This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Effect of Evobrutinib on Pharmacokinetics of a Combined Oral Contraceptive (NCT07215806), a na phase 1 study. The primary outcome is Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Ethinyl Estradiol and Norethisterone.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT07215806 |
| Phase | Phase 1 |
| Condition | Healthy |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 20 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany |
| Results posted | Yes |
2. Clinical Question
Population
Healthy female participants were enrolled. The registry lists an enrollment of 20. The pharmacokinetics analysis set was described as participants who completed the study without relevant protocol deviations or factors likely to affect comparability, had adequate intervention compliance, and had evaluable pharmacokinetic data. The record's description of this set ends before its final criterion is complete, and it does not report the number included in that analysis set.
Intervention
Participants received Evobrutinib orally at 45 mg twice daily on Days 4 to 17. The study description identifies this as 14 days of treatment. Combined oral contraceptive treatment consisted of 0.03 mg ethinyl estradiol and 0.5 mg norethisterone, taken orally on Day 1 and Day 15.
Comparator
There was no parallel control arm. The study is classified as single-group, with allocation listed as not applicable and masking listed as none. The dosing schedule places the Day 1 contraceptive assessment before Evobrutinib treatment and the Day 15 assessment during Evobrutinib treatment. These are assessments within the study schedule, not a randomized comparison between groups.
Primary question
The primary endpoint concerns the area under the plasma concentration-time curve extrapolated from time zero to infinity for ethinyl estradiol and norethisterone. This measure summarizes drug exposure over time. The registry record gives the endpoint definition and sampling schedule, but numerical exposure estimates and an estimated treatment comparison are not reported in the registry record.
In statistical terms, the study is intended to characterize whether exposure to the contraceptive components differs across the scheduled assessments associated with Evobrutinib use. The design does not include a separate untreated or placebo group, so interpretation depends on the within-study dosing sequence and the analysis used to compare the pharmacokinetic measurements. The registry record does not report a numerical estimate of that comparison, its uncertainty, or a test of a difference.
3. Trial Design
This is a phase I, open-label, multiple-dose, single-group study in healthy female participants. The registry lists enrollment of 20 and marks the study as completed. Allocation is listed as not applicable, and masking as none. The record therefore describes no randomized allocation and no blinded treatment assignment. Its stated purpose is to assess the effect of M2951, also identified in the study description as Evobrutinib, on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norethisterone.
The schedule places contraceptive dosing on Day 1 and Day 15. Evobrutinib was administered orally at 45 mg twice daily from Day 4 through Day 17. The registry describes this as 14 days of Evobrutinib treatment and two days of contraceptive treatment. Participants were resident in the Clinical Research Unit from Day -1 to Day 18; the stated study duration was up to 46 days. These schedule details establish when samples were intended to be collected relative to dosing, but do not by themselves establish the size or direction of any pharmacokinetic change.
For the primary pharmacokinetic outcome, the registry lists samples from pre-dose and multiple post-dose time points, extending to 72 hours, on Days 1, 2, 3, 4, 15, 16, 17 and 18. The primary outcome is defined separately for ethinyl estradiol and norethisterone. Its analysis population is described as a pharmacokinetics analysis set with completion, protocol-deviation, compliance, and evaluable-data criteria. The number analyzed and the handling of participants who did not meet those criteria are not reported in the registry record.
The single-group structure is important when reading the results. The scheduled Day 1 and Day 15 contraceptive assessments occur in different treatment contexts, but there is no concurrent randomized control arm. Any interpretation of a change therefore depends on the actual analysis and its assumptions. The registry record does not report a detailed statistical analysis plan, a model for comparing the assessments, or numerical primary outcome results.
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.
Overall Study
| Stage | COC + Evobrutinib |
|---|---|
| STARTED | 20 |
| COMPLETED | 20 |
| NOT COMPLETED | 0 |
Analysis population for the primary outcome, as defined in the registry: Pharmacokinetics (PK) Analysis set included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results; with adequate study intervention compliance; with evaluable PK data, i.e., no missing values for primary endpoints at each PK profile/assessment day (Day 1, Day 15).
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.
| Characteristic | Unit | COC + Evobrutinib |
|---|---|---|
| Participants analysed | 20 | |
| Age, Continuous | Years | 57 (SD 6.8) |
| Sex: Female, Male: Female | Participants | 20 |
| Sex: Female, Male: Male | Participants | 0 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 0 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 20 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 |
| Race (NIH/OMB): Asian | Participants | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 |
| Race (NIH/OMB): White | Participants | 20 |
| Race (NIH/OMB): More than one race | Participants | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 |
6. Primary Endpoint
The registry lists the primary outcome as Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Ethinyl Estradiol and Norethisterone, measured over Pre-dose, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours post-dose on Days 1, 2, 3, 4, 15, 16, 17 and 18.
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | Geometric Coefficient of Variation |
| Unit | hour × picogram per milliliter (h×pg/mL) |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the area under the plasma concentration-time curve from time zero extrapolated to infinity, abbreviated AUC0-inf, for ethinyl estradiol and norethisterone. It is expressed in hour × picogram per milliliter. AUC describes overall drug exposure across the period represented by the concentration-time profile. Unlike a single concentration measurement, it incorporates information from multiple sampling times, so it can reflect changes in the profile over a dosing interval.
The registry says AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra is an extrapolated component, calculated using the predicted concentration at the last sampling time at or above the lower limit of quantification and the apparent terminal rate constant. The terminal rate constant was determined by log-linear regression of measured concentrations during the terminal log-linear phase. Extrapolation is used because sampling ends before the concentration profile has necessarily reached zero; it therefore makes the endpoint dependent partly on the observed data and partly on the fitted terminal decline.
The endpoint is summarized using a geometric mean, with geometric coefficient of variation as the dispersion measure. These summaries suit positive, often right-skewed pharmacokinetic measurements, but the registry record does not provide the numerical summaries or an estimated comparison between dosing contexts. Consequently, the endpoint definition explains what was intended to be measured, not what magnitude of change was observed.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies a clear pharmacokinetic question: whether exposure to ethinyl estradiol and norethisterone differs across the scheduled contraceptive assessments, with Evobrutinib treatment occurring between the Day 1 and Day 15 contraceptive doses. It also identifies AUC0-inf as the primary measure and provides the sampling schedule and calculation description. However, numerical AUC estimates, a treatment comparison, confidence intervals, and p-values are not reported in the registry record. Without those results, the direction, magnitude, and precision of any difference cannot be assessed from the posted information.
The distinction between a measured endpoint and an estimated effect matters. AUC is calculated from concentration-time data, and a comparison would summarize how the endpoint differs across treatment contexts. The endpoint definition alone does not indicate whether exposure increased, decreased, or remained similar. Nor does the study's completed status establish a particular result. The registry record lists 0 analyses, so there is no posted numerical primary analysis to interpret.
The design provides a within-study dosing sequence rather than a parallel randomized control comparison. The Day 1 contraceptive dose precedes Evobrutinib treatment, while the Day 15 dose occurs during the listed Evobrutinib dosing period. This sequence can support a pharmacokinetic assessment, but a causal interpretation depends on the actual analysis and assumptions about comparability across the assessment periods. The registry record does not report the analytical model, adjustment procedures, or treatment-effect estimate needed to evaluate those assumptions.
Precision is also unavailable. A confidence interval, when reported, indicates a range of values compatible with the data under the analysis; its width helps show how precisely an effect has been estimated. No such interval is reported for the primary endpoint. The enrollment figure alone cannot substitute for an estimate of precision, because the analyzed sample, variability, and analysis method are not stated in the posted results.
The adverse-event summary is separate from the pharmacokinetic endpoint. It records 0 participants with serious adverse events, 9 with other adverse events, and 0 deaths in the listed group. Those counts do not supply evidence about the size or precision of a pharmacokinetic change, and they should not be read as a substitute for the primary outcome. The available record thus describes the question, design, endpoint, and selected safety counts, but does not report the primary numerical result needed to answer the pharmacokinetic question quantitatively.
9. Statistical Methods Explained
The statistical methods that can be described from the registry record are principally the pharmacokinetic endpoint construction and the form of its summary. The record identifies geometric means and geometric coefficients of variation for AUC0-inf, and describes how the extrapolated portion of AUC is obtained. It does not provide a full analysis plan or numerical output. The explanations below distinguish those reported methods from general statistical context.
What does AUC measure?
As a general concept, area under a concentration-time curve integrates measured concentrations across time. AUC0-inf extends that exposure measure from time zero to an estimate of the full period to infinity. This can make it useful when the question concerns overall exposure rather than a concentration at one selected sampling time. Its value depends on concentration measurements and timing, and its extrapolated tail also depends on how the terminal decline is estimated.
For this study, AUC0-inf was calculated as AUC0-t plus AUCextra. The registry describes AUCextra as an extrapolated value based on the predicted concentration at the last sampling time when measured concentration was at or above the lower limit of quantification, divided by the apparent terminal rate constant. The terminal rate constant was estimated by log-linear regression of concentrations in the terminal log-linear phase. This means the endpoint combines an area based on observed concentration-time data with a component inferred from a fitted terminal pattern. The record does not report how much of each endpoint was extrapolated for either contraceptive component.
Why use a geometric mean?
As general statistical context, pharmacokinetic quantities are positive and can have a right-skewed distribution. A geometric mean summarizes the central tendency on a multiplicative scale: it is based on averaging logarithms and transforming back to the original scale. That scale is often natural when interest concerns relative exposure rather than an absolute additive difference. Here the registry identifies the geometric mean as the parameter for the primary endpoint, but does not report the estimates.
The geometric coefficient of variation describes relative dispersion on a geometric scale. It conveys variability in relation to the typical magnitude, rather than expressing spread as an ordinary standard deviation in the original units. The registry lists this as the dispersion measure but does not give its numerical value. Without the estimate and dispersion, the reader cannot judge how variable the observed exposure measurements were.
What does the sampling schedule contribute?
Concentration measurements at multiple times help define the shape of the concentration-time profile and support calculation of the area. The listed primary sampling times include pre-dose and post-dose observations extending through 72 hours, on Days 1, 2, 3, 4, 15, 16, 17 and 18. Dense sampling can help characterize the rise and decline in concentrations, while later measurements inform the terminal phase used for extrapolation. These are general roles of timed pharmacokinetic sampling; the registry does not report concentration values, observed profiles, or the adequacy of sampling for individual participants.
The dosing sequence places a contraceptive dose on Day 1 before Evobrutinib begins on Day 4, and another contraceptive dose on Day 15 while Evobrutinib is scheduled. This creates distinct measurement contexts within the single-group study. A statistical comparison might use the paired nature of measurements from the same participant, but the record does not state whether that approach was used, how the comparison was calculated, or whether any covariates were included. It would be inappropriate to infer a particular model from the schedule alone.
What can confidence intervals and tests tell a reader?
As general statistical context, a confidence interval communicates uncertainty around an estimated effect under a specified analysis. A narrower interval indicates greater precision for that analysis, while a wider interval indicates less precision. A p-value, if reported, addresses how compatible the observed data are with a specified null hypothesis under the model; it does not quantify the size or clinical importance of an effect. Neither a confidence interval nor a p-value is reported for the primary endpoint in the registry record, so neither precision nor statistical evidence for a difference can be evaluated from the posted results.
When a study reports an exposure ratio, it is common in pharmacokinetics to express comparisons multiplicatively. That is general context only: the registry record does not provide a ratio, its confidence interval, or a stated inferential criterion for this study. No threshold for interpreting a change is reported, and no conclusion about whether an observed estimate met any such criterion can be drawn from the endpoint definition.
What does the single-group design mean statistically?
A single-group study does not estimate a randomized between-arm contrast. In this study, the schedule gives a before-and-during-treatment structure for the contraceptive assessments, but period differences and other time-related influences cannot be separated by randomization to a concurrent control group. This does not invalidate a pharmacokinetic assessment, but it makes the analysis and its assumptions central to interpretation. The registry record does not report a design-based adjustment, a model accounting for period, or other detail that would allow those assumptions to be examined.
The enrollment figure is not the same as the number contributing to every endpoint. The stated pharmacokinetics analysis set has eligibility criteria involving completion, deviations, compliance, and evaluable data. The exact analysis-set size, exclusions, missing concentration data, and endpoint-specific missingness are not reported. Therefore, the enrollment value alone cannot establish how much information entered the primary analysis.
Finally, planned sample-size calculations are not observed evidence about the outcome. The registry record describes a planning-illustration framework, but no numerical planning values are included in the listed details. General planning calculations depend on assumed effect size, variability, allocation, significance level, and target power; they do not demonstrate that an effect was observed or that an analysis had a particular degree of power after the fact. The posted information contains no primary effect estimate on which to base a quantitative assessment of precision.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 28 outcome measures and identifies AUC0-inf for ethinyl estradiol and norethisterone as the primary outcome. It also lists secondary safety and laboratory outcomes, including treatment-emergent adverse events, adverse events by severity, and changes in hematology and coagulation parameters. The record does not report how many outcomes were tested, how multiple comparisons were handled, or whether any adjustment to significance levels was planned. Any multiplicity strategy is therefore not reported in the registry record.
The registry identifies a pharmacokinetics analysis set with criteria for study completion, relevant protocol deviations and factors affecting comparability, intervention compliance, and evaluable pharmacokinetic data. The population description is incomplete at its end, and the number meeting the criteria is not reported. It is also not reported how participants who did not meet the criteria were handled in analyses or whether additional analysis populations were used.
Missing-data handling is not reported in the registry record. The available description does not state whether missing concentration measurements were imputed, whether incomplete profiles were excluded, or how missing endpoint values affected inclusion. For an endpoint partly based on observed measurements and partly on terminal extrapolation, the availability and adequacy of concentration data can matter; the record does not provide participant-level completeness or the extent of extrapolation.
The registry lists 0 analyses. Consequently, it does not provide endpoint-specific denominators, a statistical model, adjustment methods, confidence intervals, or p-values. The study status is completed, but that status does not establish which participants contributed to each outcome or how missing observations were addressed. These omissions limit assessment of the planned analysis and the robustness of any result.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| COC + Evobrutinib | 0 | 20 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| COC + Evobrutinib | 0 of 20 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| COC + Evobrutinib | 9 of 20 |
Most frequent non-serious adverse event terms
| Event term | Organ system | COC + Evobrutinib |
|---|---|---|
| Pollakiuria | Renal and urinary disorders | 6 of 20 |
| Abnormal faeces | Gastrointestinal disorders | 1 of 20 |
| Defaecation urgency | Gastrointestinal disorders | 1 of 20 |
| Flatulence | Gastrointestinal disorders | 1 of 20 |
| Gastrointestinal disorder | Gastrointestinal disorders | 1 of 20 |
| Fatigue | General disorders | 1 of 20 |
| Nasopharyngitis | Infections and infestations | 1 of 20 |
| Arthralgia | Musculoskeletal and connective tissue disorders | 1 of 20 |
| Pain in extremity | Musculoskeletal and connective tissue disorders | 1 of 20 |
| Headache | Nervous system disorders | 1 of 20 |
The registry's adverse-event summary lists the COC + Evobrutinib group with 20 participants at risk for serious adverse events and 0 participants affected by serious adverse events. It lists 20 at risk for other adverse events and 9 affected. Deaths are listed as 0. The serious-event terms list is empty.
These are participant counts in the registry's summary categories, not a complete account of event timing, duration, recurrence, or severity beyond the serious-versus-other distinction. The outcome list includes treatment-emergent adverse events and adverse events by severity, but the registry summary does not provide event-level details or the specific terms for the 9 participants with other adverse events. It is therefore not possible to characterize those events further from this record.
The number at risk indicates the group denominator used in the adverse-event summary; it does not show that all participants had the same follow-up or exposure time. Nor do the counts establish a comparison with an alternative treatment, since this was a single-group study with no parallel control arm. The counts describe what the registry reports for this group and should not be interpreted as a comparative estimate of safety or as evidence about the pharmacokinetic endpoint.
12. What the Result Does, and Does Not, Mean
The registry record establishes the study's purpose and its primary measurement: assessment of ethinyl estradiol and norethisterone exposure using AUC0-inf during a schedule that includes Evobrutinib treatment. It documents a phase I, open-label, multiple-dose study in healthy female participants, with a single group and no masking. It also describes the timing of treatment and pharmacokinetic sampling. Those details make the intended question and measurement approach understandable.
However, the posted information does not include numerical AUC estimates, an estimated comparison between the Day 1 and Day 15 assessments, confidence intervals, or p-values. It therefore does not establish whether exposure was higher, lower, or similar during the scheduled Evobrutinib treatment context, nor how precisely any difference was estimated. A completed study and a defined endpoint are not substitutes for reported outcome data.
The design also sets limits on what a result could mean. The assessments take place in one group at different times, rather than in randomized parallel groups. Any interpretation of a difference would need to consider the analysis and assumptions used to compare those periods. The registry record does not provide those details, so the potential influence of period-related changes or other sources of non-comparability cannot be assessed.
The safety summary reports 0 serious adverse events, 9 participants with other adverse events, and 0 deaths in the listed group. These counts do not answer the primary pharmacokinetic question, and the record does not provide event terms for the other adverse events. They should be read as descriptive counts, not as a treatment comparison.
Overall, the registry record provides a design and endpoint description but not the numerical primary result. It cannot support a quantitative conclusion about the size, direction, or precision of a pharmacokinetic difference. It also does not provide the analysis details needed to judge the effect estimate or a formal threshold for interpretation.
13. Why This Trial Matters Statistically
This study is statistically notable because its primary question concerns drug exposure, not a clinical outcome, and because it uses a timed single-group dosing sequence. The primary endpoint, AUC0-inf, combines a concentration-time area based on measured samples with an extrapolated terminal component. That makes the endpoint dependent on both sampling and modeling choices. The registry gives the calculation description, which helps readers understand what the measure represents, but does not provide the underlying estimates or the extent of extrapolation.
The study schedule also illustrates why design structure matters. Contraceptive dosing is scheduled before Evobrutinib treatment and again during its scheduled use, allowing pharmacokinetic assessment in different contexts within the same group. But without a parallel randomized control arm, the interpretation depends on assumptions about how comparable those assessment periods are and on the statistical method used. The record does not report that method.
Equally important is the distinction between protocol information and results. The record lists the primary endpoint, its sampling times, and the analysis-population criteria, yet lists 0 analyses and gives no numerical primary outcome. Readers can identify what the study set out to measure without being able to determine the observed change or its precision. This is a useful reminder that a detailed endpoint definition is not itself an estimate.
The record also makes clear that outcome availability, analysis populations, and missing-data handling are central to interpreting pharmacokinetic studies. The stated analysis-set criteria are more restrictive than enrollment alone, but the analyzed number and missing-data procedures are not reported. Without those details, the contribution of incomplete or excluded profiles to the result cannot be assessed. These limitations are statistical and reporting issues; they do not establish a particular pharmacokinetic or clinical conclusion.
14. 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 primary limitation for interpretation is the absence of numerical pharmacokinetic results in the registry record. Although AUC0-inf is defined and the sampling schedule is described, there are no reported estimates for ethinyl estradiol or norethisterone, no comparison between assessment contexts, and no measures of uncertainty. The record therefore does not permit assessment of effect direction, magnitude, or precision.
The single-group design has no concurrent randomized control arm. The Day 1 contraceptive assessment precedes Evobrutinib dosing, and the Day 15 assessment occurs during its scheduled dosing period. This timing makes a within-study comparison possible in principle, but its interpretation depends on the analysis and assumptions about differences across periods. The statistical model and any adjustment for period effects are not reported in the registry record.
The pharmacokinetic analysis population is described using completion, protocol-deviation, compliance, and evaluable-data criteria, but the description is incomplete at its end. The number analyzed, reasons for exclusion, and endpoint-specific denominators are not reported. Missing concentration data and the handling of incomplete profiles are also not reported. These details matter because AUC0-inf includes an extrapolated component based on the terminal concentration pattern.
Further limitations include the absence of a reported analysis plan, confidence intervals, p-values, multiplicity procedures, and event-level safety details. The registry lists 28 outcome measures but does not state how multiple outcomes were handled analytically. The adverse-event summary is descriptive and has no control-group comparison. These reporting gaps prevent a fuller evaluation of the analysis and its uncertainty.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Effect of Evobrutinib on Pharmacokinetics of a Combined Oral Contraceptive — NCT07215806.
- Registry record last updated 2025-11-14; status last verified 2025-10.
- Results first posted 2025-11-14.
- 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.
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18. Record Summary
NCT07215806 is a completed phase I, open-label, multiple-dose, single-group study in healthy female participants. The registry lists enrollment of 20 and describes Evobrutinib administration from Day 4 to Day 17 alongside contraceptive doses on Day 1 and Day 15. The primary endpoint is AUC0-inf for ethinyl estradiol and norethisterone, summarized using geometric means and geometric coefficients of variation.
The record describes the sampling schedule and the calculation of the extrapolated AUC component. It does not report numerical primary outcome estimates, a treatment comparison, confidence intervals, or p-values, and lists 0 analyses. The safety summary lists 0 participants with serious adverse events, 9 with other adverse events, and 0 deaths. Analysis-set size, missing-data handling, and multiplicity procedures are not reported in the registry record.