Tepotinib Drug-Drug Interaction Study With Carbamazepine in Healthy Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Tepotinib Drug-Drug Interaction Study With Carbamazepine in Healthy Participants (NCT05213481), 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 Tepotinib.

2. Clinical Question

The study asked whether multiple doses of carbamazepine changed the pharmacokinetics of a single dose of tepotinib in healthy participants. The planned within-participant comparison used tepotinib exposure measured after a dose on Day 1 and after a dose on Day 26, during the carbamazepine treatment period. The primary measure was tepotinib area under the plasma concentration-time curve extrapolated to infinity, or AUC0-inf.

This is a pharmacokinetic interaction question, not a study of clinical benefit. Although the registry lists safety outcomes as well, the primary endpoint concerns the concentration-time profile of tepotinib. The record does not report the estimated change in AUC0-inf, a confidence interval, or a statistical test for the comparison. The design and endpoint therefore identify what the study set out to assess, but the posted record does not establish the size or precision of the observed pharmacokinetic difference.

3. Trial Design

The registry describes a Phase I, open-label, single-sequence, cross-over study in healthy participants. It is marked as sequential, with no masking and no randomized allocation. Enrollment is listed as 18, and the study status is completed. The listed study dates are 2021-12-15 for the start and 2022-05-06 for primary completion.

Participants received tepotinib as a single oral dose of 500 milligrams (mg) on Day 1 and again on Day 26, in the morning under fed conditions. Carbamazepine was given orally twice daily, in the morning and evening under fed conditions, from Days 8 to 32. The listed carbamazepine doses are 100, 200 or 300 mg. The registry does not explain how participants were assigned to those listed dose levels or whether dose levels were changed during participation.

The study description gives a duration of up to about 10 weeks. It describes residence in a Clinical Research Unit from Days -1 to 4 and Days 25 to 29, daily ambulatory visits from Days 5 to 24 and 30 to 33, and an ambulatory visit on Day 39. These details indicate a structured period of pharmacokinetic sampling around tepotinib dosing and repeated carbamazepine dosing.

Because all participants followed a single sequence, the design does not provide a parallel, randomized untreated control group. A before-and-during comparison within participants can control for stable participant characteristics, but it does not by itself remove effects that change over time or other period-related influences. The registry record does not report a washout rationale, a carryover assessment, or the analysis used to address period effects. It also does not report a protocol-level statistical plan or sample-size justification. Those omissions limit how fully the design and the intended inference can be evaluated from the registry record alone.

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 29 participants were screened, out of which 18 participants received the study drug.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: PK analysis set included all participants who had administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. Here 'Overall number of participants analyzed' = overall number of participants evaluable for this outcome measure.

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 Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib, measured over Predose 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose.

The primary endpoint is tepotinib AUC0-inf, reported in hours* nanograms per milliliter (h*ng/mL). AUC is the area under a concentration-time curve. It represents overall systemic drug exposure across the measured period; the “0-inf” designation means the area is extended from dosing time to infinity rather than stopping at the last measured concentration.

The registry says the extrapolated portion is based on a predicted concentration at the last sampling time, estimated using a linear regression for the terminal elimination rate constant, λz. Thus, the endpoint combines observed concentrations over time with a model-based estimate for the portion beyond the last sample. The timing schedule includes predose measurements and multiple postdose samples through 168 hours for tepotinib.

General: AUC is useful in pharmacokinetic studies because it condenses a concentration-time profile into a measure of total exposure. Comparing AUC before and during another medicine’s administration can help characterize a potential pharmacokinetic interaction. AUC alone does not describe every feature of a concentration profile; peak concentration and the time to peak are separate pharmacokinetic measures.

The registry identifies the endpoint statistic as a geometric mean and its dispersion as a geometric coefficient of variation. It does not report the AUC estimates or the comparison between study periods. Consequently, the endpoint’s definition is available, but its observed magnitude and precision are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes an open-label, single-sequence, cross-over study and identifies AUC0-inf as the primary endpoint. It also names the geometric mean as the endpoint parameter and the geometric coefficient of variation as the dispersion measure. It does not report a statistical analysis entry, a numerical endpoint estimate, or a detailed analysis method. The explanations below distinguish general statistical concepts from methods explicitly described in the record.

What does a cross-over design contribute?

General: In a cross-over design, participants receive or experience more than one condition or period, and outcomes can be compared within the same participants. A participant can serve as their own reference, which may reduce the influence of stable individual characteristics on a comparison. In this study, the sequence places tepotinib dosing before and during carbamazepine administration.

A cross-over comparison is not automatically free from bias. Because periods occur in sequence, changes over time can be entangled with the exposure being compared. Residual effects from an earlier period can also matter when relevant to the treatment and timing. The registry record does not report a specific period-effect or carryover analysis, nor does it describe how such effects were incorporated into an estimator. The single-sequence design also means the registry does not describe a randomized parallel control group.

What does AUC0-inf measure?

General: AUC is a summary of the concentration-time curve and is used as a measure of total drug exposure. AUC0-inf includes the area from dosing time through the observed concentration profile and an extrapolated portion after the last measured concentration. The record says that the predicted concentration at the last sampling time and a linear regression used for λz determination contribute to this extrapolation. The endpoint therefore depends partly on observations and partly on the terminal-phase estimation procedure.

The registry lists postdose tepotinib sampling through 168 hours, along with predose measurements. Dense sampling around dosing can characterize the concentration-time profile, while later measurements help characterize its terminal portion. The registry’s description does not state how many samples were required for an individual’s endpoint, how observations below a quantification limit were handled, or what rules governed an unreliable terminal-phase fit. Those procedures are not reported in the registry record.

Why report a geometric mean and geometric coefficient of variation?

General: Pharmacokinetic measures are positive quantities and can have multiplicative rather than additive variation. A geometric mean summarizes a positive distribution on a logarithmic scale and can be more representative than an arithmetic mean when values are right-skewed. A geometric coefficient of variation expresses relative dispersion, rather than spread in the endpoint’s original units. It is not an interval estimate for the treatment comparison and does not, by itself, show the precision of that comparison.

For a comparison of exposure conditions, analyses may use transformed values or a ratio-based summary, but the registry record does not state which specific comparison model or estimator was used. It does not provide a confidence interval or p-value. Therefore, it is not possible to determine from the posted record whether uncertainty was estimated using a paired method, a model incorporating period, or another approach.

How should uncertainty and significance be understood?

General: A confidence interval describes uncertainty around an estimate under the model and assumptions used. A p-value, when reported, evaluates how compatible the data are with a specified null hypothesis under an analysis model; it is not the probability that the null hypothesis is true. For an interaction study, the estimated size of the exposure comparison and its interval are generally more informative than a significance label alone. No primary endpoint interval or test result is reported in the registry record, so no conclusion about statistical significance or precision can be drawn.

The sample-size assumptions associated with planning illustrations describe a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. These are planning assumptions, not a description of the trial’s actual single-sequence design. Any resulting sample-size illustration is not observed power and should not be read as evidence that the study was adequately or inadequately powered. The registry record does not report the trial’s own sample-size justification.

The study is marked with no analysis entries. The registry record also does not report an interim analysis, multiplicity adjustment, missing-data method, or a complete statistical analysis plan. Those items should not be inferred from the endpoint summary or the study’s completed status. In general, interpretation of a pharmacokinetic comparison requires the actual estimates, their uncertainty, the analysis population, and enough methodological detail to understand how the comparison was formed. The record does not contain those primary-result details.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and several secondary outcomes. The secondary outcomes include treatment-emergent adverse events, serious treatment-emergent adverse events, events with severity of Grade greater than or equal to 3, clinically meaningful changes in laboratory values, electrocardiograms and vital signs, and additional tepotinib pharmacokinetic measures such as clearance, apparent volume of distribution, Tmax, and terminal half-life. The record lists 11 outcome measures but does not give a multiplicity strategy.

General: When a study evaluates multiple outcomes or makes multiple statistical comparisons, the chance of at least one nominally unusual result can increase. A prespecified hierarchy, adjustment procedure, or clearly exploratory interpretation can help explain how such results should be read. The registry record does not report whether any such approach was planned or used. It also does not list statistical analysis entries, so the handling of secondary comparisons cannot be reconstructed from the posted record.

The record defines the pharmacokinetic analysis set as participants who received any study intervention, completed the study, and had no relevant protocol deviations or factors likely to affect the comparability of pharmacokinetic results. This definition indicates that not every enrolled participant necessarily belongs to that analysis set. The number included in the primary analysis is not reported in the registry record, and the record does not give participant-level exclusions or reasons for exclusion.

Missing-data procedures are also not reported in the registry record. There is no description of imputation, handling of missing concentration measurements, or rules for endpoint calculation when the terminal phase could not be estimated. Such procedures can affect which participants contribute to an AUC analysis and how precisely the comparison is estimated. The available definition of the analysis set should not be treated as a full missing-data plan.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse event counts separately for the Tepotinib, Carbamazepine, and Tepotinib Then Carbamazepine exposure groups. The reported numbers of participants with serious adverse events are 0 among 18 at risk for Tepotinib, 0 among 14 at risk for Carbamazepine, and 0 among 14 at risk for Tepotinib Then Carbamazepine. The registry also reports 0 deaths in each group.

Other adverse events were reported for 7 among 18 participants at risk in the Tepotinib group, 13 among 14 at risk in the Carbamazepine group, and 7 among 14 at risk in the Tepotinib Then Carbamazepine group. These are counts, not rates adjusted for exposure duration or a controlled comparison. The record does not provide event-level detail in the serious-event terms listing.

These groups are exposure groups within a sequential study, not randomized, like-for-like control arms. Their at-risk counts differ, and participants may contribute information across study periods. The counts therefore should not be compared as if they arose from independent treatment groups with equivalent follow-up. Zero reported serious events means none were recorded in these listed groups; it does not establish that an event is impossible or rule out uncommon risks. The registry record does not provide enough detail to characterize the timing, duration, or individual clinical context of the reported other adverse events.

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

The record establishes that a completed Phase I study was designed to assess tepotinib pharmacokinetics in healthy participants before and during multiple-dose carbamazepine administration. It identifies AUC0-inf as the primary endpoint and gives the sampling and dosing context. It also provides selected adverse event counts and a definition of the pharmacokinetic analysis population.

It does not report the primary endpoint values or the comparison between the two tepotinib dosing periods. Without those results, the size and direction of any pharmacokinetic change cannot be determined from the registry record. The record also lacks a confidence interval, a test result, and an explicit comparison estimator. There is therefore no basis in the posted results to quantify how precisely any effect was estimated.

General: A pharmacokinetic study evaluates drug concentrations and related measures of exposure or disposition. It does not by itself establish a clinical outcome, and its findings may not directly apply beyond the population and conditions studied. This study enrolled healthy participants and examined single-dose tepotinib in the setting described; the registry record does not present clinical outcome evidence.

The zero serious adverse event counts are limited to the exposure groups and reporting captured in the registry. They do not prove that serious events cannot occur. The other adverse event counts are descriptive, and the sequential design does not make them a randomized comparison of independent groups. The registry gives no event-level interpretation that would support a broader safety conclusion.

Accordingly, the appropriate reading is bounded: the record documents the study’s objective, design, primary measure, and some safety counts, but it does not report the numerical primary results needed to answer the pharmacokinetic question. Absence of a posted estimate is not evidence of no difference. Nor does the study’s completion status supply a result that the registry does not report. Any conclusion about the measured interaction would require results and analysis details not present in the registry record.

13. Why This Trial Matters Statistically

This study raises a useful statistical question about how to compare pharmacokinetic exposure before and during another medicine’s administration. A cross-over structure can make within-participant comparison possible, which may reduce the contribution of stable differences between participants. At the same time, sequential timing means that exposure condition and study period can be linked. Interpreting such a comparison depends on design and analysis details that address that structure.

The endpoint also illustrates why pharmacokinetic summaries require more than a single concentration measurement. AUC0-inf incorporates a sequence of concentrations and an extrapolated terminal portion. The estimated result can therefore depend on sampling timing and the terminal-phase estimation process, not merely on the observed concentration at one time. Reporting the estimate, its variability, and its uncertainty is important for understanding what the data support.

The registry’s use of a geometric mean and geometric coefficient of variation points to the multiplicative scale often used for pharmacokinetic data. General: on that scale, ratios can be natural descriptions of relative exposure, while interval estimates communicate uncertainty. However, the record does not report the comparison estimate or interval. The design and endpoint alone cannot show whether the observed data were precise or what magnitude of change they support.

The distinction between design information and results is especially important. Enrollment and completion status do not establish the primary outcome. Likewise, adverse event counts do not answer the pharmacokinetic question. Because the registry reports no analysis entries, the statistical treatment of the primary and secondary outcomes cannot be assessed from the record. The trial is statistically informative as an example of a defined within-participant pharmacokinetic question, but the posted record is insufficient for judging the numerical answer.

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 main limitation for interpreting this trial from the registry record is the absence of primary pharmacokinetic results. No AUC0-inf estimates, comparison estimate, confidence interval, or test result are reported. The record therefore does not permit assessment of the magnitude, direction, or precision of the primary comparison.

The design is identified as open-label, single-sequence, sequential, and cross-over, with no randomized allocation. The registry does not report how period effects, possible carryover, or other time-related influences were addressed. It also does not give the specific model or estimator used for the comparison. These omissions make it difficult to assess how the sequential measurements were translated into an inferential result.

The pharmacokinetic analysis population is described by completion and protocol-related criteria, but its size and participant-level exclusions are not reported in the registry record. Missing concentration data, endpoint calculation failures, and missing-data handling are not described. The record also does not report the trial’s sample-size justification, a detailed statistical plan, or multiplicity procedures for the listed outcomes.

The carbamazepine doses are listed as 100, 200 or 300 mg twice daily, but the record does not explain allocation to those doses or how they relate to the analyses. Safety counts are descriptive and come from exposure groups with different at-risk counts; they should not be interpreted as randomized comparative estimates. Finally, the study involved healthy participants and the described dosing conditions, so the registry record alone does not establish how results would apply to other populations or settings.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Tepotinib Drug-Drug Interaction Study With Carbamazepine in Healthy Participants — NCT05213481.
• Registry record last updated 2024-03-08; status last verified 2024-02.
• Results first posted 2024-03-08.
• 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.

18. Record Summary

The registry identifies a completed Phase I, open-label, single-sequence, cross-over study of tepotinib and carbamazepine in healthy participants. Enrollment is listed as 18. Participants received single doses of tepotinib on Day 1 and Day 26, with carbamazepine administered twice daily from Days 8 to 32. The primary endpoint was tepotinib AUC0-inf, summarized using a geometric mean and geometric coefficient of variation.

The pharmacokinetic analysis set was defined using intervention exposure, study completion, and protocol-related criteria. The registry reports selected serious and other adverse event counts across exposure groups. However, the primary endpoint results, comparison estimate, confidence interval, and analysis method are not reported in the registry record. The available record therefore describes what the study was designed to assess but does not provide the numerical result needed to quantify the pharmacokinetic comparison.