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

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Double-blind, Double-dummy, 2-parallel Arms Clinical Trial to Assess the Pharmacodynamic Effect on Plasma Folate and Red Blood Cell Folate and to Compare the Profile of Circulating Folate Metabolites During 24 Weeks of Treatment With an Oral Contraceptive Containing Ethinylestradiol, Drospirenone and L-5-methyltetrahydrofolate (SH T04532A and SH T04532C) or Yasmin (SH T04532D and SH T04532PC) Co-administered With Folic Acid (SH K04532B) Followed by 20 Weeks of Open-label Treatment With Yasmin Only (Folate Elimination Phase) in Women Seeking Contraception

Conditions
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Contraception

Intervention / Treatment
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* Drug: EE 0.03 mg/DRSP 3 mg/Metafolin + folic acid placebo
* Drug: EE 0.03 mg/DRSP 3 mg (Yasmin) + folic acid


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EE 0.03 mg/DRSP 3 mg/Metafolin + folic acid placebo<br>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. | Drug: EE 0.03 mg/DRSP 3 mg/Metafolin + folic acid placebo<br>* 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.<br>|
| Experimental: EE 0.03 mg/DRSP 3 mg (Yasmin) + folic acid<br>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. | Drug: EE 0.03 mg/DRSP 3 mg (Yasmin) + folic acid<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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) | from week 24 to week 44 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Folate Metabolite Pattern in Plasma at Baseline | Folate metabolite pattern in plasma at baseline | pre-treatment | 
| Folate Metabolite Pattern in Plasma at Cycle 3 | Folate metabolite pattern in plasma at cycle 3 | week 12 | 
| Folate Metabolite Pattern in Plasma at Cycle 6 | Folate metabolite pattern in plasma at cycle 6 | 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 | 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 | baseline, and up to 24 weeks of treatment |