Tepotinib Hepatic Impairment Trial: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Tepotinib Hepatic Impairment Trial (NCT03546608), a non-randomized phase 1 study. The primary outcome is Area Under the Plasma Concentration Time Curve From Time Zero to Infinity ( AUC0-inf ) of Tepotinib.

2. Clinical Question

The study asked how different degrees of hepatic impairment relate to tepotinib pharmacokinetics, safety and tolerability after a single dose. Its primary pharmacokinetic measure was the area under the plasma concentration-time curve from dosing to infinity, or AUC0-inf. This measure represents overall plasma exposure over time, including an extrapolated portion after the last observed concentration.

The question is pharmacokinetic rather than a test of clinical benefit. The endpoint describes drug exposure; it does not by itself establish a treatment effect or determine safety. The record also lists secondary pharmacokinetic measures, including time to maximum observed plasma concentration, apparent terminal half-life, apparent clearance, apparent volume of distribution, and measures relating to unbound tepotinib and metabolites. Results for those measures are not reported in the registry record.

3. Trial Design

This was an open-label, parallel-group Phase 1 study with non-randomized allocation and no masking. The registry describes its purpose as investigating the effect of various degrees of hepatic impairment on tepotinib pharmacokinetics, safety and tolerability. It reports an enrollment of 18 and a completed status.

There were three groups: healthy participants with normal hepatic function, participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6), and participants with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9). The safety record lists 6 participants at risk in each group. The control participants were described as matched to the moderate impairment group, but the matching method and any matching variables are not reported in the registry record.

All groups received a single oral 500 mg dose of tepotinib film-coated tablet on Day 1 after a standard breakfast. Because allocation was not randomized, the groups should not be treated as if they were created by random assignment. The record itself cautions that the arms are not a like-for-like control comparison. Group differences may therefore reflect differences between the participants as well as differences associated with hepatic-function category; the record does not describe adjustment methods that would address this concern.

The study began on 2018-06-13, reached primary completion on 2019-02-05, and is listed as completed. The primary pharmacokinetic sampling timeframe includes pre-dose and multiple post-dose time points, extending to 504 hours for participants with hepatic impairment. The record does not establish from this description whether the same sampling schedule applied to the healthy control group. The protocol’s rationale for enrollment, sample-size justification, and any interim analyses are 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: The study was planned to be conducted in 2 parts: Part 1 and Part 2. Part 2 of the study was optional and sponsor decided not to perform part 2 of the study.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK.

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.

Population: The Safety Analysis Set included all participants who received tepotinib.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Plasma Concentration Time Curve From Time Zero to Infinity ( AUC0-inf ) of Tepotinib, measured over Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1.

The primary endpoint is tepotinib AUC0-inf: the area under the plasma concentration-time curve from the dosing time to infinity. AUC is used in pharmacokinetic studies as a measure of overall exposure in plasma across time. It combines information about concentrations and their duration, rather than describing concentration at only one sampling time.

The registry defines the endpoint as an estimate based on the predicted concentration at the last sampling time and the terminal elimination rate constant. The extrapolated portion is added to the area calculated through the last measured time. Consequently, the endpoint depends both on observed concentration measurements and on the estimated terminal part of the concentration curve. The record describes the endpoint in nanogram*hour per milliliter (ng*h/mL).

The planned summary parameter is a geometric mean, with geometric coefficient of variation as the dispersion measure. In general, a geometric mean summarizes positive values on a multiplicative scale, while a geometric coefficient of variation describes relative variability on that scale. These summaries do not convey the same information as an arithmetic mean and standard deviation.

The registry record does not report the group-specific AUC0-inf estimates, their variability, confidence intervals, or a comparison between groups. Thus the endpoint definition is available, but the size and precision of any observed group differences cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record identifies a pharmacokinetic study with a continuous primary measure and a geometric-mean summary. The methods information available is enough to explain what the planned endpoint represents, but not enough to reconstruct an inferential analysis or judge its reported results. No group estimates, confidence intervals, p-values, model specification or comparison results are reported in the registry record.

What does AUC0-inf represent?

In general, an area under a concentration-time curve combines plasma concentration measurements across time. AUC0-inf extends the measure from the dose to an estimated infinity, rather than stopping at the last blood sample. The registry describes this extension as adding an extrapolated area based on the predicted last concentration and the terminal elimination rate constant. The endpoint therefore incorporates both measurements and a model-based estimate of the remaining curve.

The terminal rate is estimated from the terminal slope of the log-transformed concentration curve, according to the record. General statistical implication: estimates of the terminal slope can affect how much area is extrapolated, and uncertainty in that part can affect the overall AUC estimate. The registry does not report how much of the AUC was extrapolated for participants, or any diagnostic checks for the terminal-slope estimation.

Why use a geometric mean?

In general, pharmacokinetic measurements are often summarized on a multiplicative scale when their variation is better described by relative rather than absolute differences. A geometric mean is formed through the log scale and then expressed back on the original scale. A geometric coefficient of variation describes relative dispersion. These summaries are useful for characterizing skewed, positive measurements, but their interpretation depends on the scale and analysis assumptions. The registry specifies these summary measures for the primary endpoint but does not report the values or the precise statistical procedure used to obtain them.

What would a comparison need to show?

For a reader to judge a group contrast, the posted analysis would ordinarily need to report the group-level estimates, a measure of uncertainty, and a clear definition of the comparison. A confidence interval, in general, conveys the range of values compatible with the data and the method under repeated-sampling assumptions. It would help distinguish a relatively precise estimate from one that remains uncertain. No such interval or formal contrast is reported in the registry record, so no claim about statistical compatibility or evidence for a difference can be made from this record alone.

Because the study is non-randomized, a comparison is not protected by random allocation from differences in participant characteristics. The control group is described as matched to the moderate hepatic impairment group, but the matching procedure and any adjustments are not reported. A statistical adjustment, if used, would need to be described to understand which differences it addresses; the registry record does not provide that information. This limitation is separate from the uncertainty that would arise from small group sizes.

How should variability be understood?

The geometric coefficient of variation is the specified dispersion measure for the primary endpoint. In general, a dispersion measure describes how spread out participant values are around a summary, but it is not a confidence interval for the group estimate. A group can have a central estimate and substantial participant-to-participant variability; conversely, a reported estimate without a dispersion measure gives little information about that variability. The numerical dispersion results are not reported in the registry record.

For continuous pharmacokinetic measures, distributional features and influential observations can affect summaries and comparisons. General explanation: transformation may make some data patterns more compatible with a statistical model, but it does not remove the need to inspect assumptions and report methods. The registry record does not report transformation details beyond its description of log-transformed concentrations for estimating the terminal slope, nor does it describe outlier handling, model diagnostics or the handling of values below quantification limits.

What do the planning assumptions mean?

General explanation: a sample-size planning calculation describes the number of participants an imagined study might need under stated assumptions about significance level, allocation, effect size and statistical method. It is not an observed result and is not observed power. The registry’s planning description refers to a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects expressed as fractions of an observed effect. It also distinguishes total events for time-to-event calculations from participants per arm for other calculations. These assumptions do not establish that this Phase 1 trial used that design or that those calculations justified its enrollment. The trial’s own sample-size justification is not reported in the registry record.

Overall, the available methods information supports an explanation of the planned endpoint and its summary scale, but not an independent statistical assessment of the result. The analysis model, uncertainty estimates, assumptions checks, and numerical primary results are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 23 outcome measures and 18 analyses. It does not report a multiplicity procedure, such as a hierarchy for interpreting multiple endpoints or an adjustment to control error across multiple statistical tests. These counts alone do not establish how many formal hypotheses were tested or whether all listed measures were included in a single family of tests. The primary endpoint is identified, but the record does not describe how it was prioritized in the analysis or how secondary findings were to be interpreted alongside it.

The record does not report a missing-data analysis or explain how missing pharmacokinetic samples, incomplete concentration profiles, or unevaluable endpoint values were handled. General explanation: missing observations can affect a pharmacokinetic estimate, particularly when they occur at time points needed to characterize the terminal portion of a curve. The registry’s endpoint definition describes extrapolation from the last predicted concentration, but it does not state how incomplete profiles were treated or what rules determined whether a participant’s endpoint could be calculated.

The primary pharmacokinetic analysis population is described as including participants who received a single dose of tepotinib and had at least one post-dose pharmacokinetic measurement, without important protocol deviations, violations or events that could affect pharmacokinetics. The number included in that analysis and exclusions from it are not reported in the registry record. The safety record separately lists 6 participants at risk in each group. It does not establish whether the same participants contributed to every pharmacokinetic analysis.

The statistical plan, including any prespecified handling of missing data, multiplicity, protocol deviations and analysis-set membership, is not reported in the registry record. Those details would be needed to assess how consistently the analysis followed its planned approach.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry’s serious adverse event figures are zero in the healthy control group, zero in the mild hepatic impairment group and zero in the moderate hepatic impairment group. The record lists 6 participants at risk in each group. It also reports zero deaths in every group. These are counts for the groups and outcomes recorded; they should not be interpreted as evidence that no other adverse events occurred.

For other adverse events, the record lists 1 affected participant in the healthy control group, 0 in the mild impairment group and 2 in the moderate impairment group. These counts are distinct from the serious adverse event counts. The registry does not provide the event terms in the serious adverse event listing, and no serious terms are listed there. The record does not provide details such as event descriptions, severity, timing, relationship to study drug, or the criteria used to classify seriousness.

In general, adverse-event counts describe events observed during the recorded safety period; they do not by themselves establish causation. With 6 participants at risk in each group, the counts are descriptive and offer limited information about uncommon events. The registry record does not report inferential comparisons for safety. These figures should therefore be read as the posted counts, not as a definitive comparison of safety between groups.

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

This study addresses a focused pharmacokinetic question: whether tepotinib exposure, measured as AUC0-inf, was characterized across healthy participants and participants with mild or moderate hepatic impairment. The registry describes the endpoint, the single-dose administration and the group categories. It does not report the endpoint estimates or their uncertainty, so the record does not show the size or direction of any exposure differences.

The study’s non-randomized, open-label, parallel-group design is important to interpretation. The groups were defined by hepatic-function status rather than created by random assignment. The record notes that healthy control participants were matched to the moderate impairment group, but it does not describe the matching method. Therefore, any apparent group contrast would need to be considered in light of the possibility of differences between groups beyond hepatic-function category. The registry does not report an adjusted analysis that could clarify this issue.

The posted safety counts show no serious adverse events or deaths in any group, and they list other adverse events in the control and moderate impairment groups. Those counts are based on small groups and do not establish whether an event was caused by tepotinib. They also do not replace the absent pharmacokinetic results or provide a broad estimate of risk.

The registry record does not report results for the listed secondary pharmacokinetic measures, statistical comparisons, confidence intervals, or a detailed analysis plan. The completed status and enrollment count describe the study record, not the magnitude or certainty of its findings. A planning calculation based on an observed effect, if used for illustration, is not evidence that the trial had a particular probability of detecting a result; planning assumptions do not substitute for observed estimates and uncertainty.

Accordingly, the record supports a description of what was studied and how the primary endpoint was defined. It does not support a conclusion that tepotinib exposure was the same or different across groups, nor does it establish a comparative safety or tolerability result.

13. Why This Trial Matters Statistically

This trial is statistically notable because it frames hepatic impairment as a source of potential variation in pharmacokinetic measurements, rather than testing a randomized treatment contrast. The central endpoint, AUC0-inf, summarizes overall plasma exposure over time and includes an extrapolated component beyond the last sampling time. That makes both the concentration measurements and the estimation of the terminal portion relevant to understanding the result.

The study also illustrates the limits of interpreting small, non-randomized groups. The registry reports 18 enrolled participants and 6 at risk in each safety group. Such groups can describe observed measurements, but estimates of variability and between-group differences may remain uncertain. The non-randomized allocation further means that a group contrast cannot automatically be attributed solely to hepatic-function category. The record notes matching for the control group against moderate impairment but does not give details of the procedure.

From a statistical reporting perspective, endpoint definitions alone are not enough to evaluate findings. Group estimates, dispersion, uncertainty intervals, analysis methods and analysis-set counts would be needed to assess the precision and robustness of the primary comparison. Those primary results are not reported in the registry record. The lack of multiplicity and missing-data details also limits assessment of how multiple outcomes and incomplete measurements were handled.

The safety figures demonstrate why event counts need context: zero recorded serious adverse events in these groups does not characterize all possible events or establish equivalence. With small groups, descriptive counts should be interpreted cautiously, and the record does not report formal safety comparisons.

The statistical value of the record is therefore primarily in clarifying the design, endpoint, sampling concept and limits of the available results. It also highlights the distinction between a planned pharmacokinetic assessment and evidence that can be interpreted from posted numerical findings.

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 interpreting this trial from the registry record is that numerical results for AUC0-inf are not reported. Group estimates, variability, confidence intervals and statistical comparisons are unavailable, so the primary question cannot be answered from the registry record. Results for the secondary pharmacokinetic measures are also not reported.

The study is non-randomized and open-label. Although the healthy control group is described as matched to the moderate impairment group, the registry does not report the matching method, participant characteristics used for matching, or whether analyses adjusted for any differences. The arms are explicitly not a like-for-like control comparison. This limits causal interpretation of any group contrast.

There were 18 participants enrolled, and the safety record lists 6 at risk per group. These small group sizes constrain how precisely participant variability and uncommon events can be characterized. The registry does not report a sample-size justification for this study or explain whether enrollment was based on a specific precision target.

The endpoint includes an extrapolated portion of the concentration-time curve. The registry describes how that portion is defined but does not report its contribution to the estimates, diagnostics for terminal-slope estimation, handling of incomplete profiles, or rules for values that could not be quantified. The statistical model and uncertainty calculation are also not reported.

Finally, the registry does not report multiplicity procedures, detailed missing-data methods, protocol-deviation counts, or the number of participants included in each pharmacokinetic analysis. The adverse-event record provides counts but not event descriptions, timing, severity, or relatedness. These omissions limit interpretation of both the pharmacokinetic and safety summaries.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Tepotinib Hepatic Impairment Trial — NCT03546608.
• Registry record last updated 2024-08-12; status last verified 2024-03.
• Results first posted 2024-08-12.
• 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

NCT03546608 is a completed, open-label, non-randomized, parallel-group Phase 1 study sponsored by EMD Serono Research & Development Institute, Inc. It investigated tepotinib pharmacokinetics, safety and tolerability across healthy participants and participants with mild or moderate hepatic impairment. Enrollment was 18.

Each group received a single oral 500 mg dose after a standard breakfast on Day 1. The primary endpoint was tepotinib AUC0-inf, summarized as a geometric mean with geometric coefficient of variation. The registry record defines the endpoint and its sampling timeframe but does not report the primary endpoint results, confidence intervals or statistical comparisons.

The safety record lists no serious adverse events or deaths in any group. It lists other adverse events in the control and moderate impairment groups. The record does not provide further event details or comparative safety analyses. Statistical-plan details, including multiplicity and missing-data methods, are not reported in the registry record.