A Study to Investigate the Influence of Hepatic Impairment on Elpipodect (MK-8189) Treatment (MK-8189-012): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Investigate the Influence of Hepatic Impairment on Elpipodect (MK-8189) Treatment (MK-8189-012) (NCT04676425), 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 MK-8189.

2. Clinical Question

The study focused on pharmacokinetics: how drug concentrations in plasma change over time after a dose. AUC0-inf estimates total plasma exposure, including an extrapolated portion after the final measured concentration. The registry describes this as Part 1 of a study. Its stated purpose was to compare pharmacokinetics in moderate hepatic impairment with those in healthy participants.

The record says a decision about whether to initiate Part 2 would follow review of Part 1 safety and pharmacokinetic data. If undertaken, Part 2 would compare participants with mild hepatic impairment with healthy participants. Whether Part 2 was initiated is not reported in the registry record. Numerical AUC0-inf estimates and a numerical between-group comparison are also not reported in the registry record, so the direction and size of any pharmacokinetic difference cannot be described from the recorded results.

3. Trial Design

This was a completed Phase 1, open-label, nonrandomized, parallel-group study. Its official title describes a two-part, single-dose study of the influence of hepatic impairment on MK-8189 pharmacokinetics. The record identifies this as Part 1, whose focus was moderate hepatic impairment. The listed enrollment is 14. The two groups were moderate hepatic impairment participants and healthy participants, with 7 reported at risk in each group for adverse-event summaries.

Participants in the moderate hepatic impairment group received a single oral dose of elpipodect 4 mg on Day 1. Healthy participants received a single oral dose of MK-8189 4 mg on Day 1. The study was open-label, so masking was not used. Allocation was nonrandomized, and the groups were not assigned by random allocation. The registry specifically cautions that the arms are not a like-for-like control comparison. Differences between groups therefore cannot automatically be attributed to hepatic impairment alone.

The study began on 2021-03-17, had primary completion on 2022-01-16, and is recorded as completed. Blood collection for the primary pharmacokinetic endpoint was scheduled before dosing and at multiple post-dose times. The listed common timepoints were pre-dose (0), 2, 6, 8, 10, 12, 16, 24, 36, 48, 72 and 96 hours for both groups; additional times of 60, 84, 108 and 120 hours were listed for the hepatic impairment group.

The study also listed secondary safety outcomes concerning participants who experienced one or more adverse events and participants who discontinued due to an adverse event. Details of any planned sample-size justification, interim analyses, or broader statistical 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: All participants who were compliant with the study procedures and have available data from at least one treatment.

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 to Infinity (AUC0-inf) of MK-8189, measured over Pre-dose (0), 2, 6, 8, 10, 12, 16, 24, 36, 48, 72 and 96 hours post-dose (hepatic impairment and healthy participants); 60, 84, 108 and 120 hours post-dose (hepatic impairment participants).

The primary endpoint was the area under the plasma concentration-time curve from time zero to infinity, AUC0-inf, for MK-8189. It is expressed in h*nmol/L. AUC0-inf is intended to represent total plasma drug exposure after administration, including an extrapolation from observed concentrations toward infinity. Blood samples taken before and after dosing at the listed timepoints were used to estimate this quantity.

Pharmacokinetic exposure is relevant to a study of hepatic impairment because the study question concerns whether the concentration-time profile differs between participants with moderate impairment and healthy participants. AUC combines information across the concentration profile rather than describing a single sampling time. It can therefore provide a measure of overall exposure, while still depending on the quality and completeness of the concentration measurements and the extrapolation used for the unobserved tail.

The registry describes the endpoint summary as a geometric least-squares mean with a 95% confidence interval. The model was fitted to natural log-transformed AUC0-inf values using a linear fixed effects model. A confidence interval conveys uncertainty around an estimated quantity under the model; it does not guarantee that the true value lies within the interval. Numerical estimates, confidence limits, and a numerical comparison between groups are not reported in the registry record. Consequently, the endpoint definition and method are available, but the observed pharmacokinetic result cannot be interpreted for magnitude, direction, or precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The main statistical method described for the primary endpoint is a linear fixed effects model applied to natural log-transformed AUC0-inf values. The registry states that the resulting summaries are geometric least-squares means with 95% confidence intervals. It does not provide the model specification beyond that description, including which effects or covariates were included. Those details are not reported in the registry record.

Why analyze a transformed endpoint?

As a general statistical concept, pharmacokinetic measures such as total exposure can have a right-skewed distribution: a small number of comparatively high values may stretch the upper tail. A natural logarithm compresses large values and can make the distribution more compatible with the assumptions of a linear model. This transformation changes the scale of analysis. An additive contrast on the log scale corresponds, after back-transformation, to a multiplicative comparison on the original scale. This general explanation does not establish what distribution the study data actually had. Diagnostics and their results are not reported in the registry record.

A geometric least-squares mean is a model-based summary, not simply an arithmetic average of the untransformed observations. The term “least-squares” indicates that the estimate comes from the fitted model; “geometric” reflects the log-scale analysis and back-transformation. The registry reports this summary type but does not provide the numerical estimates. It also does not state whether an explicit ratio or another contrast was the prespecified primary comparison. Such a contrast is not reported in the registry record.

What does the confidence interval describe?

In general, a confidence interval expresses uncertainty in an estimate under the assumptions of the analysis model and sampling process. A narrower interval indicates greater precision than a wider interval, all else being equal. It is not a measure of the range of individual participant responses, and it does not by itself establish clinical importance. The registry specifies a 95% confidence interval for the geometric least-squares mean, but the actual interval limits are not reported in the registry record. The statistical interpretation of precision therefore cannot be made for the study result.

The model uses AUC0-inf values estimated from plasma concentrations collected over time. AUC0-inf includes an extrapolated contribution after observed sampling ends. As a general matter, that extrapolation depends on the measured concentration profile and the method used to characterize its terminal decline. The registry gives the sampling schedule and endpoint definition, but does not report the extrapolation fraction, terminal-phase estimation details, or participant-level concentration data. These elements are not reported in the registry record.

How should the group comparison be viewed?

This was a nonrandomized parallel-group study, rather than a randomized comparison. In general, random allocation helps balance measured and unmeasured characteristics across groups on average. Without randomization, group differences may reflect hepatic status, other group characteristics, or both. That is not proof that a particular bias occurred; it is a design limitation that affects causal interpretation. The registry explicitly cautions that the arms are not a like-for-like control comparison. Details of adjustment for possible group differences are not reported in the registry record.

The study was open-label. For a pharmacokinetic endpoint based on laboratory concentration measurements, lack of masking does not change the definition of AUC, but open-label status remains part of the study design and may matter for other aspects of study conduct. The registry does not describe whether laboratory personnel were masked or how concentration assays were managed. Those details are not reported in the registry record.

What can sample-size planning tell a reader?

In general, a sample-size calculation is a planning exercise based on assumptions about the effect to detect, variability, significance level, allocation, and analysis method. It is distinct from a result observed in the trial. A planning illustration based on an observed effect is not observed power and does not show how likely the trial was to detect a different effect. The record describes assumptions for a planning illustration: two-sided significance level 0.05, equal allocation, a normal approximation, and effects expressed as fractions of the observed effect. It also notes that ordinary outcome illustrations use participants per arm, whereas time-to-event illustrations use total events. Numerical planning outputs are not reported in the registry record, and these assumptions should not be treated as the study's own design justification.

The record does not report the full analysis plan, model diagnostics, missing-data procedures, or a detailed account of how the primary comparison was estimated. Accordingly, the method description supports an understanding of the intended summary approach, but not an independent reproduction or appraisal of the fitted analysis. The numerical primary results are also not reported in the registry record, limiting any assessment of effect size and statistical precision.

10. Multiplicity, Missing Data and Analysis Populations

Multiplicity concerns the risk of false-positive findings when several hypotheses or outcomes are tested. As a general statistical principle, a plan may identify a primary outcome, distinguish confirmatory from exploratory analyses, or adjust interpretation for multiple comparisons. The registry identifies AUC0-inf as the primary endpoint and lists secondary safety outcomes. It does not report whether any multiplicity adjustment was planned, which analyses were considered confirmatory, or how secondary outcomes were to be interpreted. These details are not reported in the registry record.

The record describes a population for the primary endpoint consisting of participants compliant with study procedures who had available data from at least one treatment. This definition indicates that endpoint analysis depended on both compliance and data availability. It does not give the number included in the primary analysis, reasons for exclusion, amount or pattern of missing pharmacokinetic data, or sensitivity analyses. Missing-data methods and the handling of incomplete concentration profiles are not reported in the registry record.

The record also lists secondary outcomes concerning participants who experienced one or more adverse events and participants who discontinued due to an adverse event. The adverse-event summary reports counts for serious and other adverse events, but a discontinuation result is not reported in the registry record. The record does not explain whether participants with missing safety follow-up were included in the relevant summaries or how missing safety information was handled.

These omissions limit assessment of whether the reported analysis population matched the intended population and whether results might be sensitive to missing observations or multiple testing. In general, missingness can matter when the likelihood of unavailable data is related to participant characteristics or outcomes. That general concern does not establish that missingness biased this study; the information needed to assess it is not reported in the registry record.

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 reports no serious adverse events among the 7 participants at risk in the moderate hepatic impairment group and none among the 7 participants at risk in the healthy group. No deaths were recorded in either group. The other adverse-event count was 4 among 7 participants at risk in the moderate hepatic impairment group and 0 among 7 participants at risk in the healthy group.

These are descriptive counts, not evidence from a randomized safety comparison. The groups were nonrandomized and the registry cautions that they are not like-for-like control groups. The record does not provide event terms for the other adverse events, their severity, timing, or relationship to treatment. It also does not report the number of participants who discontinued because of an adverse event. Those details are not reported in the registry record.

Zero recorded serious events in these groups does not establish that serious events cannot occur; it describes what was recorded in this study. General statistical caution is warranted when interpreting safety counts from small groups: uncommon events may not be observed, and differences between groups may be imprecise. The record does not report a formal statistical test or confidence interval for the safety counts.

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

This study addresses a focused pharmacokinetic question: how AUC0-inf after a single dose of elpipodect compares between participants with moderate hepatic impairment and healthy participants. It records the endpoint definition, the dosing, the sampling schedule, and the analysis approach. The numerical primary endpoint estimates and a numerical group comparison are not reported in the registry record. Therefore, the posted information does not establish the direction, magnitude, or precision of a pharmacokinetic difference.

The design is a nonrandomized, open-label parallel-group study. It can describe the groups studied, but a difference between them would not automatically demonstrate that hepatic impairment caused the difference. Other group characteristics could contribute, and the registry does not report adjustment details. The registry also states that the arms are not a like-for-like control comparison.

The safety record reports no serious adverse events or deaths in either group and reports other adverse events in the moderate hepatic impairment group but not the healthy group. Those counts should be read as descriptive observations from this study, not as a definitive comparative safety estimate. Event descriptions and the discontinuation outcome are not reported in the registry record.

The registry describes Part 1 as a study of moderate hepatic impairment and says a decision about Part 2 would follow review of safety and pharmacokinetic data. Whether Part 2, intended to examine mild hepatic impairment, was initiated is not reported in the registry record. The results recorded for Part 1 cannot answer questions about mild hepatic impairment, repeated dosing, or outcomes beyond the listed pharmacokinetic and safety measures.

In sum, the record clarifies the study question and method, but its missing numerical AUC0-inf results prevent interpretation of the primary comparison. The available safety counts provide limited descriptive information and do not support broader conclusions about treatment effects or risk.

13. Why This Trial Matters Statistically

Pharmacokinetic studies in hepatic impairment ask whether drug exposure differs across groups defined by liver function. AUC0-inf is useful for this question because it represents estimated total plasma exposure rather than concentration at only one sampling time. The endpoint is constructed from measurements taken over time and includes extrapolation beyond the last observed concentration, making clear reporting of both the estimate and its uncertainty important.

This study also illustrates how design affects the meaning of a comparison. Nonrandomized parallel groups can provide descriptive pharmacokinetic information, but they do not have the same protection against group imbalance as randomized allocation. Here, the registry explicitly warns that the groups are not a like-for-like control comparison. Statistical interpretation therefore depends not only on the model but also on careful attention to who was compared and how the groups were formed.

The analysis description is informative in specifying natural log-transformed values, a linear fixed effects model, geometric least-squares means, and 95% confidence intervals. At the same time, the registry does not report numerical primary results, the model's detailed specification, or the full missing-data and multiplicity approaches. This highlights a basic reporting principle: readers need estimates and uncertainty, not only an endpoint definition and a method, to assess the strength and precision of evidence.

The safety summaries likewise show why counts need context. Recorded events can be described, but small, nonrandomized groups and absent event detail constrain comparative interpretation. This study is statistically relevant as an example of an early-phase, single-dose pharmacokinetic comparison whose design and analysis description are available while the numerical primary outcome is not reported in the registry record.

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 the study is that numerical AUC0-inf estimates, confidence limits, and a numerical between-group comparison are not reported in the registry record. Without these, the main pharmacokinetic result cannot be assessed for direction, magnitude, or precision.

The comparison was nonrandomized, open-label, and explicitly not a like-for-like control comparison. The registry does not report participant characteristics beyond the impairment grouping, nor does it describe adjustment for possible differences between groups. As a general matter, this makes causal attribution of any observed group difference difficult. The absence of reported adjustment details should not be taken as proof that no adjustment was made.

AUC0-inf incorporates extrapolation beyond measured concentrations. Although the sampling times are listed, details of the terminal-phase estimation and the extrapolated contribution are not reported in the registry record. The analysis population is described as compliant participants with available data from at least one treatment, but inclusion counts, exclusions, missingness patterns, and sensitivity analyses are not reported.

The safety results are limited to summary counts. The specific terms and severity of other adverse events, their timing and relationship to treatment, and the result for discontinuation due to an adverse event are not reported in the registry record. The registry also does not report multiplicity handling, detailed model specification, or whether any interim analysis was conducted. These limitations restrict independent assessment of the primary analysis and the breadth of conclusions that can be drawn from the recorded safety information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Investigate the Influence of Hepatic Impairment on Elpipodect (MK-8189) Treatment (MK-8189-012) — NCT04676425.
• Registry record last updated 2026-04-29; status last verified 2026-04.
• Results first posted 2023-10-06.
• 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

NCT04676425 is a completed Phase 1, open-label, nonrandomized, parallel-group study of a single dose of elpipodect in participants with moderate hepatic impairment and healthy participants. The listed enrollment is 14. Each group received a single oral dose of 4 mg on Day 1. The primary endpoint was AUC0-inf, analyzed using a linear fixed effects model on natural log-transformed values and summarized as geometric least-squares means with 95% confidence intervals.

The record reports no serious adverse events or deaths in either group, and other adverse events in 4 participants in the moderate hepatic impairment group and none in the healthy group. Numerical primary endpoint results and a numerical group comparison are not reported in the registry record. The registry describes this as Part 1 and states that a decision about Part 2 would follow review; whether Part 2 was initiated is not reported in the registry record.