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): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for 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) (NCT01253174), a randomized phase 1 study. The primary outcome is Mean Maximum Concentration (Cmax) of EE Incl. Bioequivalence (BE) Evaluation.

2. Clinical Question

This is a pharmacokinetic comparison: it concerns measured drug concentrations after administration, not a clinical outcome such as pregnancy prevention. The registry describes the investigation as examining uptake in the body for the combination formulation and for Metafolin with or without Yasmin. That broader study objective should be distinguished from the primary result, which is specifically about maximum ethinylestradiol concentration.

3. Trial Design

This was a phase 1, randomized, open-label, three-fold crossover study sponsored by Bayer. Its status is completed. The registry lists enrollment of 48, while the official title describes a study in 42 healthy young women. The primary outcome analysis includes 42 participants in each of its two treatment groups. Because the study used a crossover model, participants received different formulations over the course of the study; each participant can therefore contribute observations under more than one treatment condition.

The listed interventions were a single oral administration of a Yasmin tablet containing 0.030 mg ethinylestradiol and 3 mg drospirenone; a single oral administration of a tablet containing those same stated amounts plus 0.451 mg Metafolin; and a single oral administration of a tablet containing 0.451 mg Metafolin alone. The record distinguishes the formulations by the form of ethinylestradiol used, but the primary endpoint is the measured ethinylestradiol concentration.

Randomization and crossover allocation can support within-participant comparisons, because measurements from the same participant may be compared across formulations. Open-label means the registry lists no masking. The record does not report the sequence assignments, treatment periods, washout intervals, or any additional details about how the crossover was implemented. Those design details should not be inferred from the phrase “three-fold crossover.”

The primary outcome was mean maximum concentration of ethinylestradiol, with concentrations assessed up to 96 hours after administration. The registry also lists secondary pharmacokinetic outcomes, including time to maximum concentration for ethinylestradiol, drospirenone, and L-5-methyl-THF, and mean drospirenone area under the concentration-time curve from administration up to 72 hours. The record lists 12 outcome measures and 9 analyses overall, while four secondary outcomes are posted. It does not report a detailed statistical analysis plan or explain the difference between the number of listed outcome measures and posted secondary outcomes.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: 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.

Period 1

Reasons for not completing this period:

Period 2

Reasons for not completing this period:

Period 3

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Note that not all samples were evaluable for each outcome measure. Therefore the number of participants analyzed not necessarily matches the number of completers.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Mean Maximum Concentration (Cmax) of EE Incl. Bioequivalence (BE) Evaluation, measured over up to 96 hours after administration.

The primary endpoint is mean maximum concentration, abbreviated Cmax, of ethinylestradiol. It represents the highest measured concentration after administration. The registry describes collecting blood samples over time and measuring the drug concentration in each sample; the maximum among those measurements is the participant-level Cmax. The stated timeframe is up to 96 hours after administration.

Cmax is a pharmacokinetic measure of peak exposure. In a formulation comparison, it helps assess whether the amount of drug reaching the measured concentration peak is similar between formulations. This is one aspect of bioequivalence evaluation, rather than a measure of a clinical benefit or a longer-term health outcome. Other pharmacokinetic features, such as the timing of the peak and total exposure over a specified period, are represented by different measures. The registry lists some of those as secondary outcomes.

The primary group summaries are geometric means in pg/mL, with 95% confidence intervals. The Yasmin group summary is 58.5 pg/mL, with a 95% confidence interval from 53.1 to 64.4; the combination-formulation group summary is 61.6 pg/mL, with a 95% confidence interval from 56.6 to 67.0. Each group has 42 participants in the posted primary analysis.

A geometric mean summarizes values on a multiplicative scale, which is commonly useful for concentration data that are analyzed after a logarithmic transformation. The interval describes uncertainty around the group estimate; it does not give the range of individual participants’ concentrations. The registry’s primary comparison is separately reported as a mean ratio with a 90% confidence interval. The rationale for using both 95% intervals for the group summaries and a 90% interval for the bioequivalence comparison is not detailed in the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

For the primary outcome, the registry reports geometric mean concentrations and an ANOVA comparison expressed as a mean ratio. These are related but distinct summaries. The geometric means describe the estimated concentration in each treatment group on a multiplicative scale. The mean ratio expresses the relative concentration estimate for the two formulations. The registry reports the ratio as 102.26 and its 90% confidence interval as 96.65 to 108.20.

What does the confidence interval describe?

In general, a confidence interval is a range of estimates compatible with the observed data under the statistical model and its assumptions. It communicates uncertainty about an estimated quantity, rather than listing the values observed in individual participants. A narrower interval indicates greater precision than a wider interval for the same quantity and analysis. The interval does not, on its own, say whether a comparison meets a decision rule. For a bioequivalence assessment, the interval must be interpreted against the specified acceptance limits. Those limits are not reported in the registry record.

The primary comparison uses a 90% confidence interval, while the separate geometric mean summaries use 95% confidence intervals. These confidence levels refer to different reported quantities and should be read as stated. The registry does not explain the choice of confidence level or give the protocol-level decision procedure. A reader should therefore distinguish the published result from any conclusion that would require unreported criteria.

Why use geometric means and a ratio?

General statistical practice often uses logarithmic analysis for pharmacokinetic concentrations because these measurements can be multiplicative in nature. On a logarithmic scale, treatment contrasts can be estimated and then expressed as ratios on the original scale. A ratio near 100, when reported in percentage terms, represents estimates near equality. This is a general interpretation of a ratio scale; the registry does not describe the transformation or the exact ANOVA model used for this analysis.

A crossover design also creates a statistical feature that differs from a comparison of two independent groups. Measurements from one participant under different formulations are related. In general, a suitable analysis accounts for the within-participant structure, rather than treating every observation as independent. The registry identifies an ANOVA analysis but does not report enough model details to determine precisely how participant, period, sequence, or other terms were handled. It also does not state whether the primary analysis followed a particular population definition.

What role does the trial design play?

Randomization can reduce systematic differences in how treatment sequences are assigned, while a crossover can allow each participant to serve as a basis for comparing formulations. Open-label status means masking was not used according to the registry. The record does not describe the treatment sequence, periods, washout, or any assessment of carryover. These details matter to interpretation of crossover data because they can affect whether observed differences are attributable to formulation or to the way treatment was delivered over time. No conclusion about those features can be drawn from the registry fields listed for this study.

The primary endpoint is Cmax, the highest measured concentration during the stated measurement period. This is not the same as total exposure over time, which is represented by an area-under-the-curve measure, or the time required to reach the maximum, represented by Tmax. The registry lists some of these as secondary outcomes. Results for those outcomes are not included in the primary result.

How should planning illustrations be read?

In general, a sample-size planning calculation asks how many participants per arm would be needed under specified assumptions to detect an effect at a chosen significance level and power. Such calculations are planning illustrations, not descriptions of the trial’s observed power. The registry’s stated planning assumptions use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect defined as a stated fraction of the observed effect. For time-to-event calculations, the stated convention is a total number of events; other calculations are expressed as participants per arm. The corresponding numerical planning results and the effect fractions are not reported in the registry record described for this analysis, so no sample-size estimate can be stated.

The trial’s enrollment of 48 and the 42 participants in each primary analysis group are observed registry counts, not substitutes for a planning calculation. Nor do those counts establish the power of the study. The number analyzed can differ across outcomes because not all samples were evaluable, as the registry explicitly notes.

What information is missing from the statistical description?

The registry does not report the bioequivalence decision limits, a detailed analysis plan, model terms, a missing-data method, or a clear account of the analysis population. It also does not report whether interim analyses were planned or conducted, or how the number of participants was justified for design purposes. These omissions do not invalidate the posted result, but they limit independent assessment of the statistical choices and the exact decision process. The most direct interpretation is therefore the one supported by the reported estimate, interval, endpoint definition, and stated limitations.

10. Analyses Reported by the Sponsor

The registry reports the sponsor’s primary comparison as an ANOVA mean ratio of 102.26, with a 90% confidence interval from 96.65 to 108.20. It does not report a separate recalculated comparison for this primary endpoint. Consequently, the sponsor’s analysis is the direct inferential result available in the registry record; no second estimate should be substituted for it.

The registry does not flag a discrepancy between the sponsor’s analysis and a recalculation. The result can therefore be read as the posted sponsor analysis without a stated conflict between those sources. The estimate and interval indicate the reported relative Cmax result and its uncertainty, but the record does not give the acceptance limits needed to determine whether the study’s bioequivalence criterion was met.

The group geometric means are descriptive summaries, while the ANOVA ratio is the direct comparative analysis. Comparing the two group means informally or deriving a new ratio from rounded summaries would not reproduce the sponsor’s model-based analysis. The registry does not provide model details sufficient to independently reconstruct that analysis. The most appropriate reading is to retain the reported ANOVA result and treat its interpretation as limited by the absence of the decision limits and model specification.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 12 outcome measures and 9 analyses, with four secondary outcomes posted. These include time to maximum concentration for ethinylestradiol, drospirenone, and L-5-methyl-THF, and mean drospirenone area under the concentration-time curve from administration up to 72 hours. The primary endpoint is mean maximum concentration of ethinylestradiol. This range of outcomes makes it important to know whether one endpoint was designated as primary in advance and how any multiple testing was handled.

The registry identifies a primary outcome and labels the reported primary comparison as a bioequivalence evaluation. However, multiplicity procedures, a hierarchy of hypotheses, and a detailed statistical analysis plan are not reported in the registry record. It is therefore not possible to determine whether the secondary outcomes were intended as confirmatory tests, descriptive measures, or exploratory analyses, or how their interpretation was adjusted for the number of analyses.

The primary outcome description states that not all samples were evaluable for each outcome measure. It also warns that the number of participants analyzed need not match the number of completers. The primary analysis lists 42 participants in each treatment group, but the registry does not specify the number of evaluable samples for each secondary endpoint or describe how missing measurements were handled. Reasons for missing or unevaluable samples, imputation methods, and sensitivity analyses are not reported.

The registry does not describe the analysis population, such as whether it was defined by randomized assignment, treatment received, or evaluable pharmacokinetic data. It also does not state how deviations from the crossover schedule were handled. These details matter because the number and characteristics of participants included can affect estimates, especially when analysis depends on evaluable blood samples. The posted counts and outcome summaries should be interpreted as registry-reported analyses, without assuming an unreported missing-data method or multiplicity adjustment.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports zero serious adverse events among 44 participants at risk in the Yasmin group, 43 at risk in the combination-formulation group, and 43 at risk in the Metafolin-only group. The serious adverse event counts are therefore reported as none in each listed group. The number at risk for safety monitoring differs from the 42 participants in each group of the primary outcome analysis, so these sets of counts should not be assumed to describe identical analysis populations.

Other adverse events were reported for 27 of 44 participants in the Yasmin group, 31 of 43 in the combination-formulation group, and 16 of 43 in the Metafolin-only group. These are the registry’s counts of participants affected by other adverse events; they are not evidence on their own about causation or comparative risk. The record does not list top serious adverse event terms. Death counts are not reported in the registry record.

A report of zero serious events means none were recorded among the stated at-risk counts in this study. It does not establish that serious events cannot occur, or provide a precise estimate of uncommon harms. The registry does not provide further detail about event definitions, severity grading for other events, timing, or attribution. Safety counts should be read within the study’s healthy-volunteer setting and alongside the limited scope of the posted reporting.

13. What the Result Does, and Does Not, Mean

The primary result is a pharmacokinetic comparison of ethinylestradiol peak concentration after administration of two formulations: Yasmin and a formulation containing ethinylestradiol, drospirenone, and Metafolin. The reported ANOVA mean ratio is 102.26, with a 90% confidence interval from 96.65 to 108.20. The group geometric mean estimates are 58.5 pg/mL and 61.6 pg/mL, respectively, each based on 42 participants. These results describe measured concentration, not a clinical outcome.

The confidence interval communicates uncertainty in the relative Cmax estimate. It includes a range of values around the point estimate, rather than establishing one exact ratio. Whether that interval satisfies a bioequivalence rule depends on decision limits, which are not reported in the registry record. The result should not be described as meeting or failing a specific bioequivalence standard without those limits.

The study does not establish whether the formulations differ in pregnancy outcomes, longer-term safety, adherence, or other clinical outcomes. Its primary endpoint is a concentration measure collected up to 96 hours after administration. The registry’s broader description also concerns uptake of Metafolin with or without Yasmin, but the primary result is the ethinylestradiol Cmax comparison.

The results apply to the healthy young women studied, not automatically to other populations or patterns of use. The open-label randomized crossover design and the posted analyses provide a framework for comparing formulations, but important operational and modeling details are absent. The record also notes that not all samples were evaluable for every outcome. Overall, the defensible conclusion is about the reported Cmax estimate and its precision; broader clinical conclusions are outside the evidence reported for this endpoint.

14. Why This Trial Matters Statistically

This trial illustrates how a formulation comparison can be framed around pharmacokinetic measures rather than clinical events. Maximum concentration, total exposure over a specified interval, and time to maximum concentration answer different questions about drug concentration over time. The registry’s primary endpoint is Cmax of ethinylestradiol, while several secondary measures address timing or exposure for ethinylestradiol, drospirenone, or L-5-methyl-THF.

The study also demonstrates why the scale of the analysis matters. Concentration comparisons can be expressed as geometric means and ratios, and the ratio’s confidence interval is the relevant direct comparative result reported for the bioequivalence evaluation. Group-specific confidence intervals and the comparative interval describe different quantities. Treating them as interchangeable, or using overlap between group intervals as the formal test, would confuse descriptive and inferential summaries.

The crossover model makes the within-participant structure important. In general, observations from the same participant across formulations are related, so interpretation depends on an analysis that reflects that structure. The registry identifies ANOVA but does not supply its model specification. This creates a useful distinction between knowing the headline estimate and being able to independently assess every modeling decision.

Finally, a numerical ratio and confidence interval do not define a bioequivalence conclusion without the applicable decision limits. The posted result allows readers to assess the estimate and its precision, while the unreported limits and analysis details set boundaries on what can be concluded. The trial is statistically instructive precisely because the endpoint, comparison, design, and missing decision information must be read together.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record leaves several trial-specific details unclear. Although the study is described as a three-fold crossover, it does not report treatment sequences, periods, washout intervals, or how potential carryover was assessed. It states that the study was open-label but does not describe whether any outcome assessment or laboratory work was masked. These omissions prevent a full review of the crossover implementation.

The registry’s enrollment is 48, while the official title describes 42 healthy young women and the primary analysis lists 42 participants in each of its two treatment groups. The safety summaries use at-risk counts of 44, 43, and 43. Those numbers refer to different reported contexts, and the record does not explain the relationship among enrollment, treatment exposure, completion, and evaluability. It explicitly cautions that not all samples were evaluable and that analysis counts need not equal completer counts.

The statistical reporting is also incomplete for independent reproduction. ANOVA is named, but the model specification, transformation details, treatment of participant and period effects, analysis population, and missing-data methods are not reported. The confidence interval for the primary comparison is available, but the bioequivalence decision limits are not. The registry also does not give a detailed multiplicity plan or sample-size justification.

Safety reporting is limited to participant counts for serious and other adverse events, without further event detail in the listed results. The study population is described as healthy young women, and its primary pharmacokinetic endpoint is a concentration measure after administration. The record does not support generalization to unstudied populations or conclusions about clinical outcomes beyond the measures reported.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: 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) — NCT01253174.
• Registry record last updated 2013-08-07; status last verified 2013-08.
• Results first posted 2011-05-09.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

This completed phase 1 study was a randomized, open-label, three-fold crossover investigation sponsored by Bayer. It compared formulations containing ethinylestradiol and drospirenone with and without 0.451 mg Metafolin, and also included a Metafolin-only formulation. The registry lists enrollment of 48; the official title describes 42 healthy young women.

The primary endpoint was mean maximum ethinylestradiol concentration up to 96 hours after administration. The primary analysis lists 42 participants per treatment group and reports an ANOVA mean ratio of 102.26, with a 90% confidence interval from 96.65 to 108.20. The registry does not report the bioequivalence decision limits or a detailed model specification.

The record lists 12 outcome measures and 9 analyses, with four secondary outcomes posted. It notes that not all samples were evaluable for every outcome. Serious adverse events were reported as zero in each listed safety group; other adverse events were also recorded. The findings concern pharmacokinetic measurements in the study population, not clinical outcomes.