Evaluate Severe Hepatic Impairment on Dacomitinib PK: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluate Severe Hepatic Impairment on Dacomitinib PK (NCT03865446), a non-randomized phase 1 study. The primary outcome is Maximum Observed Plasma Concentration (Cmax) of Dacomitinib.

2. Clinical Question

The study’s stated purpose was to evaluate the effect of severe hepatic impairment on dacomitinib pharmacokinetics. Its primary endpoint, maximum observed plasma concentration (Cmax), captures the highest measured concentration after the dose. The registry record describes the endpoint and measurement schedule, but numerical Cmax results, a between-group estimate, and its uncertainty are not reported in the registry record. The magnitude and precision of any pharmacokinetic difference therefore cannot be determined from the reported information.

The study also collected safety outcomes, including laboratory, physical examination, vital sign, ECG, and adverse event measures. Those outcomes address different questions from Cmax: they describe recorded safety findings rather than the concentration profile itself. The registry record lists no serious adverse events, other adverse events, or deaths in either group, but a small study with no events cannot establish that events would not occur in a broader population.

3. Trial Design

This was a Phase 1, open-label, single-dose, parallel-group study of dacomitinib. It was completed, with a reported enrollment of 16 participants. The registry record identifies one cohort with severe hepatic impairment and another with normal hepatic function. The safety figures list 8 participants at risk in each group.

Allocation was non-randomized, and masking was absent. The two cohorts therefore should not be treated as randomized or necessarily interchangeable groups. The study’s design compares pharmacokinetic measurements across hepatic-function groups; it does not have the protections against selection differences that random allocation can provide. Characteristics that might differ between cohorts, and any methods used to address such differences, are not reported in the registry record.

The study began on 2019-04-05, and its primary completion date was 2019-10-24. Dacomitinib was administered once. The stated Cmax measurement schedule was pre-dose and at 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216 and 264 hours post dose on Day 1. These repeated measurements are used to identify the maximum observed concentration over the specified collection schedule.

The primary pharmacokinetic population was defined as participants who took one dose of dacomitinib and had at least one dacomitinib plasma pharmacokinetic parameter of primary interest. The registry record does not report how many participants met that definition or whether any enrolled participants were excluded from that population.

Safety outcomes listed in the record include laboratory abnormalities, physical examination abnormalities, vital sign and ECG parameters meeting criteria of potential clinical concern, and treatment-emergent adverse events and serious adverse events. The specific analysis methods, detailed follow-up period for safety, and any protocol-level analysis plan 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) population included all participants who took one dose of dacomitinib and had at least one dacomitinib plasma PK parameters of primary interest.

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: Safety analysis set included all participants assigned to dacomitinib and who take 1 dose of dacomitinib.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Observed Plasma Concentration (Cmax) of Dacomitinib, measured over Pre-dose and 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216 and 264 hours post dose on Day 1.

The primary endpoint was the maximum observed plasma concentration (Cmax) of dacomitinib, measured in nanograms per milliliter. It is a pharmacokinetic measure: it describes the highest concentration observed in the sampled blood measurements after dosing. The registry record states that Cmax was analyzed as a geometric mean, with geometric coefficient of variation as the dispersion measure.

In general, Cmax is used to characterize peak exposure after a dose. Comparing it across groups can help describe whether the observed concentration profiles differ by group. Its interpretation depends on the sampling schedule, because the maximum observed value is the highest measurement actually collected and may not be identical to the true peak between sampling times. Here, the record specifies repeated post-dose measurements through 264 hours, alongside a pre-dose measurement.

Cmax is only one aspect of pharmacokinetics. It does not by itself describe the full concentration-time profile or every measure of exposure. The registry record identifies eight outcome measures overall, but does not report their numerical results in the information available for this analysis. In particular, numerical Cmax values by group, a comparative estimate, and a confidence interval are not reported in the registry record. The endpoint definition alone therefore does not establish the size or precision of any difference.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a pharmacokinetic quantity, not a clinical event count. Cmax means the highest observed plasma concentration after dosing. The record gives its unit as nanograms per milliliter and identifies the geometric mean as the summary measure, with geometric coefficient of variation describing dispersion. It also gives repeated sampling times from pre-dose through 264 hours post dose on Day 1. The following concepts are general explanations of these statistical methods; the registry record does not report the full statistical analysis plan.

Why use a geometric mean?

General: concentration measurements are often positive and can have a right-skewed distribution, where a small number of high observations stretch the upper tail. The arithmetic mean can be strongly influenced by such high values. A geometric mean is based on log-transformed observations and is often used to summarize positive measurements that vary multiplicatively. It describes a central value on a multiplicative scale. It does not indicate that every participant had a value near that summary, and it does not replace a description of the spread of individual observations.

A comparison of geometric means is often expressed as a ratio, because ratios fit the multiplicative scale. But the registry record does not report a ratio or any comparative Cmax estimate. No ratio, difference, or other effect estimate can be inferred from the endpoint definition or group sizes alone. The geometric mean is the specified summary for Cmax; it is not a complete report of the statistical comparison.

What does geometric coefficient of variation describe?

General: a geometric coefficient of variation (GCV) is a measure of relative dispersion for data analyzed on a logarithmic scale. It gives information about variability around a geometric mean and can help readers understand how widely measurements vary relative to the typical level. It is not a confidence interval for the mean and is not a measure of uncertainty in a between-group contrast. A group can have a reported geometric mean and GCV without the reader knowing how precisely the mean or a comparison has been estimated.

The registry record does not provide numerical GCV values. It also does not state whether comparative estimates were accompanied by confidence intervals, how the analysis handled values below an assay’s quantification limit, or whether a particular model was used. Those details are not reported in the registry record and should not be assumed.

Why does the sampling schedule matter?

General: Cmax is determined from observed concentration measurements. Sampling times therefore affect how well the measurement schedule captures the peak. If the peak occurs between scheduled samples, the maximum observed value can differ from the unobserved true peak. Frequent measurements around the expected peak can improve its characterization, while measurements over later times can describe the decline in concentration. The schedule reported for this study extends from pre-dose to 264 hours post dose, but the registry record does not state whether the schedule was selected on the basis of a particular pharmacokinetic model or prior evidence.

Repeated measurements within one participant are correlated: values from the same person are not independent observations. General analyses of concentration-time data account for the repeated structure or derive participant-level pharmacokinetic parameters before comparing groups. The registry record says that Cmax was analyzed, but does not identify the specific computation or model used. It therefore is not possible to evaluate model assumptions from the record alone.

How should precision be assessed?

General: a confidence interval gives a range of values compatible with the data and the specified statistical procedure, under its assumptions. A narrow interval indicates greater precision than a wide interval, while neither width nor statistical significance by itself establishes clinical importance. For a group comparison on a multiplicative scale, an interval for a ratio can show the precision of the relative contrast. No confidence interval or other measure of uncertainty for Cmax is reported in the registry record, so precision cannot be evaluated.

A p-value, if reported, would address compatibility of the data with a specified null hypothesis under a statistical model. It would not measure the probability that the null hypothesis is true, the size of an effect, or the clinical importance of a result. No Cmax p-value or hypothesis-testing method is reported in the registry record. The absence of a reported p-value should not be interpreted as evidence of either similarity or difference.

What do the planning assumptions mean?

General: sample-size planning considers how many participants may be needed to detect an effect under stated assumptions. The planning illustration described for this study uses a two-sided significance level of 0.05, equal allocation between groups, and a normal approximation; it sets the effect to detect as a stated fraction of an observed effect. Such calculations are conditional on those assumptions. They are planning illustrations, not observed power, and they do not establish that the study was designed around that method. The registry record does not report a trial-specific sample-size justification, and no numerical planning estimates are available in the information.

A planning calculation based on an observed effect is especially dependent on the estimate used as its starting point. If that estimate is uncertain, the planning result inherits that uncertainty. It should not be treated as a probability that the study would produce a significant result, nor as evidence that the study had adequate precision. The registry record does not provide the numerical observed effect required to inspect such a calculation.

What is not specified?

The record defines the pharmacokinetic population as participants who received one dose and had at least one primary-interest dacomitinib plasma parameter. It does not report the number included in that population, the number with usable Cmax measurements, or the handling of missing or incomplete concentration data. It also does not identify covariate adjustment, transformation details beyond the geometric summaries, or a method for comparing groups. These omissions prevent a full independent appraisal of the statistical analysis. The appropriate interpretation is limited to the reported design and endpoint definitions, with numerical findings and analysis details not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists eight outcome measures overall and identifies Cmax as the primary endpoint. It also lists secondary safety measures covering laboratory findings, physical examination abnormalities, vital signs, ECG parameters, and treatment-emergent adverse events and serious adverse events. The record does not report how many formal hypotheses were tested, whether any tests were planned as confirmatory, or how multiplicity across endpoints or comparisons was handled. A multiplicity adjustment, testing hierarchy, or other control strategy is not reported in the registry record.

Multiplicity matters in general when several statistical tests are conducted: the chance of at least one apparently unusual result can rise as the number of tests increases. The implications depend on which outcomes were tested, how they were related, and whether the analyses were intended to be descriptive or inferential. Those details are not reported, so no conclusion about the control of false-positive findings is possible. The mere listing of multiple outcomes does not establish that each was tested for statistical significance.

The primary pharmacokinetic population is defined as participants who took one dose and had at least one dacomitinib plasma pharmacokinetic parameter of primary interest. The registry record does not report how missing concentrations, missed sampling times, or incomplete profiles were handled. It does not state whether values were imputed, excluded, or addressed through another method. The number of participants included in the endpoint analysis is also not reported in the registry record.

For safety, the record gives the numbers at risk for the two groups, but does not specify the detailed safety analysis population, event-collection period, or handling of incomplete safety follow-up. No missing-data assumptions or sensitivity analyses are reported. Accordingly, the reported definitions and counts can be described, but the effect of missingness or the analysis choices on the results cannot be assessed.

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.

The registry record reports the following observed safety counts: in the severe hepatic impairment group, 8 participants were at risk for serious adverse events, 8 for other adverse events, and 8 for deaths; the corresponding affected counts were zero. In the normal hepatic function group, 8 participants were at risk for each category, and the affected counts were also zero. The record lists no top serious adverse event terms.

These figures describe events recorded among the participants counted as at risk. They do not establish that the risks in the two groups are identical, and they do not show that an event is impossible. With a small number of participants, the absence of a recorded event provides limited information about uncommon outcomes. No percentages or rates are needed to interpret the stated counts, and none are reported.

The registry record also lists other safety outcomes, including laboratory and examination abnormalities, and vital sign and ECG parameters meeting criteria of potential clinical concern. Their numerical results are not reported in the registry record. The event-count summary should therefore not be mistaken for a complete account of all safety measurements. Detailed follow-up duration, event definitions beyond the listed categories, and information about missing safety observations are not reported in the registry record.

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

This study addresses a focused pharmacokinetic question: the comparison of dacomitinib Cmax after a single dose between participants with severe hepatic impairment and participants with normal hepatic function. The registry record reports the study design, endpoint definition, sampling schedule, and the way Cmax was summarized. It does not report numerical Cmax results or a comparative estimate, so the size and precision of any observed difference cannot be established from the registry record.

The non-randomized design is important to the meaning of a group comparison. The cohorts were not formed by random assignment, and the registry record does not describe adjustment for differences in participant characteristics. An observed contrast, if available, would therefore need to be understood in the context of potentially different groups. The record also does not include the full statistical plan needed to assess modeling, missing data, or multiplicity.

The safety counts show no serious adverse events, other adverse events, or deaths recorded in either group during the reporting represented by those counts. They do not establish an absence of risk. The record’s additional safety outcome definitions do not come with numerical results in the available information, limiting any broader description of observed safety findings.

General: pharmacokinetic measurements and safety event counts answer distinct questions. A concentration endpoint characterizes drug exposure, while safety outcomes describe recorded events or measurements. Neither type of information alone establishes every aspect of a treatment’s effects. No medical conclusion about dacomitinib should be drawn from endpoint definitions or the absence of events in these small groups. In particular, without the numerical Cmax results, the central comparison cannot be quantified.

The record does establish that the study was completed, enrolled 16 participants, and used a parallel-group, open-label, non-randomized design. It also defines the primary pharmacokinetic population and the scheduled measurement times. These registry entries describe how the question was studied, but they do not substitute for the unreported endpoint estimates, uncertainty measures, or full analysis details.

13. Why This Trial Matters Statistically

Pharmacokinetic studies often ask whether measured exposure differs across groups defined by a characteristic that cannot be randomized, such as hepatic function. This study is an example: it compares a severe hepatic impairment cohort with a normal hepatic function cohort after a single dose of dacomitinib. The statistical challenge is not only to define an exposure measure, but also to describe its variability and the uncertainty in the group contrast.

Cmax is useful for characterizing peak concentration, but it is one summary of a concentration-time profile. The repeated sampling schedule provides observations at specified times, and the maximum among those measurements depends on that schedule. Clear reporting of group estimates, variability, and comparative uncertainty would be needed to judge the precision of the result. Those numerical Cmax findings are not reported in the registry record.

The non-randomized design also highlights the distinction between a group association and a causal effect. Participants in the two hepatic-function cohorts may differ in ways beyond the condition defining the groups. Without reported participant characteristics or adjustment methods, a statistical contrast cannot be separated from possible group differences. This is a design consideration, not a claim that any particular imbalance occurred.

Finally, safety counts with no events are informative as a description of what was observed, but they have limited ability to characterize uncommon outcomes in a small study. A careful statistical reading distinguishes observed counts from conclusions about underlying risk. Together, these issues show why endpoint values, uncertainty intervals, analysis populations, missing-data methods, and the basis for the comparison matter alongside the study’s headline design.

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 the primary question is that numerical Cmax findings are not reported in the registry record. There are no group geometric means, GCV values, comparative estimates, or confidence intervals in the information. Consequently, neither the magnitude nor the precision of the pharmacokinetic comparison can be evaluated.

The study enrolled 16 participants, and the safety counts list 8 at risk in each group. The registry record does not report the number included in the primary pharmacokinetic analysis, so the analyzed sample size for Cmax is not established. It also does not report participant characteristics that might help readers assess comparability between the cohorts.

Because allocation was non-randomized, differences between groups cannot automatically be attributed to hepatic-function status alone. The record does not report covariate adjustment or other methods addressing potential group differences. Masking was absent, and the information reported does not describe whether this could affect outcome assessment or data handling.

The statistical analysis plan is not reported in detail. Methods for comparing Cmax, confidence interval construction, missing concentration data, multiplicity, and any sensitivity analyses are not reported in the registry record. The sample-size justification for the study is also not reported. A planning illustration based on an observed effect is not a substitute for a trial-specific justification or for uncertainty around the actual endpoint estimate.

For safety, the record gives zero affected participants for serious adverse events, other adverse events, and deaths in both groups, but detailed safety results for the other listed outcomes are not reported. The safety follow-up period and handling of incomplete safety observations are also not reported. These limitations mean the registry information supports a description of design and recorded counts, but only a restricted assessment of pharmacokinetic and safety findings.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Evaluate Severe Hepatic Impairment on Dacomitinib PK — NCT03865446.
• Registry record last updated 2020-11-06; status last verified 2020-10.
• Results first posted 2020-11-06.
• 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 completed Phase 1 study evaluated dacomitinib after a single dose in participants with severe hepatic impairment and participants with normal hepatic function. It was open-label, non-randomized, and parallel-group, with 16 participants enrolled. The primary endpoint was maximum observed plasma concentration, summarized as a geometric mean with geometric coefficient of variation, using measurements scheduled from pre-dose through 264 hours post dose on Day 1.

The primary pharmacokinetic population was defined by receipt of one dose and availability of at least one primary-interest plasma pharmacokinetic parameter. Numerical Cmax results, comparative estimates, uncertainty intervals, and detailed statistical methods are not reported in the registry record. Safety counts list no serious adverse events, other adverse events, or deaths in either group, with 8 participants at risk in each group. These counts describe the registry record and do not establish that such events cannot occur.