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 Drug-Drug Interaction Study of Evobrutinib and Transporter Substrates (NCT05064488), a non-randomized phase 1 study. The primary outcome is Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Digoxin.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT05064488 |
| Phase | Phase 1 |
| Condition | Healthy |
| Allocation | Non-Randomized |
| Design model | Sequential |
| Masking | None (open label) |
| Enrollment | 40 |
| 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 participants were enrolled in this Phase I study. The registry lists total enrollment as 40. The primary pharmacokinetic population was defined as participants who completed the study without relevant protocol deviations or factors likely to affect comparability of pharmacokinetic results, and with adequate study intervention compliance. The number included in that population is not reported in the registry record.
Intervention
The study evaluated multiple doses of evobrutinib, given orally at 45 mg twice a day, alongside single doses of transporter substrates. In Part 1, the substrates were digoxin, metformin, and rosuvastatin, administered together as a cocktail. In Part 2, the substrate was sumatriptan. Dosing took place under fed conditions.
Comparator
There was no randomized, like-for-like control comparison. Each part included a substrate-only dosing occasion and a later occasion when the substrate was given with evobrutinib. The registry describes the study as non-randomized, open-label, and sequential. These features mean that differences between occasions cannot be interpreted as though participants had been randomly assigned to concurrent treatment groups.
Primary question
For the primary endpoint, the study asked how digoxin exposure, measured by the area under its plasma concentration-time curve extrapolated from time zero to infinity, was characterized on the cocktail dosing occasion compared with the occasion when the cocktail was given with evobrutinib. The endpoint definition is reported, but the result of this comparison is not reported in the registry record.
The registry describes two related but distinct investigations. Part 1 focused on digoxin, metformin, and rosuvastatin, while Part 2 focused on sumatriptan. The stated aim was to evaluate pharmacokinetics, safety, and tolerability during multiple-dose evobrutinib exposure. The listed primary measure pertains specifically to digoxin in Part 1; it should not be treated as the primary result for every substrate or for Part 2.
The clinical question is therefore narrow: what pharmacokinetic pattern was observed for the named substrates when their single doses were administered in the context of repeated evobrutinib dosing? The registry describes the intended measurements and dosing schedules, but does not report the numerical primary outcome estimate or a corresponding uncertainty interval. It also does not report a comparative endpoint estimate for metformin, rosuvastatin, or sumatriptan in the record summarized by these registry entries. Without those results, the direction and precision of any pharmacokinetic difference cannot be described.
3. Trial Design
This is a Phase I, open-label, non-randomized study using a sequential model. The registry reports enrollment of 40 healthy participants and a completed status. The recorded study start was 2021-10-04 and primary completion was 2021-12-10. The registry lists Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany, as sponsor.
The study had two parts. In Part 1, participants received a single oral cocktail dose of digoxin 0.25 mg, metformin 10 mg, and rosuvastatin 10 mg on Day 1 under fed conditions. Evobrutinib 45 mg was then given orally twice a day on Days 4 to 12. On Day 10, the cocktail was administered with evobrutinib. The primary endpoint concerns digoxin exposure in this part, although the cocktail also contained the other two transporter substrates.
In Part 2, a single oral dose of sumatriptan 25 mg was given on Day 1 under fed conditions. Evobrutinib 45 mg was given orally twice a day on Days 2 to 8, and sumatriptan was given again with evobrutinib on Day 8. Both parts therefore include a substrate-only occasion and a later occasion with evobrutinib, but the schedules differ between parts.
Open-label means masking was absent according to the registry; non-randomized means allocation was not random. The sequential model and dosing schedules describe how the study was organized, but they do not establish that every participant completed every planned occasion or that all occasions were evaluable. Participant flow by part and the number of participants contributing to each pharmacokinetic analysis are not reported in the registry record.
The record lists 35 outcome measures and 12 analyses. Those counts indicate a broader set of registered assessments than the primary digoxin endpoint alone, but do not by themselves reveal which results were reported, how outcomes were prioritized statistically, or whether all listed assessments were analyzed. A detailed statistical analysis plan, including the prespecified model for comparisons, is not reported in the registry record.
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: A total of 40 healthy participants were enrolled in two parts single-sequences: Part 1 (Evobrutinib and Cocktail \[digoxin, metformin, and rosuvastatin\] as transporter substrates) and Part 2 (Evobrutinib and Sumatriptan as transporter substrate) with each part consists of 20 participants.
Overall Study
| Stage | Part 1: All Participants | Part 2: All Participants |
|---|---|---|
| STARTED | 20 | 20 |
| Part 1: Cocktail (Day 1) | 20 | 0 |
| Part 1: Evobrutinib + Cocktail (Day 10) | 19 | 0 |
| Part 2: Sumatriptan (Day 1) | 0 | 20 |
| Part 2: Evobrutinib (Days 2 to 8) | 0 | 20 |
| Part 2: Evobrutinib + Sumatriptan (Day 8) | 0 | 20 |
| Part 1: Evobrutinib (Days 4 to 12) | 20 | 0 |
| COMPLETED | 18 | 20 |
| NOT COMPLETED | 2 | 0 |
Reasons for not completing this period:
| Reason | Part 1: All Participants | Part 2: All Participants |
|---|---|---|
| Withdrawal by Subject | 2 | 0 |
Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) population 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.
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 | Part 1: All Participants | Part 2: All Participants | Total |
|---|---|---|---|---|
| Participants analysed | 20 | 20 | 40 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 20 | 20 | 40 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 0 |
| Sex: Female, Male: Female | Participants | 11 | 14 | 25 |
| Sex: Female, Male: Male | Participants | 9 | 6 | 15 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 0 | 0 | 0 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 20 | 20 | 40 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): White | Participants | 20 | 20 | 40 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
6. Primary Endpoint
The registry lists the primary outcome as Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Digoxin, measured over Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10.
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | Geometric Coefficient of Variation |
| Unit | Hour*nanogram per milliliter (h*ng/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 (AUC0-inf) for digoxin, measured in hour*nanogram per milliliter (h*ng/mL). AUC represents drug exposure over time, rather than a single concentration measurement. Extending the area to infinity is intended to represent exposure beyond the final sampling time as well as exposure during the observed sampling period.
The registry defines AUC0-inf as the area from time zero to the last sampling time with a concentration at or above the lower limit of quantification, plus an extrapolated terminal component. The latter uses the predicted concentration at the last sampling time and the apparent terminal rate constant, lambda z. The area was calculated using the mixed log-linear trapezoidal rule, described as linear up and log down. These details define how the exposure summary is constructed; the numerical AUC result and its comparison are not reported in the registry record.
The endpoint was measured after dosing on Days 1 and 10, with plasma sampling listed from pre-dose through 16 hours post-dose. Day 1 corresponds to the cocktail occasion without evobrutinib in the Part 1 schedule, and Day 10 corresponds to the occasion when the cocktail was given with evobrutinib. AUC0-inf is useful in pharmacokinetic research because it condenses a concentration-time profile into an overall exposure measure. General statistical context: a summary measure can make a comparison easier to interpret, but its precision depends on the observed data and analysis population. Neither the estimate nor its precision is reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record describes the question, treatment schedules, endpoint definition, and safety counts, but does not report the numerical primary pharmacokinetic result. Consequently, the direction, size, and precision of the evobrutinib-associated difference in digoxin AUC0-inf cannot be stated from this record. No estimate, confidence interval, or primary comparison p-value is reported in the registry record.
This absence matters because endpoint definitions alone do not establish what was observed. AUC0-inf is the planned measure of digoxin exposure, and the record specifies that it was assessed on Days 1 and 10 in Part 1. However, without the posted values for those occasions and an analysis of their relationship, it is not possible to describe whether the measured exposure was higher, lower, or similar when digoxin was administered with evobrutinib. It is also not possible to state how compatible the data are with a range of possible effects.
The study is non-randomized and open-label. Its sequential structure offers a within-study contrast between substrate-only and substrate-plus-evobrutinib dosing occasions, but it is not a randomized concurrent comparison. The registry explicitly notes that the arms are not a like-for-like control comparison. Interpretation should therefore retain the actual design context rather than imply that a randomized treatment effect was estimated. The record does not give enough detail to characterize how period, sequence, or other potential sources of variation were handled statistically.
The primary endpoint applies to digoxin in Part 1. It does not directly answer the corresponding pharmacokinetic questions for metformin, rosuvastatin, or sumatriptan. The study registered other pharmacokinetic outcomes, including time to maximum observed plasma concentration for the Part 1 substrates, but the presence of registered outcomes is not itself evidence of a particular finding. Results for these measures are not reported in the registry record.
Safety counts are available for the listed study groups. No serious adverse events and no deaths are recorded in any listed group. Other adverse events are recorded in each group, with counts ranging from 6 to 10 among groups with 19 or 20 participants at risk. These are descriptive counts for the recorded groups, not a randomized comparison. They do not provide enough detail to assess event types, timing, severity distributions, or causal attribution. A report of zero serious events in these group counts should not be read as proof that serious events cannot occur.
General statistical context: a confidence interval communicates the range of effect sizes reasonably compatible with an estimate under the analysis assumptions. A point estimate without an uncertainty measure can be hard to interpret, and no primary estimate or interval is reported in the registry record. Statistical significance, if reported elsewhere, would not by itself convey clinical importance; in this record, the primary comparison result needed to make even that statistical interpretation is not reported.
9. Statistical Methods Explained
General statistical context: pharmacokinetic studies often compare concentration-time profiles or summaries derived from them. In this study, the primary summary is AUC0-inf for digoxin. AUC captures exposure accumulated over time, while a single concentration reflects only a particular sampling time. Extrapolating the area to infinity extends the observed profile using an estimated terminal phase, so the endpoint depends both on measured concentrations and on the fitted terminal-rate information described in the registry.
What does the AUC0-inf calculation represent?
The registry defines the observed portion as AUC from dosing time to the last sampling time at which concentration is at or above the lower limit of quantification. It then adds an extrapolated terminal portion based on the predicted concentration at that last sampling time and lambda z, described as the apparent terminal rate constant. The registry states that AUC was calculated with the mixed log-linear trapezoidal rule, linear up and log down. In general, this approach uses one interpolation convention while concentrations rise and another while they decline. The numerical contribution of the extrapolated portion, and diagnostic information about the terminal fit, are not reported in the registry record.
Plasma sampling was scheduled pre-dose and at 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10. These time points describe the planned measurement schedule, not proof that every sample was collected or used. Sample completion, the number of evaluable concentration profiles, and rules for handling incomplete profiles are not reported in the registry record.
How should geometric summaries be understood?
The primary endpoint parameter is identified as a geometric mean, with geometric coefficient of variation as its dispersion measure. General statistical context: geometric summaries are commonly used for measurements that are positive and may vary multiplicatively. A geometric mean is based on the logarithmic scale and is then expressed back on the original scale. The geometric coefficient of variation describes relative dispersion on that scale; it is not the same quantity as a standard deviation in the original measurement units. The actual geometric mean and geometric coefficient of variation for this endpoint are not reported in the registry record.
When comparing pharmacokinetic measurements across occasions, an analysis may use transformed measurements or a model tailored to repeated observations. The registry information summarized in this record does not specify the model, transformation, covariates, estimation procedure, or variance method used for the primary comparison. These details are not reported in the registry record, so they should not be inferred from the endpoint parameter alone.
Why does the design affect interpretation?
The study is open-label, non-randomized, and sequential. The schedule places substrate dosing alone before substrate dosing with evobrutinib within each part, while the specific days differ between Part 1 and Part 2. General statistical context: in a sequential design, observations made at different times can reflect both the intervention context and changes associated with time or study period. Random allocation can help balance some sources of variation between groups, but this study is not randomized. Its design therefore needs to be described as a sequential pharmacokinetic evaluation, not as a randomized controlled trial. The registry does not report the analysis methods used to address period or sequence effects.
The registry's primary pharmacokinetic population includes participants who completed the study without relevant protocol deviations or factors likely to affect comparability of pharmacokinetic results, and with adequate intervention compliance. This definition identifies a selected analysis population. The number of participants meeting it, exclusions, and the effect of exclusions on the estimate are not reported in the registry record. General statistical context: restricting an analysis to evaluable participants can be reasonable for pharmacokinetic measurements, but transparent reporting of exclusions and missing measurements helps readers assess the representativeness and reliability of the results.
What can adverse-event counts tell readers?
Safety outcomes include counts of participants with treatment-emergent adverse events and serious treatment-emergent adverse events, along with severity and clinically relevant changes in laboratory parameters, vital signs, and electrocardiogram findings. The available group counts record no serious adverse events and no deaths. Other adverse-event counts are also listed. These counts are descriptive; they do not establish comparative risk, particularly in a non-randomized study. The event-level details, exposure-adjusted rates, and comparative safety analysis are not reported in the registry record.
The registry lists 35 outcome measures and 12 analyses, but that does not disclose the statistical methods for each. Multiplicity adjustment, treatment of missing data, interim analyses, and detailed prespecification of statistical tests are not reported in the registry record. General statistical context: when many outcomes or comparisons are examined, multiplicity can increase the chance of chance findings if results are interpreted without accounting for the analysis plan. The record does not allow readers to determine whether or how that issue was addressed.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 35 outcome measures and 12 analyses. Those counts indicate that the study registered multiple assessments across its two parts, including pharmacokinetic and safety outcomes. They do not establish which outcomes were analyzed together, which were designated primary or secondary in the analysis plan, or whether statistical adjustments were applied when interpreting multiple results. Multiplicity methods are not reported in the registry record.
Missing-data handling is also not described. The primary pharmacokinetic population is defined using study completion, absence of relevant protocol deviations or factors likely to affect comparability, and adequate intervention compliance. However, the number of participants meeting this definition, the number with missing samples, reasons for missingness, and any imputation or other handling rules are not reported in the registry record. These details matter because the endpoint depends on a concentration-time profile and an extrapolated terminal component.
The registry specifies sampling times and a pharmacokinetic population definition, but does not report a detailed statistical analysis plan, model specification, or interim-analysis procedures. Sample-size justification is not reported in the registry record. The total enrollment is listed as 40, but that figure alone does not explain the intended precision or power for the primary comparison, nor does it show how many participants contributed to each part or analysis.
General statistical context: multiplicity concerns arise when several outcomes or comparisons are considered, while missing-data concerns arise when planned measurements are unavailable or excluded. Both can affect how confidently findings are interpreted. In this record, the relevant procedures and primary results needed to evaluate these issues are not reported, so no claim about adjustment or missing-data robustness is warranted.
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 |
|---|---|---|---|
| Part 1: Cocktail | 0 | 20 | 0.0% |
| Part 1: Evobrutinib | 0 | 20 | 0.0% |
| Part 1: Evobrutinib + Cocktail | 0 | 19 | 0.0% |
| Part 2: Sumatriptan | 0 | 20 | 0.0% |
| Part 2: Evobrutinib | 0 | 20 | 0.0% |
| Part 2: Evobrutinib + Sumatriptan | 0 | 20 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Part 1: Cocktail | 0 of 20 |
| Part 1: Evobrutinib | 0 of 20 |
| Part 1: Evobrutinib + Cocktail | 0 of 19 |
| Part 2: Sumatriptan | 0 of 20 |
| Part 2: Evobrutinib | 0 of 20 |
| Part 2: Evobrutinib + Sumatriptan | 0 of 20 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Part 1: Cocktail | 7 of 20 |
| Part 1: Evobrutinib | 9 of 20 |
| Part 1: Evobrutinib + Cocktail | 6 of 19 |
| Part 2: Sumatriptan | 6 of 20 |
| Part 2: Evobrutinib | 10 of 20 |
| Part 2: Evobrutinib + Sumatriptan | 8 of 20 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Part 1: Cocktail | Part 1: Evobrutinib | Part 1: Evobrutinib + Cocktail | Part 2: Sumatriptan | Part 2: Evobrutinib | Part 2: Evobrutinib + Sumatriptan |
|---|---|---|---|---|---|---|---|
| Headache | Nervous system disorders | 4 of 20 | 0 of 20 | 1 of 19 | 3 of 20 | 4 of 20 | 3 of 20 |
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | 1 of 20 | 1 of 20 | 1 of 19 | 0 of 20 | 0 of 20 | 2 of 20 |
| Abdominal pain | Gastrointestinal disorders | 0 of 20 | 2 of 20 | 1 of 19 | 0 of 20 | 1 of 20 | 0 of 20 |
| Cough | Respiratory, thoracic and mediastinal disorders | 2 of 20 | 2 of 20 | 0 of 19 | 0 of 20 | 0 of 20 | 0 of 20 |
| Dizziness | Nervous system disorders | 1 of 20 | 0 of 20 | 0 of 19 | 1 of 20 | 0 of 20 | 2 of 20 |
| Diarrhoea | Gastrointestinal disorders | 0 of 20 | 1 of 20 | 0 of 19 | 0 of 20 | 1 of 20 | 1 of 20 |
| Nausea | Gastrointestinal disorders | 1 of 20 | 0 of 20 | 0 of 19 | 0 of 20 | 1 of 20 | 1 of 20 |
| Fatigue | General disorders | 0 of 20 | 0 of 20 | 0 of 19 | 1 of 20 | 1 of 20 | 1 of 20 |
| Abnormal faeces | Gastrointestinal disorders | 0 of 20 | 1 of 20 | 1 of 19 | 0 of 20 | 0 of 20 | 0 of 20 |
| Faeces soft | Gastrointestinal disorders | 0 of 20 | 0 of 20 | 1 of 19 | 0 of 20 | 1 of 20 | 0 of 20 |
The registry lists six study groups spanning the two parts and their dosing occasions. For serious adverse events, the count is 0 in each listed group; deaths are also recorded as 0 in each group. The number at risk is 20 in most groups and 19 in the Part 1 evobrutinib-plus-cocktail group. These are group-specific counts, not a pooled study-wide estimate.
Other adverse events are recorded for 7 participants in Part 1: Cocktail, 9 in Part 1: Evobrutinib, and 6 in Part 1: Evobrutinib + Cocktail. In Part 2, the corresponding counts are 6 for Sumatriptan, 10 for Evobrutinib, and 8 for Evobrutinib + Sumatriptan. These figures are descriptive and should not be interpreted as a randomized comparison of treatment effects. The sequential, non-randomized design does not establish like-for-like control groups, and the record does not provide a comparative safety analysis.
The registry also identifies outcomes for adverse-event severity and clinically relevant changes in laboratory parameters, vital signs, and 12-lead ECG findings. Their numerical results are not reported in the registry record. The serious-event counts alone do not describe all safety experience, event duration, severity, or attribution. Zero recorded serious events in these groups means none are listed for these participants and occasions; it does not establish that the risk is zero.
12. What the Result Does, and Does Not, Mean
The record establishes that investigators planned a two-part Phase I evaluation of multiple-dose evobrutinib alongside single doses of transporter substrates in healthy participants. It gives the dosing schedules, defines digoxin AUC0-inf as the primary endpoint, and reports selected adverse-event counts. These registry entries clarify what was studied and how the primary pharmacokinetic measure was defined.
It does not establish the magnitude or direction of the primary pharmacokinetic result. The primary AUC0-inf estimate, its uncertainty, and the comparison result are not reported in the registry record. Therefore, the record does not support a numerical statement about how digoxin exposure differed between the substrate-only and evobrutinib-plus-cocktail occasions. Nor does it provide a basis for describing the precision of that difference.
The primary measure is specifically for digoxin in Part 1. Although metformin and rosuvastatin were included in the same cocktail and sumatriptan was studied in Part 2, the digoxin endpoint should not be generalized as a result for those other substrates. Their registered outcomes and measures require their own reported estimates. Those results are not reported in the registry record.
The study was conducted in healthy participants and was open-label, non-randomized, and sequential. Its findings, if available elsewhere, would need to be interpreted in that design and population context. This record does not provide a randomized comparison, and it does not report enough analysis detail to assess how time-related or other design features were handled. The safety counts are likewise descriptive and cannot establish comparative safety.
General statistical context: a finding is most informative when readers can see the estimate, uncertainty, analysis population, and methods used to produce it. The registry record contains endpoint definitions and some safety counts, but omits the primary numerical result and key analysis details. It therefore supports an account of the study question and design, not a conclusion about the size, precision, or practical importance of a pharmacokinetic effect.
13. Why This Trial Matters Statistically
This study is statistically useful as an example of a pharmacokinetic question framed around repeated exposure to one medicine and single doses of transporter substrates. It separates the question into two parts: a cocktail of digoxin, metformin, and rosuvastatin in Part 1, and sumatriptan in Part 2. The primary endpoint then narrows the main reported question to digoxin AUC0-inf rather than treating all substrates as interchangeable outcomes.
The record also illustrates why a detailed endpoint definition matters. AUC0-inf includes both observed concentration data and an extrapolated terminal component, and the registry specifies the sampling schedule, integration approach, and terminal-rate calculation. These features help readers understand what the measure represents and why an endpoint value would depend on more than one blood concentration. Yet definitions cannot substitute for results: without the estimate and uncertainty, the magnitude and precision of the comparison remain unknown.
Design is also central to statistical interpretation. The sequential, non-randomized, open-label structure differs from a randomized concurrent comparison. It gives context for how substrate-only and coadministration occasions were scheduled, but does not justify treating the occasions as randomly assigned arms. A careful reading keeps the design limitations visible rather than framing the result as a definitive causal comparison.
Finally, the record distinguishes registered outcomes from reported findings. It lists multiple outcome measures and analyses and provides selected safety counts, but does not report the primary pharmacokinetic result or several details needed to assess analysis choices. This is a useful reminder that statistical transparency depends not only on naming outcomes, but also on reporting estimates, uncertainty, analysis populations, and methods. The record supports understanding the intended question; it does not allow the primary effect to be quantified.
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 principal limitation for interpretation is that the numerical primary endpoint result is not reported in the registry record. The digoxin AUC0-inf estimate, comparison, and uncertainty interval are unavailable in this record, preventing assessment of effect direction, magnitude, or precision. Results for the other substrate pharmacokinetic outcomes are also not reported.
The design was non-randomized, open-label, and sequential, and the registry states that the arms are not a like-for-like control comparison. The occasions also occurred on different days, with distinct schedules in the two parts. The record does not report how the analysis accounted for period or sequence effects, or whether other factors affecting pharmacokinetic comparability were modeled.
Although the primary pharmacokinetic population is defined, the number included in that population and participant flow by part are not reported in the registry record. The number with complete concentration profiles, reasons for exclusion or missing samples, and handling of incomplete data are also not reported. These omissions limit assessment of how representative the analyzed population was and how robust the endpoint calculation may be.
The record lists multiple outcome measures and analyses, but does not report multiplicity procedures, a detailed statistical analysis plan, sample-size justification, or interim-analysis methods. Safety results are limited to group counts for serious events, deaths, and other events in the information. Event-level details and numerical findings for the listed severity and clinical-change outcomes are not reported in the registry record.
The study population consisted of healthy participants. Findings from this population would not, by themselves, establish what would be observed in other populations. That limitation is separate from the missing primary result: even a fully reported estimate would need to be interpreted according to the study population and non-randomized design.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Drug-Drug Interaction Study of Evobrutinib and Transporter Substrates — NCT05064488.
- Registry record last updated 2025-12-05; status last verified 2025-11.
- Results first posted 2025-12-05.
- 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
NCT05064488 is a completed Phase I, open-label, non-randomized, sequential study in healthy participants, with enrollment listed as 40. It evaluated multiple-dose evobrutinib alongside single-dose digoxin, metformin, and rosuvastatin in Part 1 and sumatriptan in Part 2. The primary endpoint was digoxin AUC0-inf in Part 1, defined using observed concentrations and an extrapolated terminal component.
The registry records no serious adverse events or deaths in any listed group. Other adverse-event counts range from 6 to 10 among groups with 19 or 20 participants at risk. The primary pharmacokinetic estimate, its uncertainty, detailed analysis methods, multiplicity procedures, and missing-data methods are not reported in the registry record. Accordingly, the record describes the study design and endpoint but does not permit quantification of the primary comparison.