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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT01258660
First received: December 10, 2010
Last updated: September 15, 2013
Last verified: September 2013
  Purpose

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.


Condition Intervention Phase
Contraception
Drug: EE 0.03 mg/DRSP 3 mg/Metafolin + folic acid placebo
Drug: EE 0.03 mg/DRSP 3 mg (Yasmin) + folic acid
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Bayer:

Primary Outcome Measures:
  • 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) [ Time Frame: up to 24 weeks of treatment ] [ Designated as safety issue: No ]
    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.

  • Area Under the Curve From Time 0 to 24 Weeks [AUC(0-24weeks)] for Plasma Folate and RBC (Red Blood Cell) Folate (Baseline Corrected) [ Time Frame: up to 24 weeks of treatment ] [ 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.

  • 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 ] [ Designated as safety issue: No ]
    Proportion of participants with RBC folate below 906 nmol/L in the Yasmin + Metafolin group in the folate elimination phase (week 24 to 44)


Secondary Outcome Measures:
  • Folate Metabolite Pattern in Plasma at Baseline [ Time Frame: pre-treatment ] [ Designated as safety issue: No ]
    Folate metabolite pattern in plasma at baseline

  • Folate Metabolite Pattern in Plasma at Cycle 3 [ Time Frame: week 12 ] [ Designated as safety issue: No ]
    Folate metabolite pattern in plasma at cycle 3

  • Folate Metabolite Pattern in Plasma at Cycle 6 [ Time Frame: week 24 ] [ Designated as safety issue: No ]
    Folate metabolite pattern in plasma at cycle 6

  • Homocysteine Concentrations in Plasma at Baseline and at the End of Treatment (Week 24) With Metafolin [ Time Frame: baseline and week 24 ] [ Designated as safety issue: No ]
    Homocysteine concentrations in plasma at baseline (median of baseline concentrations) and at the end of treatment (week 24) with Metafolin

  • Homocysteine Concentrations in Plasma at Baseline and at the End of Treatment (Week 24) With Folic Acid [ Time Frame: baseline, and up to 24 weeks of treatment ] [ Designated as safety issue: No ]
    Homocysteine concentrations in plasma at baseline (median of baseline concentrations) and at the end of treatment (week 24) with folic acid


Enrollment: 172
Study Start Date: December 2006
Study Completion Date: January 2008
Primary Completion Date: January 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: 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.
Experimental: EE 0.03 mg/DRSP 3 mg (Yasmin) + folic acid
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
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

Ages Eligible for Study:   18 Years to 40 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01258660

Locations
Germany
Nuvisan GmbH
Neu-Ulm, Bayern, Germany, 89231
Sponsors and Collaborators
Bayer
Investigators
Study Director: Bayer Study Director Bayer
  More Information

Additional Information:
Publications:
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT01258660     History of Changes
Other Study ID Numbers: 91509, 2006-003522-29, 309763
Study First Received: December 10, 2010
Results First Received: April 19, 2011
Last Updated: September 15, 2013
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Drospirenone
Drospirenone and ethinyl estradiol combination
Ethinyl Estradiol
Folic Acid
Vitamin B Complex
Cardiovascular Agents
Diuretics
Diuretics, Potassium Sparing
Estrogens
Growth Substances
Hematinics
Hematologic Agents
Hormone Antagonists
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Micronutrients
Mineralocorticoid Receptor Antagonists
Natriuretic Agents
Pharmacologic Actions
Physiological Effects of Drugs
Reproductive Control Agents
Therapeutic Uses
Vitamins

ClinicalTrials.gov processed this record on October 22, 2014