: cholestyramine, methotrexate, trimethoprim, sulfasalazine, salicylic acid, cotrimoxazol, antacids or antiepileptic drugs. * Pregnancy, lactation (at least three cycles have to follow delivery, abortion, or lactation before start of treatment) * Vascular or metabolic disease including existing or previous arterial thromboembolic diseases (myocardial infarction, stroke), existing or previous venous thromboembolic diseases (deep vein thrombosis, pulmonary embolism), and any condition which could increase the risk to suffer any of the above mentioned disorders * Any disease or condition that could compromise the function of the body systems and could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the study medication. * Any disease that may worsen under hormonal treatment or might interfere with the conduct of the study or the interpretation of the results (e.g., herpes gestationis or idiopathic icterus pregnancy; middle-ear deafness ; Sydenham's chorea, porphyria, disturbances in the bile flow. * Liver diseases: Presence or history of severe hepatic diseases including benign or malignant tumors

Outcomes

Primary Outcomes

Area Under the Curve (AUC) From Time 0 to 24 Weeks [AUC(0-24weeks)] for Plasma Folate and RBC (Red Blood Cell) Folate (Baseline Uncorrected)

The Area under the curve (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 frame: up to 24 weeks of treatment

Area Under the Curve From Time 0 to 24 Weeks [AUC(0-24weeks)] for Plasma Folate and RBC (Red Blood Cell) Folate (Baseline Corrected)

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 frame: up to 24 weeks of treatment

Proportion of Participants With RBC Folate Below 906 Nmol/L in the Yasmin + Metafolin Group in the Folate Elimination Phase (Week 24 to 44)

Proportion of participants with RBC folate below 906 nmol/L in the Yasmin + Metafolin group in the folate elimination phase (week 24 to 44)

Time frame: from week 24 to week 44

Secondary Outcomes

Folate Metabolite Pattern in Plasma at Baseline

Folate metabolite pattern in plasma at baseline

Time frame: pre-treatment

Folate Metabolite Pattern in Plasma at Cycle 3

Folate metabolite pattern in plasma at cycle 3

Time frame: week 12

Folate Metabolite Pattern in Plasma at Cycle 6

Folate metabolite pattern in plasma at cycle 6

Time frame: week 24

Homocysteine Concentrations in Plasma at Baseline and at the End of Treatment (Week 24) With Metafolin

Homocysteine concentrations in plasma at baseline (median of baseline concentrations) and at the end of treatment (week 24) with Metafolin

Time frame: baseline and week 24

Homocysteine Concentrations in Plasma at Baseline and at the End of Treatment (Week 24) With Folic Acid

Homocysteine concentrations in plasma at baseline (median of baseline concentrations) and at the end of treatment (week 24) with folic acid

Time frame: baseline, and up to 24 weeks of treatment