To Assess the Pharmacokinetics, Safety and Tolerability of Selumetinib in Patients With Hepatic Impairment and Healthy Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for To Assess the Pharmacokinetics, Safety and Tolerability of Selumetinib in Patients With Hepatic Impairment and Healthy Subjects (NCT02063230), a non-randomized phase 1 study. The primary outcome is AUC (0 to Infinity) of Total Selumetinib.

2. Clinical Question

The study asks how the pharmacokinetics, safety, and tolerability of selumetinib differ between healthy volunteers and people grouped by severity of hepatic impairment. Its primary endpoint is total selumetinib AUC from zero to infinity after a single oral dose. That measure represents drug exposure over time, rather than a clinical outcome such as tumor response.

This is a pharmacokinetic question: it concerns the concentration-time profile of the study drug. The record also identifies safety and tolerability as study aims, but the primary endpoint specified in the registry is an exposure measure. The findings described in the record therefore cannot by themselves answer questions about clinical benefit or effectiveness.

3. Trial Design

This is a phase 1, open-label, non-randomized, parallel-group study. It enrolled 32 participants and is recorded as completed. The official title describes a single oral dose of selumetinib in healthy subjects and subjects with mild, moderate, or severe hepatic impairment. The registry lists March 2014 as the start and November 2014 as the primary completion.

The parallel-group structure means participants were assessed in distinct groups rather than being described as crossing through every impairment category. The groups are healthy volunteers and people with mild, moderate, or severe impairment. The record identifies the impairment categories as Child Pugh A, Child Pugh B, and Child Pugh C. It does not report random allocation; instead, allocation is recorded as non-randomized. No masking is recorded.

Selumetinib 50mg and Selumetinib 25mg are listed as interventions. The primary endpoint description notes that, in the moderate group, 2 patients received Selumetinib 25mg and are not included in the primary AUC outcome, although they are included in the dose-normalized AUC outcome. The registry record does not report a complete account of how doses were assigned across all groups, so group-specific dosing should not be inferred beyond that note.

The non-randomized design is important when reading group comparisons. Differences in exposure between groups may be consistent with a relationship to hepatic impairment, but the study design does not make the groups interchangeable in the way random assignment aims to do. Other group differences could also contribute. The record does not report a planned adjustment strategy that would address such differences.

The condition field lists Solid Tumors, while the study description focuses on pharmacokinetics in people with hepatic impairment and healthy volunteers. The record does not describe a tumor efficacy comparison as a study objective. It lists six outcome measures and zero analysis records. The statistical analysis plan and the original sample-size justification 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: In the moderate group, 2 patients received Selumetinib 25mg and are not included here but are included in the Dose Normalised AUC 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 AUC (0 to Infinity) of Total Selumetinib, measured over 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96 and 120 hours post dose.

The primary endpoint is the AUC of total selumetinib from zero to infinity, reported as a geometric mean in ng*h/mL, with geometric coefficient of variation as its dispersion measure. The registry specifies post-dose assessment times of 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours.

In general, AUC is the area under a drug concentration-versus-time curve. It is used in pharmacokinetics because it summarizes exposure across the measured time course rather than focusing on one concentration at one time. Extending the measure to infinity involves estimating exposure beyond the final measured time point; the registry names this endpoint but does not report how that estimate was obtained.

A geometric mean is a way to summarize positive values when a multiplicative scale is appropriate. In general, a geometric coefficient of variation describes relative spread on that scale; it is not the same as a standard deviation on the original scale. These summaries can help characterize group exposure and variability, but they do not establish why groups differ.

The primary endpoint description says that 2 patients in the moderate group who received Selumetinib 25mg are excluded from this AUC measure and included in the dose-normalized AUC outcome. The numerical AUC results and the corresponding geometric coefficients of variation are not reported in the registry record. Consequently, the endpoint definition can be described, 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 registry identifies a geometric mean and geometric coefficient of variation for the primary AUC endpoint. It does not provide the numerical endpoint summaries or a detailed statistical analysis plan. The explanations below describe general statistical concepts relevant to these measures and to the design; they should not be read as claims about analyses that the study performed.

What does AUC measure?

In general, pharmacokinetic measurements follow drug concentration over time. AUC represents the area under that concentration-time curve and combines information across the assessment period. AUC from zero to infinity includes exposure after the last scheduled measurement as well as the portion observed during the listed time points. General methods for estimating the remaining exposure can differ; the estimation approach is not reported in the registry record.

AUC is a measure of exposure, not a direct measure of clinical benefit. It does not by itself state whether a person’s condition improved, whether a drug is effective for a particular use, or whether one group experienced a better clinical outcome. The registry’s primary endpoint is pharmacokinetic, even though the condition field lists Solid Tumors.

Why use a geometric summary?

In general, pharmacokinetic values are often analyzed on a multiplicative scale. A geometric mean summarizes values by averaging on a logarithmic scale and expressing the result back on the original scale. This can be useful when variability is better understood in relative rather than absolute terms. The registry explicitly specifies a geometric mean for the primary endpoint, but does not report whether values were transformed for analysis or how missing or unusual measurements were handled.

A geometric coefficient of variation is a measure of relative dispersion associated with a geometric summary. It communicates how variable the measurements are in multiplicative terms. It is not interchangeable with a standard deviation, and its meaning depends on the scale and method used to calculate it. Because the registry does not give the actual values, the amount of observed variability cannot be assessed.

How should group comparisons be understood?

General statistical explanation: comparing group summaries can describe how observed measurements differ, but the design determines how strongly those differences support a causal interpretation. This study is recorded as non-randomized and open-label, with parallel groups. The registry does not report random assignment or masking. Participants were grouped by hepatic-impairment status or healthy-volunteer status, so differences in group composition may accompany differences in impairment category.

A randomized comparison aims to make groups comparable in expectation through assignment. A non-randomized comparison does not provide that design protection. Adjustment for relevant characteristics can sometimes address measured differences, but the registry record does not report an adjustment model or covariate set. No adjusted group estimates are reported. Therefore, a contrast between groups should be treated as a description of this study’s groups, not as a definitive causal estimate.

What does the endpoint timeframe imply?

The listed sampling schedule extends from time zero through 120 hours after dosing. In general, more sampling times can describe the concentration-time profile in greater detail, while the timing and completeness of measurements affect how well the profile is characterized. AUC to infinity also requires an estimate beyond the last listed measurement. The registry gives the planned times but does not report actual sample completion, concentration data, the fraction of the total AUC estimated beyond the final time, or the calculation method.

The primary endpoint is total selumetinib AUC. The registry notes that 2 participants in the moderate group who received Selumetinib 25mg are excluded from this endpoint and included in the dose-normalized AUC outcome. Dose normalization is generally used to express exposure relative to dose, which can support comparisons when dose levels differ. The specific dose-normalization procedure and the resulting estimates are not reported in the registry record.

What do planning calculations mean?

General statistical explanation: a sample-size calculation asks how many participants would be needed under specified assumptions to detect a chosen effect with a stated error rate and power. The planning illustrations associated with this study are described as using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is stated as a fraction of the observed effect. The original trial’s own sample-size justification is not reported in the registry record.

Because these illustrations are calculated from an observed effect, they are hypothetical planning exercises rather than a description of the study’s original design. Their outputs do not constitute observed power. General statistical explanation: observed power is not a substitute for interpreting an estimate and its uncertainty; after a study, the effect estimate and its precision are more informative than a retrospective power calculation. Numerical planning outputs are not reported in the registry record.

What can be concluded from the available statistical record?

The registry specifies the endpoint, groups, study design, and some adverse-event counts. It does not report the primary AUC estimates, uncertainty intervals, inferential tests, or a full analysis plan. Those omissions limit any assessment of the size, precision, and statistical significance of exposure differences. General concepts can clarify what the chosen measures mean, but cannot fill in absent study results.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures, but the record does not describe how multiple outcomes were prioritized or whether any adjustment for multiple testing was planned. The primary endpoint is identified as total selumetinib AUC from zero to infinity. No statistical analysis plan or analysis records are reported. It is therefore not possible to determine whether the study used a prespecified hierarchy, adjusted significance thresholds, or another approach to multiplicity.

In general, examining multiple outcomes or multiple group contrasts can increase the chance of a false-positive finding if each is tested without accounting for the number of tests. Adjustment methods can address that issue, while a clear prespecified hierarchy can identify which analyses are confirmatory and which are exploratory. These are general considerations, not a description of methods used in this study. The registry record does not report enough detail to establish how multiplicity was handled.

The record also does not report missing-data handling, exclusions beyond the primary endpoint note for 2 moderate-group participants who received Selumetinib 25mg, or the analysis population for every outcome. It does not give a participant flow by analysis, the number of completed concentration measurements, or reasons for missing measurements. The 2 participants’ inclusion in the dose-normalized AUC outcome is stated, but the registry does not explain the calculation or analysis population for that outcome.

In general, missing observations can affect estimates when their occurrence is related to participant characteristics or measured outcomes. Appropriate methods depend on why data are missing and on the outcome and design. Since those details are not reported in the registry record, the extent and possible impact of missing data cannot be assessed. The absence of reported methods should not be interpreted as evidence that there were no missing observations or no multiplicity concerns.

11. Safety Results

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

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 lists serious adverse-event counts by group. For the mild, moderate, severe, and normal groups, the number of participants at risk is 8 in each, and the number affected by a serious adverse event is 0 in each. These figures describe the reported counts; they do not establish that the groups have identical safety profiles or that the risk is absent.

The other adverse-event counts are 2 in the mild group, 2 in the moderate group, 0 in the severe group, and 1 in the normal group. The number at risk is 8 in each group. These are participant counts as presented in the registry record. No event terms are listed among the top serious terms. Death counts are not reported in the registry record.

In general, safety counts should be interpreted with attention to the number of participants observed, the event definitions, the observation period, and the completeness of reporting. The registry gives no detailed event descriptions or statistical comparisons for these counts. The study was non-randomized, so cross-group count differences should not be treated as causal evidence. These limited counts do not provide a comprehensive account of safety or tolerability.

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

This study is relevant to the statistical question of how to describe pharmacokinetic exposure across groups defined by hepatic-impairment status. It specifies total selumetinib AUC from zero to infinity as its primary endpoint and uses a geometric mean with geometric coefficient of variation. The endpoint and group structure are clear enough to identify the intended comparison, but the numerical primary results are not reported in the registry record.

That absence matters. Without group estimates and measures of precision, readers cannot judge the magnitude of observed exposure differences, their variability, or how compatible the results are with a range of possible values. The registry also does not report inferential tests or confidence intervals for the primary endpoint. The design is non-randomized, so even reported differences would need to be interpreted as group comparisons rather than proof that hepatic impairment alone caused them.

The record does not establish clinical effectiveness. AUC describes drug exposure, not a tumor response or another patient-centered outcome. The study is described as assessing pharmacokinetics, safety, and tolerability, and the primary endpoint is pharmacokinetic. No efficacy result is reported in the registry record.

The adverse-event counts provide a limited descriptive snapshot: no participants are listed as affected by serious adverse events in any group, while other adverse events are recorded in some groups. Counts of zero in a small group do not prove that an event cannot occur, and differences in counts do not establish a treatment effect. Deaths are not reported in the registry record.

The most defensible reading is therefore about scope, not an unreported effect: this was a phase 1, open-label, parallel-group, non-randomized study of single-dose selumetinib in healthy volunteers and people with varying hepatic impairment. It identifies a suitable exposure measure for the pharmacokinetic question, but the registry record does not provide the numerical results needed to answer that question quantitatively.

13. Why This Trial Matters Statistically

Pharmacokinetic studies ask how exposure varies across people and groups, and a carefully defined endpoint helps make that question explicit. Here, the primary measure is total selumetinib AUC from zero to infinity, with a geometric mean and geometric coefficient of variation. That choice focuses attention on overall exposure and relative variability rather than on a single concentration measurement.

The study also illustrates why design information is essential to statistical interpretation. Healthy volunteers and people with mild, moderate, or severe hepatic impairment form distinct, non-randomized groups. A group comparison can be informative descriptively, but it does not automatically isolate the effect of hepatic impairment. Readers need to consider that group membership was not assigned at random and that the registry does not report an adjustment strategy.

It matters just as much to distinguish an endpoint definition from an endpoint result. The registry gives the primary measure and a detailed schedule of post-dose assessment times, yet does not report numerical AUC estimates or their precision. A well-defined outcome alone cannot show the direction, magnitude, or certainty of an observed difference. This is a useful reminder that statistical interpretation depends on both design and results reporting.

The safety counts similarly demonstrate the limits of sparse summaries. Serious adverse events are listed as affecting zero participants in each group, while other events are reported in some groups. Those counts can describe what the record reports, but without event details, a fuller follow-up description, or comparative analyses they do not establish that risks are equal or absent.

Finally, sample-size planning illustrations should not be confused with the trial’s design justification or with observed power. The registry says the illustrations use an observed effect and specified assumptions, but does not report the original sample-size rationale. Separating these ideas helps prevent a hypothetical planning exercise from being mistaken for evidence about the study’s ability to detect an effect.

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 results is that the registry record does not report the numerical primary AUC outcome. It also does not report confidence intervals, other precision measures for the primary estimate, or statistical tests. As a result, the magnitude and uncertainty of the pharmacokinetic findings cannot be assessed from the registry record.

The non-randomized, open-label design limits causal interpretation of group differences. The groups correspond to healthy-volunteer status or categories of hepatic impairment, rather than randomized assignment. The registry does not report adjustment for group differences or enough participant characteristics to assess their influence. The record also does not give a complete dose allocation across groups, although it identifies two Selumetinib 25mg recipients in the moderate group and specifies how they are treated for two AUC outcomes.

Important analysis details are not reported in the registry record. These include the original sample-size justification, the detailed statistical plan, how AUC to infinity was estimated, how missing measurements were handled, and the analysis population for each outcome. The registry lists six outcome measures and zero analysis records. It does not establish whether all planned measurements were obtained or whether any analyses were adjusted for multiplicity.

The safety information is limited to group-level counts. The registry does not report deaths, and no top serious adverse-event terms are listed. It does not provide event-level descriptions, timing, duration, or a comparative safety analysis. The counts should therefore be treated as limited descriptive information rather than a complete safety profile.

These limitations concern what can be learned from the registry record. They do not establish that the study lacked procedures or analyses; such details are simply not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: To Assess the Pharmacokinetics, Safety and Tolerability of Selumetinib in Patients With Hepatic Impairment and Healthy Subjects — NCT02063230.
• Registry record last updated 2016-07-21; status last verified 2016-06.
• Results first posted 2015-11-02.
• 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 describes a completed phase 1 study of single-dose oral selumetinib in healthy volunteers and people with mild, moderate, or severe hepatic impairment. The design is open-label, non-randomized, and parallel-group, with total enrollment of 32. Selumetinib 50mg and Selumetinib 25mg are listed as interventions.

The primary endpoint is total selumetinib AUC from zero to infinity, summarized as a geometric mean with geometric coefficient of variation. The record lists six outcome measures and zero analysis records, but does not report the numerical primary endpoint result or its precision. It notes that 2 moderate-group patients who received Selumetinib 25mg are excluded from the primary AUC outcome and included in the dose-normalized AUC outcome.

Serious adverse events are listed for zero participants in each group, with 8 at risk per group. Other adverse-event counts are 2 for mild impairment, 2 for moderate impairment, 0 for severe impairment, and 1 for the normal group. Deaths are not reported in the registry record. The design and outcome definition are documented, but the numerical pharmacokinetic findings and several analysis details are not reported in the registry record.