Contraception
Conditions
Brief summary
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.
Interventions
DRUGEE 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.
DRUGEE 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.
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | up to 24 weeks of treatment | 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) | up to 24 weeks of treatment | 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) | from week 24 to week 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Homocysteine Concentrations in Plasma at Baseline and at the End of Treatment (Week 24) With Metafolin | baseline and week 24 | Homocysteine concentrations in plasma at baseline (median of baseline concentrations) and at the end of treatment (week 24) with Metafolin |
| Folate Metabolite Pattern in Plasma at Baseline | pre-treatment | Folate metabolite pattern in plasma at baseline |
| Homocysteine Concentrations in Plasma at Baseline and at the End of Treatment (Week 24) With Folic Acid | baseline, and up to 24 weeks of treatment | Homocysteine concentrations in plasma at baseline (median of baseline concentrations) and at the end of treatment (week 24) with folic acid |
| Folate Metabolite Pattern in Plasma at Cycle 3 | week 12 | Folate metabolite pattern in plasma at cycle 3 |
| Folate Metabolite Pattern in Plasma at Cycle 6 | week 24 | Folate metabolite pattern in plasma at cycle 6 |
Countries
Germany
Participant flow
Recruitment details
Healthy female volunteers aged 18 - 40 (inclusive), desiring contraception, with Red Blood Cell folate \> 317 nmol/L and \< 906 nmol/L, with no concomitant intake of vitamin supplements or medication containing folate or interacting with folate, and no vitamin B12 deficiency, were enrolled from 11 December 2006 to 15 January 2008 at 1 German center
Pre-assignment details
235 female volunteers were screened according to the inclusion and exclusion criteria to determine that the volunteer was in a good state of health and appropriate for inclusion in the study, and 172 volunteers were randomized at one center.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 86 |
| 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. | 86 |
| Total | 172 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 |
| Overall Study | due to relocation | 2 | 0 |
| Overall Study | Invalid for primary analysis data set | 4 | 6 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | EE 0.03 mg/DRSP 3 mg (Yasmin) + Folic Acid | Total |
|---|---|---|---|
| Age Continuous | 28.4 years STANDARD_DEVIATION 5.8 | 27.0 years STANDARD_DEVIATION 5.49 | 27.7 years STANDARD_DEVIATION 5.68 |
| Sex: Female, Male Female | 86 Participants | 86 Participants | 172 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 84 / 86 | 84 / 86 |
| serious Total, serious adverse events | 6 / 86 | 3 / 86 |
Outcome results
Primary
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
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | 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) | plasma folate | 1030 nmol·week/L |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | 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) | RBC folate | 24176 nmol·week/L |
| EE 0.03 mg/DRSP 3 mg (Yasmin) + Folic Acid | 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) | plasma folate | 904 nmol·week/L |
| EE 0.03 mg/DRSP 3 mg (Yasmin) + Folic Acid | 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) | RBC folate | 21876 nmol·week/L |
Primary
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
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Area Under the Curve From Time 0 to 24 Weeks [AUC(0-24weeks)] for Plasma Folate and RBC (Red Blood Cell) Folate (Baseline Corrected) | plasma folate | 640 nmol·week/L |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Area Under the Curve From Time 0 to 24 Weeks [AUC(0-24weeks)] for Plasma Folate and RBC (Red Blood Cell) Folate (Baseline Corrected) | RBC folate | 10427 nmol·week/L |
| EE 0.03 mg/DRSP 3 mg (Yasmin) + Folic Acid | Area Under the Curve From Time 0 to 24 Weeks [AUC(0-24weeks)] for Plasma Folate and RBC (Red Blood Cell) Folate (Baseline Corrected) | plasma folate | 561 nmol·week/L |
| EE 0.03 mg/DRSP 3 mg (Yasmin) + Folic Acid | Area Under the Curve From Time 0 to 24 Weeks [AUC(0-24weeks)] for Plasma Folate and RBC (Red Blood Cell) Folate (Baseline Corrected) | RBC folate | 8863 nmol·week/L |
Primary
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Proportion of Participants With RBC Folate Below 906 Nmol/L in the Yasmin + Metafolin Group in the Folate Elimination Phase (Week 24 to 44) | week 24 | 0.053 proportion of participants |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Proportion of Participants With RBC Folate Below 906 Nmol/L in the Yasmin + Metafolin Group in the Folate Elimination Phase (Week 24 to 44) | week 26 | 0.067 proportion of participants |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Proportion of Participants With RBC Folate Below 906 Nmol/L in the Yasmin + Metafolin Group in the Folate Elimination Phase (Week 24 to 44) | week 28 | 0.147 proportion of participants |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Proportion of Participants With RBC Folate Below 906 Nmol/L in the Yasmin + Metafolin Group in the Folate Elimination Phase (Week 24 to 44) | week 30 | 0.213 proportion of participants |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Proportion of Participants With RBC Folate Below 906 Nmol/L in the Yasmin + Metafolin Group in the Folate Elimination Phase (Week 24 to 44) | week 32 | 0.400 proportion of participants |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Proportion of Participants With RBC Folate Below 906 Nmol/L in the Yasmin + Metafolin Group in the Folate Elimination Phase (Week 24 to 44) | week 34 | 0.533 proportion of participants |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Proportion of Participants With RBC Folate Below 906 Nmol/L in the Yasmin + Metafolin Group in the Folate Elimination Phase (Week 24 to 44) | week 36 | 0.707 proportion of participants |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Proportion of Participants With RBC Folate Below 906 Nmol/L in the Yasmin + Metafolin Group in the Folate Elimination Phase (Week 24 to 44) | week 38 | 0.760 proportion of participants |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Proportion of Participants With RBC Folate Below 906 Nmol/L in the Yasmin + Metafolin Group in the Folate Elimination Phase (Week 24 to 44) | week 40 | 0.827 proportion of participants |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Proportion of Participants With RBC Folate Below 906 Nmol/L in the Yasmin + Metafolin Group in the Folate Elimination Phase (Week 24 to 44) | week 42 | 0.867 proportion of participants |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Proportion of Participants With RBC Folate Below 906 Nmol/L in the Yasmin + Metafolin Group in the Folate Elimination Phase (Week 24 to 44) | week 44 | 0.907 proportion of participants |
Secondary
Folate Metabolite Pattern in Plasma at Baseline
Folate metabolite pattern in plasma at baseline
Time frame: pre-treatment
Population: Note that not all samples were evaluable for each outcome measure. Therefore the number of participants analyzed not necessarily matches the number of completers.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Folate Metabolite Pattern in Plasma at Baseline | Tetrahydrofolate (THF) | 4.07 nmol/L | Standard Deviation 0.357 |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Folate Metabolite Pattern in Plasma at Baseline | 5,10-methenyl-THF | 1.57 nmol/L | Standard Deviation 0.412 |
| EE 0.03 mg/DRSP 3 mg (Yasmin) + Folic Acid | Folate Metabolite Pattern in Plasma at Baseline | 5,10-methenyl-THF | 1.63 nmol/L | Standard Deviation 0.372 |
| EE 0.03 mg/DRSP 3 mg (Yasmin) + Folic Acid | Folate Metabolite Pattern in Plasma at Baseline | Tetrahydrofolate (THF) | 4.60 nmol/L | Standard Deviation 0.656 |
Secondary
Folate Metabolite Pattern in Plasma at Cycle 3
Folate metabolite pattern in plasma at cycle 3
Time frame: week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Folate Metabolite Pattern in Plasma at Cycle 3 | THF | 4.98 nmol/L | Standard Deviation 1.851 |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Folate Metabolite Pattern in Plasma at Cycle 3 | 5,10-methenyl-THF | 1.76 nmol/L | Standard Deviation 0.603 |
| EE 0.03 mg/DRSP 3 mg (Yasmin) + Folic Acid | Folate Metabolite Pattern in Plasma at Cycle 3 | THF | 5.28 nmol/L | Standard Deviation 1.806 |
| EE 0.03 mg/DRSP 3 mg (Yasmin) + Folic Acid | Folate Metabolite Pattern in Plasma at Cycle 3 | 5,10-methenyl-THF | 1.45 nmol/L | Standard Deviation 0.282 |
Secondary
Folate Metabolite Pattern in Plasma at Cycle 6
Folate metabolite pattern in plasma at cycle 6
Time frame: week 24
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Folate Metabolite Pattern in Plasma at Cycle 6 | 5,10-methenyl-THF | 1.46 nmol/L | Standard Deviation 0.238 |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Folate Metabolite Pattern in Plasma at Cycle 6 | THF | 5.92 nmol/L | Standard Deviation 2.318 |
| EE 0.03 mg/DRSP 3 mg (Yasmin) + Folic Acid | Folate Metabolite Pattern in Plasma at Cycle 6 | THF | 5.76 nmol/L | Standard Deviation 2.835 |
| EE 0.03 mg/DRSP 3 mg (Yasmin) + Folic Acid | Folate Metabolite Pattern in Plasma at Cycle 6 | 5,10-methenyl-THF | 1.95 nmol/L | Standard Deviation 1.166 |
Secondary
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Homocysteine Concentrations in Plasma at Baseline and at the End of Treatment (Week 24) With Folic Acid | baseline | 9.2 µmol/L | Standard Deviation 1.9 |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Homocysteine Concentrations in Plasma at Baseline and at the End of Treatment (Week 24) With Folic Acid | 24 weeks | 7.6 µmol/L | Standard Deviation 1.4 |
Secondary
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Homocysteine Concentrations in Plasma at Baseline and at the End of Treatment (Week 24) With Metafolin | baseline | 9.3 µmol/L | Standard Deviation 2.2 |
| EE 0.03 mg/DRSP 3 mg/Metafolin + Folic Acid Placebo | Homocysteine Concentrations in Plasma at Baseline and at the End of Treatment (Week 24) With Metafolin | 24 weeks | 7.5 µmol/L | Standard Deviation 1.6 |