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Trial record 1 of 53 for:    DROSPIRENONE AND ETHINYL ESTRADIOL AND containing
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Investigation of Bioequivalence of Ethinylestradiol (EE) and Drospirenone (DRSP) in Two Different Tablet Formulations: Yasmin and Yasmin + Levomefolate Calcium (Metafolin) & L-5-MTHF in Two Different Tablet Formulations: Levomefolate Calcium (Metafolin) and Yasmin + Levomefolate Calcium (Metafolin)

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ClinicalTrials.gov Identifier: NCT01253174
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 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131)
Drug: EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca)
Drug: L-5-MTHF Ca 0.451 mg (Metafolin)
Enrollment 48
Recruitment Details Healthy young women, aged 18 – 38 years inclusive, who were nonsmokers were enrolled from 16 August 2006 to 4 July 2007 at one center in Germany.
Pre-assignment Details 147 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 48 volunteers were randomized at one center.
Arm/Group Title Treatment Sequence A: Yasmin, EE30/DRSP/L-5-MTHF Ca, Metafolin Treatment Sequence B: Yasmin, Metafolin, EE30/DRSP/L-5-MTHF Ca Treatment Sequence C: EE30/DRSP/L-5-MTHF Ca, Yasmin, Metafolin Treatment Sequence D: EE30/DRSP/L-5-MTHF Ca, Metafolin, Yasmin Treatment Sequence E: Metafolin, Yasmin, EE30/DRSP/L-5-MTHF Ca Treatment Sequence F: Metafolin, EE30/DRSP/L-5-MTHF Ca, Yasmin
Hide Arm/Group Description Yasmin for Period 1; EE30/DRSP/L-5-MTHF Ca for Period 2; Metafolin for Period 3. Yasmin: single oral administration of 1 film-coated SHT470FA tablet (Yasmin with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP) / EE30/DRSP/L-5-MTHF Ca: single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca]) / Metafolin: single oral administration of 1 coated tablet SHT04532C, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca]). Yasmin for Period 1; Metafolin for Period 2; EE30/DRSP/L-5-MTHF Ca for Period 3. Yasmin: single oral administration of 1 film-coated SHT470FA tablet (Yasmin with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP) / Metafolin: single oral administration of 1 coated tablet SHT04532C, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca]) / EE30/DRSP/L-5-MTHF Ca: single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca]). EE30/DRSP/L-5-MTHF Ca for Period 1; Yasmin for Period 2; Metafolin for Period 3. EE30/DRSP/L-5-MTHF Ca: single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca]) / Yasmin: single oral administration of 1 film-coated SHT470FA tablet (Yasmin with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP) / Metafolin: single oral administration of 1 coated tablet SHT04532C, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca]). EE30/DRSP/L-5-MTHF Ca for Period 1; Metafolin for Period 2; Yasmin for Period 3. EE30/DRSP/L-5-MTHF Ca: single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca]) / Metafolin: single oral administration of 1 coated tablet SHT04532C, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca]) / Yasmin: single oral administration of 1 film-coated SHT470FA tablet (Yasmin with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP). Metafolin for Period 1; Yasmin for Period 2; EE30/DRSP/L-5-MTHF Ca for Period 3. Metafolin: single oral administration of 1 coated tablet SHT04532C, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca]) / Yasmin: single oral administration of 1 film-coated SHT470FA tablet (Yasmin with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP) / EE30/DRSP/L-5-MTHF Ca: single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca]). Metafolin for Period 1; EE30/DRSP/L-5-MTHF Ca for Period 2; Yasmin for Period 3. Metafolin: single oral administration of 1 coated tablet SHT04532C, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca]) / EE30/DRSP/L-5-MTHF Ca: single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca]) / Yasmin: single oral administration of 1 film-coated SHT470FA tablet (Yasmin with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP).
Period Title: Period 1
Started 6 10 9 7 9 7
Completed 6 9 8 7 8 7
Not Completed 0 1 1 0 1 0
Reason Not Completed
Randomized but not treated             0             1             1             0             1             0
Period Title: Period 2
Started 6 9 8 7 8 7
Completed 6 9 7 7 8 7
Not Completed 0 0 1 0 0 0
Reason Not Completed
Adverse Event             0             0             1             0             0             0
Period Title: Period 3
Started 6 9 7 7 8 7
Completed 6 8 6 7 7 7
Not Completed 0 1 1 0 1 0
Reason Not Completed
Withdrawal by Subject             0             1             0             0             1             0
Pregnancy             0             0             1             0             0             0
Arm/Group Title Entire Study Population
Hide Arm/Group Description Includes all participants treated
Overall Number of Baseline Participants 45
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 45 participants
29.7  (4.62)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 45 participants
Female
45
 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 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131) EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT470FA tablet (Yasmin with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP)
single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 42 42
Geometric Mean (95% Confidence Interval)
Unit of Measure: pg/mL
58.5
(53.1 to 64.4)
61.6
(56.6 to 67.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131), EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca)
Comments 41 volunteers qualified for statistical analysis of BE whereas all 42 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 102.26
Confidence Interval 90%
96.65 to 108.20
Estimation Comments Point estimate for the ratio [(EE30/DRSP/L-5-MTHF Ca) / Yasmin]. 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 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131) EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT470FA tablet (Yasmin with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP)
single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 42 42
Geometric Mean (95% Confidence Interval)
Unit of Measure: pg∙h/mL
573
(521 to 632)
595
(544 to 651)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131), EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca)
Comments 41 volunteers qualified for statistical analysis of BE whereas all 42 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 101.13
Confidence Interval 90%
97.65 to 104.75
Estimation Comments Point estimate for the ratio [(EE30/DRSP/L-5-MTHF Ca) / Yasmin]. 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 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131) EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT470FA tablet (Yasmin with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP)
single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 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: ng/mL
26.3
(23.9 to 28.9)
27.2
(25.3 to 29.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131), EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca)
Comments 39 volunteers qualified for statistical analysis of BE whereas 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 98.66
Confidence Interval 90%
93.37 to 104.24
Estimation Comments Point estimate for the ratio [(EE30/DRSP/L-5-MTHF Ca) / Yasmin]. 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 (AUC) 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 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131) EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT470FA tablet (Yasmin with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP)
single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 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: ng∙h/mL
433
(397 to 473)
447
(417 to 479)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131), EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca)
Comments 39 volunteers qualified for statistical analysis of BE whereas 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 99.45
Confidence Interval 90%
96.70 to 102.28
Estimation Comments Point estimate for the ratio [(EE30/DRSP/L-5-MTHF Ca) / Yasmin]. 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 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451 mg (Metafolin)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
single oral administration of 1 coated tablet SHT04532C, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 41 43
Geometric Mean (95% Confidence Interval)
Unit of Measure: nmol/L
51.7
(47.1 to 56.9)
48.7
(44.5 to 53.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca), L-5-MTHF Ca 0.451 mg (Metafolin)
Comments 41 volunteers qualified for statistical analysis of BE whereas all 41 (EE30/DRSP/L-5-MTHF Ca) and 43 (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 106.19
Confidence Interval 90%
99.18 to 113.68
Estimation Comments Point estimate for the ratio [(EE30/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 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451 mg (Metafolin)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
single oral administration of 1 coated tablet SHT04532C, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 41 43
Geometric Mean (95% Confidence Interval)
Unit of Measure: nmol∙h/L
236
(218 to 256)
239
(221 to 259)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca), L-5-MTHF Ca 0.451 mg (Metafolin)
Comments 41 volunteers qualified for statistical analysis of BE whereas all 41 (EE30/DRSP/L-5-MTHF Ca) and 43 (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 97.98
Confidence Interval 90%
94.19 to 101.93
Estimation Comments Point estimate for the ratio [(EE30/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 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451 mg (Metafolin)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
single oral administration of 1 coated tablet SHT04532C, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 41 43
Geometric Mean (95% Confidence Interval)
Unit of Measure: nmol/L
65.2
(59.3 to 71.6)
61.8
(56.6 to 67.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca), L-5-MTHF Ca 0.451 mg (Metafolin)
Comments 41 volunteers qualified for statistical analysis of BE whereas all 41 (EE30/DRSP/L-5-MTHF Ca) and 43 (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 104.90
Confidence Interval 90%
98.83 to 111.34
Estimation Comments Point estimate for the ratio [(EE30/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 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451 mg (Metafolin)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
single oral administration of 1 coated tablet SHT04532C, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 41 43
Geometric Mean (95% Confidence Interval)
Unit of Measure: nmol∙h/L
393
(356 to 435)
390
(353 to 431)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca), L-5-MTHF Ca 0.451 mg (Metafolin)
Comments 41 volunteers qualified for statistical analysis of BE whereas all 41 (EE30/DRSP/L-5-MTHF Ca) and 43 (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 99.63
Confidence Interval 90%
95.73 to 103.69
Estimation Comments Point estimate for the ratio [(EE30/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 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131) EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT470FA tablet (Yasmin with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP)
single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 42 42
Median (Full Range)
Unit of Measure: hour
2.00
(0.50 to 4.00)
2.00
(1.00 to 4.00)
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
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 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131) EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT470FA tablet (Yasmin with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP)
single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 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: ng∙h/mL
352
(323 to 383)
366
(346 to 388)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EE 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131), EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca)
Comments 38 volunteers qualified for statistical analysis of BE whereas 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 99.57
Confidence Interval 90%
97.32 to 101.87
Estimation Comments Point estimate for the ratio [(EE30/DRSP/L-5-MTHF Ca) / Yasmin]. 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
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 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131) EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT470FA tablet (Yasmin with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP)
single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 40 40
Median (95% Confidence Interval)
Unit of Measure: hour
1.50
(1.00 to 3.00)
1.50
(0.50 to 3.00)
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 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451 mg (Metafolin)
Hide Arm/Group Description:
single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
single oral administration of 1 coated tablet SHT04532C, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
Overall Number of Participants Analyzed 41 43
Median (Full Range)
Unit of Measure: hour
0.50
(0.50 to 1.50)
0.50
(0.50 to 1.50)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title EE 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131) EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451mg (Metafolin)
Hide Arm/Group Description single oral administration of 1 film-coated SHT470FA tablet (Yasmin with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP) single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca]) single oral administration of 1 coated tablet SHT04532C, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium [L-5-MTHF Ca])
All-Cause Mortality
EE 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131) EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451mg (Metafolin)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
EE 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131) EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451mg (Metafolin)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/44 (0.00%)      0/43 (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 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131) EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca) L-5-MTHF Ca 0.451mg (Metafolin)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   27/44 (61.36%)      31/43 (72.09%)      16/43 (37.21%)    
Blood and lymphatic system disorders       
Iron deficiency anaemia * 1  1/44 (2.27%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0
Gastrointestinal disorders       
Abdominal discomfort * 1  1/44 (2.27%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0
Abdominal pain * 1  2/44 (4.55%)  2 0/43 (0.00%)  0 0/43 (0.00%)  0
Abdominal pain upper * 1  1/44 (2.27%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0
Diarrhoea * 1  0/44 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0
Nausea * 1  10/44 (22.73%)  10 6/43 (13.95%)  6 0/43 (0.00%)  0
Vomiting * 1  2/44 (4.55%)  2 9/43 (20.93%)  9 2/43 (4.65%)  2
General disorders       
Vessel puncture site haematoma * 1  1/44 (2.27%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0
Vessel puncture site pain * 1  0/44 (0.00%)  0 0/43 (0.00%)  0 1/43 (2.33%)  2
Infections and infestations       
Bronchitis * 1  1/44 (2.27%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0
Nasopharyngitis * 1  1/44 (2.27%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0
Oral herpes * 1  0/44 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0
Investigations       
Serum ferritin decreased * 1  9/44 (20.45%)  9 12/43 (27.91%)  12 7/43 (16.28%)  7
Weight increased * 1  0/44 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Musculoskeletal stiffness * 1  1/44 (2.27%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0
Nervous system disorders       
Dizziness * 1  2/44 (4.55%)  2 2/43 (4.65%)  2 0/43 (0.00%)  0
Headache * 1  7/44 (15.91%)  8 4/43 (9.30%)  4 6/43 (13.95%)  7
Syncope vasovagal * 1  1/44 (2.27%)  2 1/43 (2.33%)  1 0/43 (0.00%)  0
Psychiatric disorders       
Mood swings * 1  1/44 (2.27%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0
Renal and urinary disorders       
Enuresis * 1  1/44 (2.27%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0
Reproductive system and breast disorders       
Breast discomfort * 1  0/44 (0.00%)  0 2/43 (4.65%)  2 0/43 (0.00%)  0
Metrorrhagia * 1  3/44 (6.82%)  3 7/43 (16.28%)  8 0/43 (0.00%)  0
Skin and subcutaneous tissue disorders       
Dermatitis allergic * 1  0/44 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0
Pityriasis rosea * 1  0/44 (0.00%)  0 0/43 (0.00%)  0 1/43 (2.33%)  1
Urticaria generalised * 1  1/44 (2.27%)  1 0/43 (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
EMail: clinical-trials-contact@bayerhealthcare.com
Layout table for additonal information
Responsible Party: Head Clinical Pharmacology, Bayer Healthcare AG
ClinicalTrials.gov Identifier: NCT01253174     History of Changes
Other Study ID Numbers: 91457
2005-001913-16 ( EudraCT Number )
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