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Trial record 13 of 101 for:    DROSPIRENONE AND ETHINYL ESTRADIOL

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

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ClinicalTrials.gov Identifier: NCT01253187
Recruitment Status : Completed
First Posted : December 3, 2010
Results First Posted : May 9, 2011
Last Update Posted : August 7, 2013
Sponsor:
Information provided by:
Bayer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Contraception
Interventions Drug: EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300)
Drug: EE 0.02 mg/DRSP 3 mg/L-5-MTHF Ca 0.451 mg (EE20/DRSP/L-5-MTHF Ca)
Drug: L-5-MTHF 0.451mg (Metafolin)
Enrollment 44
Recruitment Details Healthy young women, aged 18 – 38 years inclusive, who were nonsmokers were enrolled from 20 October 2006 to 13 September 2007 at one center in Germany.
Pre-assignment Details 77 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 44 volunteers were randomized at one center.
Arm/Group Title Treatment Sequence A: YAZ, EE20/DRSP/L-5-MTHF Ca, Metafolin Treatment Sequence B: YAZ, Metafolin, EE20/DRSP/L-5-MTHF Ca Treatment Sequence C: EE20/DRSP/L-5-MTHF Ca, YAZ, Metafolin Treatment Sequence D: EE20/DRSP/L-5-MTHF Ca, Metafolin, YAZ Treatment Sequence E: Metafolin, YAZ, EE20/DRSP/L-5-MTHF Ca Treatment Sequence F: Metafolin, EE20/DRSP/L-5-MTHF Ca, YAZ
Hide Arm/Group Description YAZ for Period 1; EE20/DRSP/L-5-MTHF Ca for Period 2; Metafolin for Period 3. YAZ: single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) / EE20/DRSP/L-5-MTHF Ca: single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca]) / Metafolin: single oral administration of 1 coated SHT04532C tablet, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca]). YAZ for Period 1; Metafolin for Period 2; EE20/DRSP/L-5-MTHF Ca for Period 3. YAZ: single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) / Metafolin: single oral administration of 1 coated SHT04532C tablet, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca]) / EE20/DRSP/L-5-MTHF Ca: single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca]). EE20/DRSP/L-5-MTHF Ca for Period 1; YAZ for Period 2; Metafolin for Period 3. EE20/DRSP/L-5-MTHF Ca: single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca]) / YAZ: single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) / Metafolin: single oral administration of 1 coated SHT04532C tablet, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca]). EE20/DRSP/L-5-MTHF Ca for Period 1; Metafolin for Period 2; YAZ for Period 3. EE20/DRSP/L-5-MTHF Ca: single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca]) / Metafolin: single oral administration of 1 coated SHT04532C tablet, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca]) / YAZ: single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP). Metafolin for Period 1; YAZ for Period 2; EE20/DRSP/L-5-MTHF Ca for Period 3. Metafolin: single oral administration of 1 coated SHT04532C tablet, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca]) / YAZ: single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) / EE20/DRSP/L-5-MTHF Ca: single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca]). Metafolin for Period 1; EE20/DRSP/L-5-MTHF Ca for Period 2; YAZ for Period 3. Metafolin: single oral administration of 1 coated SHT04532C tablet, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca]) / EE20/DRSP/L-5-MTHF Ca: single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca]) / YAZ: single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP).
Period Title: Period 1
Started 7 8 7 7 9 6
Completed 7 8 7 7 9 6
Not Completed 0 0 0 0 0 0
Period Title: Period 2
Started 7 8 7 7 9 6
Completed 7 8 7 7 8 6
Not Completed 0 0 0 0 1 0
Reason Not Completed
Withdrawal by Subject             0             0             0             0             1             0
Period Title: Period 3
Started 7 8 7 7 8 6
Completed 6 7 7 7 7 6
Not Completed 1 1 0 0 1 0
Reason Not Completed
Pregnancy             1             0             0             0             0             0
difficulty with blood sampling             0             1             0             0             0             0
non-compliance             0             0             0             0             1             0
Arm/Group Title Entire Study Population
Hide Arm/Group Description Includes all participants treated
Overall Number of Baseline Participants 44
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 44 participants
26.3  (6.33)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 44 participants
Female
44
 100.0%
Male
0
   0.0%
1.Primary Outcome
Title Mean Maximum Concentration (Cmax) of EE Incl. Bioequivalence (BE) Evaluation
Hide Description 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
Time Frame up to 96 hours after administration
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP)
single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 39 39
Geometric Mean (95% Confidence Interval)
Unit of Measure: pg/mL
39.6
(35.7 to 44.0)
41.9
(37.6 to 46.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300), EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca)
Comments 38 volunteers qualified for statistical analysis of BE whereas all 39 volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis
Type of Statistical Test Non-Inferiority or Equivalence
Comments A sample size of 6 volunteers per sequence was considered sufficient to establish bioequivalence, id est the 90%-confidence interval for the mean ratio is located completely within the equivalence interval limits of 80% and 125%.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments The equivalence test was done using a 90% confidence interval, no p-value was to be calculated.
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter mean ratio
Estimated Value 106.03
Confidence Interval 90%
98.86 to 113.72
Estimation Comments Point estimate for the ratio [(EE20/DRSP/L-5-MTHF Ca) / YAZ]. Bioequivalence is established if the 90% confidence interval fall within the equivalence interval limits of 80-125%
2.Primary Outcome
Title Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of EE Incl. Bioequivalence (BE) Evaluation
Hide Description 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 96 hours after administration
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP)
single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 39 39
Geometric Mean (95% Confidence Interval)
Unit of Measure: pg·h/mL
358
(320 to 400)
370
(332 to 412)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300), EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca)
Comments 38 volunteers qualified for statistical analysis of BE whereas all 39 volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis
Type of Statistical Test Non-Inferiority or Equivalence
Comments A sample size of 6 volunteers per sequence was considered sufficient to establish bioequivalence, id est the 90%-confidence interval for the mean ratio is located completely within the equivalence interval limits of 80% and 125%.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments The equivalence test was done using a 90% confidence interval, no p-value was to be calculated.
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter mean ratio
Estimated Value 103.47
Confidence Interval 90%
99.16 to 107.98
Estimation Comments Point estimate for the ratio [(EE20/DRSP/L-5-MTHF Ca) / YAZ]. Bioequivalence is established if the 90% confidence interval fall within the equivalence interval limits of 80-125%
3.Primary Outcome
Title Mean Maximum Concentration (Cmax) of DRSP Incl. Bioequivalence (BE) Evaluation
Hide Description 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
Time Frame up to 168 hours after administration
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP)
single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 35 36
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng/mL
25.4
(23.3 to 27.7)
26.7
(24.5 to 29.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300), EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca)
Comments 33 volunteers qualified for statistical analysis of BE whereas all 35 (YAZ) and 36 (EE20/DRSP/L-5-MTHF Ca) volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis
Type of Statistical Test Non-Inferiority or Equivalence
Comments A sample size of 6 volunteers per sequence was considered sufficient to establish bioequivalence, id est the 90%-confidence interval for the mean ratio is located completely within the equivalence interval limits of 80% and 125%.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments The equivalence test was done using a 90% confidence interval, no p-value was to be calculated.
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter mean ratio
Estimated Value 105.24
Confidence Interval 90%
97.30 to 113.83
Estimation Comments Point estimate for the ratio [(EE20/DRSP/L-5-MTHF Ca) / YAZ]. Bioequivalence is established if the 90% confidence interval fall within the equivalence interval limits of 80-125%
4.Primary Outcome
Title Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of DRSP Incl. Bioequivalence (BE) Evaluation
Hide Description 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 168 hours after administration
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP)
single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 35 36
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng·h/mL
386
(352 to 424)
383
(346 to 424)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300), EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca)
Comments 33 volunteers qualified for statistical analysis of BE whereas all 35 (YAZ) and 36 (EE20/DRSP/L-5-MTHF Ca) volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis
Type of Statistical Test Non-Inferiority or Equivalence
Comments A sample size of 6 volunteers per sequence was considered sufficient to establish bioequivalence, id est the 90%-confidence interval for the mean ratio is located completely within the equivalence interval limits of 80% and 125%.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments The equivalence test was done using a 90% confidence interval, no p-value was to be calculated.
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter mean ratio
Estimated Value 100.48
Confidence Interval 90%
97.28 to 103.79
Estimation Comments Point estimate for the ratio [(EE20/DRSP/L-5-MTHF Ca) / YAZ]. Bioequivalence is established if the 90% confidence interval fall within the equivalence interval limits of 80-125%
5.Primary Outcome
Title Mean Maximum Concentration (Cmax) of L-5-methyl-THF (Baseline Corrected) Incl. Bioequivalence (BE) Evaluation
Hide Description 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.
Time Frame up to 12 hours after administration
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451 mg (Metafolin)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
single oral administration of 1 coated SHT04532C tablet, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium) [L-5-MTHF Ca]
Overall Number of Participants Analyzed 39 40
Geometric Mean (95% Confidence Interval)
Unit of Measure: nmol/L
44.3
(40.0 to 49.2)
44.2
(39.1 to 49.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca), L-5-MTHF Ca 0.451 mg (Metafolin)
Comments 39 volunteers qualified for statistical analysis of BE whereas all 39 (EE20/DRSP/L-5-MTHF Ca) and 40 (Metafolin) volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis
Type of Statistical Test Non-Inferiority or Equivalence
Comments A sample size of 6 volunteers per sequence was considered sufficient to establish bioequivalence, id est the 90%-confidence interval for the mean ratio is located completely within the equivalence interval limits of 80% and 125%.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments The equivalence test was done using a 90% confidence interval, no p-value was to be calculated.
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter mean ratio
Estimated Value 99.88
Confidence Interval 90%
91.24 to 109.34
Estimation Comments Point estimate for the ratio [(EE20/DRSP/L-5-MTHF Ca) / Metafolin]. Bioequivalence is established if the 90% confidence interval fall within the equivalence interval limits of 80-125%
6.Primary Outcome
Title 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
Hide Description 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.
Time Frame up to 12 hours after administration
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451 mg (Metafolin)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
single oral administration of 1 coated SHT04532C tablet, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 39 40
Geometric Mean (95% Confidence Interval)
Unit of Measure: nmol·h/L
214
(195 to 235)
217
(199 to 237)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca), L-5-MTHF Ca 0.451 mg (Metafolin)
Comments 39 volunteers qualified for statistical analysis of BE whereas all 39 (EE20/DRSP/L-5-MTHF Ca) and 40 (Metafolin) volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis
Type of Statistical Test Non-Inferiority or Equivalence
Comments A sample size of 6 volunteers per sequence was considered sufficient to establish bioequivalence, id est the 90%-confidence interval for the mean ratio is located completely within the equivalence interval limits of 80% and 125%.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments The equivalence test was done using a 90% confidence interval, no p-value was to be calculated.
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter mean ratio
Estimated Value 98.16
Confidence Interval 90%
93.95 to 102.57
Estimation Comments Point estimate for the ratio [(EE20/DRSP/L-5-MTHF Ca) / Metafolin]. Bioequivalence is established if the 90% confidence interval fall within the equivalence interval limits of 80-125%
7.Primary Outcome
Title Mean Maximum Concentration (Cmax) of L-5-methyl-THF (Baseline Uncorrected) Incl. Bioequivalence (BE) Evaluation
Hide Description 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.
Time Frame up to 12 hours after administration
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451 mg (Metafolin)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
single oral administration of 1 coated SHT04532C tablet, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 40 40
Geometric Mean (95% Confidence Interval)
Unit of Measure: nmol/L
57.9
(52.6 to 63.6)
57.7
(51.7 to 64.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca), L-5-MTHF Ca 0.451 mg (Metafolin)
Comments 40 volunteers qualified for statistical analysis of BE and all 40 volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis
Type of Statistical Test Non-Inferiority or Equivalence
Comments A sample size of 6 volunteers per sequence was considered sufficient to establish bioequivalence, id est the 90%-confidence interval for the mean ratio is located completely within the equivalence interval limits of 80% and 125%.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments The equivalence test was done using a 90% confidence interval, no p-value was to be calculated.
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter mean ratio
Estimated Value 100.28
Confidence Interval 90%
93.15 to 107.95
Estimation Comments Point estimate for the ratio [(EE20/DRSP/L-5-MTHF Ca) / Metafolin]. Bioequivalence is established if the 90% confidence interval fall within the equivalence interval limits of 80-125%
8.Primary Outcome
Title 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
Hide Description 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.
Time Frame up to 12 hours after administration
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451 mg (Metafolin)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
single oral administration of 1 coated SHT04532C tablet, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 40 40
Geometric Mean (95% Confidence Interval)
Unit of Measure: nmol·h/L
370
(333 to 412)
370
(334 to 411)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca), L-5-MTHF Ca 0.451 mg (Metafolin)
Comments 40 volunteers qualified for statistical analysis of BE and all 40 volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis
Type of Statistical Test Non-Inferiority or Equivalence
Comments A sample size of 6 volunteers per sequence was considered sufficient to establish bioequivalence, id est the 90%-confidence interval for the mean ratio is located completely within the equivalence interval limits of 80% and 125%.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments The equivalence test was done using a 90% confidence interval, no p-value was to be calculated.
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter mean ratio
Estimated Value 99.88
Confidence Interval 90%
95.38 to 104.58
Estimation Comments Point estimate for the ratio [(EE20/DRSP/L-5-MTHF Ca) / Metafolin]. Bioequivalence is established if the 90% confidence interval fall within the equivalence interval limits of 80-125%
9.Secondary Outcome
Title Time to Reach Maximum Concentration (Tmax) of EE
Hide Description 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
Time Frame up to 96 hours after administration
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP)
single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 39 39
Median (Full Range)
Unit of Measure: hours
1.50
(0.50 to 4.00)
1.52
(1.00 to 4.18)
10.Secondary Outcome
Title Mean Area Under the Concentration-time Curve From Administration up to 72h AUC(0-72h) of DRSP
Hide Description 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 72 hours after administration
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Hide Analysis Population Description
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/Group Title EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP)
single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 34 36
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng·h/mL
350
(328 to 373)
344
(319 to 371)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300), EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca)
Comments 32 volunteers qualified for statistical analysis of BE whereas all 34 (YAZ) and 36 (EE20/DRSP/L-5-MTHF Ca) volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis
Type of Statistical Test Non-Inferiority or Equivalence
Comments A sample size of 6 volunteers per sequence was considered sufficient to establish bioequivalence, id est the 90%-confidence interval for the mean ratio is located completely within the equivalence interval limits of 80% and 125%.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments The equivalence test was done using a 90% confidence interval, no p-value was to be calculated.
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter mean ratio
Estimated Value 100.30
Confidence Interval 90%
97.65 to 103.02
Estimation Comments Point estimate for the ratio [(EE20/DRSP/L-5-MTHF Ca) / YAZ]. Bioequivalence is established if the 90% confidence interval fall within the equivalence interval limits of 80-125%
11.Secondary Outcome
Title Time to Reach Maximum Concentration (Tmax) of DRSP
Hide Description 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
Time Frame up to 168 hours after administration
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Hide Analysis Population Description
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/Group Title EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP)
single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 35 36
Median (Full Range)
Unit of Measure: hours
2.00
(0.50 to 4.00)
2.00
(0.50 to 4.10)
12.Secondary Outcome
Title Time to Reach Maximum Concentration (Tmax) of L-5-methyl-THF
Hide Description 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
Time Frame up to 12 hours after administration
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451 mg (Metafolin)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca])
single oral administration of 1 coated SHT04532C tablet, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 40 40
Median (Full Range)
Unit of Measure: hours
0.50
(0.00 to 4.00)
0.50
(0.50 to 2.00)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451 mg (Metafolin)
Hide Arm/Group Description single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca]) single oral administration of 1 coated SHT04532C tablet, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [MTHF-Ca])
All-Cause Mortality
EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451 mg (Metafolin)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451 mg (Metafolin)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/43 (0.00%)      0/41 (0.00%)      0/43 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451 mg (Metafolin)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   37/43 (86.05%)      30/41 (73.17%)      34/43 (79.07%)    
Blood and lymphatic system disorders       
Lymphadenopathy * 1  0/43 (0.00%)  0 0/41 (0.00%)  0 1/43 (2.33%)  1
Cardiac disorders       
Palpitations * 1  2/43 (4.65%)  2 0/41 (0.00%)  0 0/43 (0.00%)  0
Ear and labyrinth disorders       
Ear pain * 1  0/43 (0.00%)  0 1/41 (2.44%)  1 0/43 (0.00%)  0
Eye disorders       
Conjunctivitis * 1  0/43 (0.00%)  0 1/41 (2.44%)  1 0/43 (0.00%)  0
Dry eye * 1  0/43 (0.00%)  0 1/41 (2.44%)  1 0/43 (0.00%)  0
Eyelid irritation * 1  0/43 (0.00%)  0 0/41 (0.00%)  0 1/43 (2.33%)  1
Blepharospasm * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Gastrointestinal disorders       
Abdominal discomfort * 1  4/43 (9.30%)  4 2/41 (4.88%)  2 1/43 (2.33%)  1
Abdominal distension * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Abdominal pain * 1  2/43 (4.65%)  2 4/41 (9.76%)  4 1/43 (2.33%)  1
Abdominal pain lower * 1  0/43 (0.00%)  0 1/41 (2.44%)  1 0/43 (0.00%)  0
Diarrhoea * 1  7/43 (16.28%)  7 5/41 (12.20%)  5 2/43 (4.65%)  2
Dry mouth * 1  0/43 (0.00%)  0 1/41 (2.44%)  1 0/43 (0.00%)  0
Eructation * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Nausea * 1  6/43 (13.95%)  6 11/41 (26.83%)  11 5/43 (11.63%)  5
Vomiting * 1  1/43 (2.33%)  1 4/41 (9.76%)  4 2/43 (4.65%)  2
General disorders       
Asthenia * 1  4/43 (9.30%)  4 0/41 (0.00%)  0 0/43 (0.00%)  0
Catheter site haematoma * 1  0/43 (0.00%)  0 1/41 (2.44%)  1 0/43 (0.00%)  0
Catheter site pain * 1  1/43 (2.33%)  1 3/41 (7.32%)  3 0/43 (0.00%)  0
Catheter site related reaction * 1  2/43 (4.65%)  3 1/41 (2.44%)  1 0/43 (0.00%)  0
Chest discomfort * 1  0/43 (0.00%)  0 1/41 (2.44%)  3 0/43 (0.00%)  0
Discomfort * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 1/43 (2.33%)  1
Fatigue * 1  5/43 (11.63%)  6 5/41 (12.20%)  6 2/43 (4.65%)  2
Feeling cold * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Influenza like illness * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Orthostatic intolerance * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Peripheral coldness * 1  2/43 (4.65%)  2 0/41 (0.00%)  0 0/43 (0.00%)  0
Puncture site pain * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Thirst * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Vessel puncture site pain * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Immune system disorders       
Seasonal allergy * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 1/43 (2.33%)  1
Infections and infestations       
Acarodermatitis * 1  0/43 (0.00%)  0 0/41 (0.00%)  0 1/43 (2.33%)  1
Influenza * 1  1/43 (2.33%)  1 2/41 (4.88%)  2 1/43 (2.33%)  1
Nasopharyngitis * 1  2/43 (4.65%)  2 1/41 (2.44%)  1 3/43 (6.98%)  3
Rhinitis * 1  0/43 (0.00%)  0 1/41 (2.44%)  1 0/43 (0.00%)  0
Upper respiratory tract infection * 1  0/43 (0.00%)  0 0/41 (0.00%)  0 1/43 (2.33%)  1
Urinary tract infection * 1  0/43 (0.00%)  0 1/41 (2.44%)  1 0/43 (0.00%)  0
Injury, poisoning and procedural complications       
Periorbital haematoma * 1  0/43 (0.00%)  0 1/41 (2.44%)  1 0/43 (0.00%)  0
Scratch * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Investigations       
Serum ferritin decreased * 1  7/43 (16.28%)  7 6/41 (14.63%)  6 8/43 (18.60%)  8
Weight increased * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Arthralgia * 1  2/43 (4.65%)  2 0/41 (0.00%)  0 0/43 (0.00%)  0
Back pain * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Musculoskeletal discomfort * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Neck pain * 1  0/43 (0.00%)  0 1/41 (2.44%)  1 1/43 (2.33%)  1
Pain in extremity * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Nervous system disorders       
Dizziness * 1  2/43 (4.65%)  4 3/41 (7.32%)  3 1/43 (2.33%)  1
Headache * 1  15/43 (34.88%)  17 9/41 (21.95%)  11 11/43 (25.58%)  13
Hypoaesthesia * 1  1/43 (2.33%)  2 1/41 (2.44%)  1 0/43 (0.00%)  0
Syncope vasovagal * 1  7/43 (16.28%)  8 3/41 (7.32%)  4 2/43 (4.65%)  2
Tremor * 1  2/43 (4.65%)  2 0/41 (0.00%)  0 0/43 (0.00%)  0
Psychiatric disorders       
Anxiety * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Emotional disorder * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Restlessness * 1  0/43 (0.00%)  0 1/41 (2.44%)  1 0/43 (0.00%)  0
Sleep disorder * 1  0/43 (0.00%)  0 1/41 (2.44%)  1 0/43 (0.00%)  0
Reproductive system and breast disorders       
Dysmenorrhoea * 1  0/43 (0.00%)  0 2/41 (4.88%)  2 1/43 (2.33%)  1
Metrorrhagia * 1  10/43 (23.26%)  10 9/41 (21.95%)  9 0/43 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Apnoea * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Dyspnoea * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Pharyngolaryngeal pain * 1  0/43 (0.00%)  0 1/41 (2.44%)  1 0/43 (0.00%)  0
Skin and subcutaneous tissue disorders       
Acne * 1  0/43 (0.00%)  0 1/41 (2.44%)  1 1/43 (2.33%)  1
Blister * 1  0/43 (0.00%)  0 0/41 (0.00%)  0 1/43 (2.33%)  1
Dermal cyst * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Dermatitis * 1  0/43 (0.00%)  0 0/41 (0.00%)  0 1/43 (2.33%)  1
Dry skin * 1  0/43 (0.00%)  0 1/41 (2.44%)  1 0/43 (0.00%)  0
Surgical and medical procedures       
Dental treatment * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Vascular disorders       
Flushing * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
Haematoma * 1  1/43 (2.33%)  1 0/41 (0.00%)  0 0/43 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (10.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
PI (principal investigator) of CRO (contract research organization) will refrain from publishing any data or information generated or derived as a result of the performance of the Services.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Therapeutic Area Head
Organization: Bayer HealthCare AG
EMail: clinical-trials-contact@bayerhealthcare.com
Layout table for additonal information
Responsible Party: Head Clinical Pharmacology, Bayer Healthcare AG
ClinicalTrials.gov Identifier: NCT01253187     History of Changes
Other Study ID Numbers: 91460
2005-003049-15 ( EudraCT Number )
309664 ( Other Identifier: Company Internal )
First Submitted: December 2, 2010
First Posted: December 3, 2010
Results First Submitted: December 9, 2010
Results First Posted: May 9, 2011
Last Update Posted: August 7, 2013