Pharmacokinetics (PK) Study of Gepotidacin (GSK2140944) in Adult Subjects With Varying Degrees of Hepatic Impairment and in Matched Control Subjects With Normal Hepatic Function: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetics (PK) Study of Gepotidacin (GSK2140944) in Adult Subjects With Varying Degrees of Hepatic Impairment and in Matched Control Subjects With Normal Hepatic Function (NCT03562117), a non-randomized phase 1 study. The primary outcome is Area Under the Plasma Concentration-time Curve (AUC) From Time Zero (Pre-dose) Extrapolated to Infinity (AUC[0-inf]) for Plasma Gepotidacin.

2. Clinical Question

The study was intended to characterize exposure after a single dose across hepatic-function groups. Its brief summary says results were intended to support development of dosing recommendations for people with impaired hepatic function. That stated purpose is not itself evidence of a particular exposure difference or dosing recommendation.

3. Trial Design

This was a Phase I, open-label, non-randomized, parallel, two-part study. The registry record gives an enrollment of 25 and a planned total of 48. It lists the study as completed, with a start date of 2018-06-14 and primary completion date of 2018-12-26. The reason the enrolled number was below the planned total is not reported in the registry record.

In Part 1, the plan was to enroll participants with moderate hepatic impairment and participants with normal hepatic function. Normal-function participants in Group D were to be enrolled after completion of all Day 3 assessments for the corresponding hepatically impaired participant. Part 2 was intended to include participants with severe impairment and normal hepatic function concurrently, based on Part 1 pharmacokinetic, safety, and tolerability data. Mild impairment was an optional group, to be studied if there were a significant pharmacokinetic difference between moderate impairment and normal function. Whether those decision conditions were met, and the enrollment by group, are not reported in the registry record.

All listed groups received a single oral dose of gepotidacin, 1500 mg, on Day 1. The group descriptions identify moderate impairment as a Child-Pugh score of 7 to 9 and mild impairment as a score of 5 to 6. The severe-impairment description also gives a Child-Pugh score of 7 to 9, the same range stated for moderate impairment. This apparent inconsistency is not resolved in the registry record.

Although the study describes matched normal-function participants, allocation was non-randomized and masking was absent. The record warns that the arms are not a like-for-like control comparison. Matching criteria, baseline characteristics, and any adjusted comparisons 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: Twenty five participants were enrolled in the study. In part 1, normal hepatic function participants were matched to moderate hepatic impaired participants. In Part 2, participants with severe hepatic impairment were matched to normal hepatic function participants who participated in Part1.

Part 1, Up to 3 Days

Reasons for not completing this period:

Part 2, Up to 3 Days

Analysis population for the primary outcome, as defined in the registry: PK Parameter Population.

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 (AUC) From Time Zero (Pre-dose) Extrapolated to Infinity (AUC[0-inf]) for Plasma Gepotidacin, measured over Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.

The primary endpoint is the area under the plasma concentration-time curve from time zero, before dosing, extrapolated to infinity, for gepotidacin (AUC[0-inf]). It is expressed in hours*nanograms per milliliter. Blood samples were scheduled from pre-dose through 48 hours post-dose at the time points listed in the registry record. The endpoint belongs to the PK Parameter Population: participants for whom valid and evaluable pharmacokinetic parameters were derived.

As a general pharmacokinetic concept, an area-under-the-curve measure represents drug exposure across time. Extending the estimate to infinity includes an extrapolated portion beyond the last measured concentration, so interpretation depends in part on the concentration-time measurements and the extrapolation used. The registry record identifies the endpoint as a geometric mean with geometric coefficient of variation as its dispersion measure, but does not report the group estimates, their variability, or the method used to obtain the extrapolated portion.

Exposure measures are useful in a study of hepatic impairment because the study asks whether drug exposure differs across hepatic-function groups after the same stated dose. The endpoint can characterize exposure; by itself, it does not establish clinical benefit, harm, or a dosing recommendation. Numerical primary-endpoint results and statistical comparisons are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a continuous pharmacokinetic measure: AUC[0-inf] for plasma gepotidacin. The registry record says it is summarized as a geometric mean, with geometric coefficient of variation to describe dispersion. It identifies blood sampling time points from pre-dose through 48 hours after dosing, and defines the PK Parameter Population as participants with valid and evaluable derived PK parameters. The numerical summaries and the procedures used to calculate them are not reported in the registry record.

What does a geometric mean describe?

As a general statistical concept, a geometric mean summarizes positive measurements on a multiplicative scale. It is often used for pharmacokinetic quantities because such values can vary proportionally rather than by a fixed additive amount. A geometric coefficient of variation describes relative spread on that scale. These summaries do not reveal the distribution of individual values or the precision of a group estimate on their own. Confidence intervals or other uncertainty measures would help convey precision, but are not reported in the registry record.

Why does the design matter?

This is a parallel-group, non-randomized study. In general, random allocation can help balance participant characteristics across intervention groups; this study instead compares groups defined by hepatic function. For its pharmacokinetic aim, the groups provide observations under different hepatic-function conditions after the stated dose. But an observed group difference would not automatically be attributable solely to hepatic function. The record says normal-function participants were to be matched with impaired participants, but does not report the matching variables, whether matching was completed, or how matching was handled in analysis. It also explicitly cautions against treating the arms as a like-for-like control comparison.

Open-label means masking was absent. For an objective concentration-based pharmacokinetic measure, the relevance of masking may differ from its relevance to subjective outcomes, but the registry record does not describe any safeguards or laboratory procedures. It is therefore not possible to assess those details from the record.

What can the analysis population tell readers?

The stated PK Parameter Population includes participants for whom valid and evaluable PK parameters were derived. This is a defined analysis population, but its size, exclusions, and relationship to all enrolled participants are not reported in the registry record. General statistical interpretation requires knowing how many observations contributed to each estimate and why measurements or participants were excluded. Missing-sample handling, rules for evaluability, and sensitivity analyses are not reported in the registry record.

How should uncertainty be read?

In general, a confidence interval gives a range of values compatible with the data and a specified statistical procedure. A narrow interval indicates greater precision than a wide interval, while neither interval alone determines clinical importance. The registry record does not give confidence intervals for AUC[0-inf] or other primary-endpoint uncertainty estimates. It also does not report a model, transformation details, or inferential procedure for comparing hepatic-function groups.

Geometric coefficients of variation, if reported, would describe relative variability among measured exposure values; they would not be a substitute for a confidence interval around a group estimate. The numerical geometric means and coefficients of variation are not reported in the registry record, so their observed variability cannot be discussed.

What does the record say about planning?

The brief summary states that 48 participants were planned, whereas the enrollment record gives 25. The sample-size justification, assumptions used in the trial's own planning, and any revisions are not reported in the registry record. A separate planning illustration based on an observed effect is not the same as the trial's original design justification. Such illustrations are hypothetical planning aids, not observed power, and depend on their stated assumptions. The observed primary effect and numerical planning outputs are not reported in the registry record.

The record lists zero analyses. It does not report p-values, adjusted estimates, or model-based comparisons. Any recalculation from summary statistics would be an unadjusted recalculation and should not replace a sponsor analysis if the posted figures were inconsistent; no numerical recalculations or discrepancy are reported in the registry record.

Why can over-dispersion matter?

As a general explanation, over-dispersion occurs when data vary more than a statistical model assumes. If present and ignored, estimated uncertainty can be too small, making results appear more precise than they are. Pharmacokinetic measurements can show substantial between-participant variability, but the registry record does not report a model that assumes a particular variance structure or evidence about over-dispersion. This is therefore a general consideration, not a finding about this study.

The secondary outcomes include additional exposure and time-course measures, such as AUC from zero to the last quantifiable concentration, time to peak concentration, apparent oral clearance, and terminal-phase measures. ECG findings are also listed. The registry record identifies these outcomes but does not report their numerical results or analysis methods. The endpoint list alone does not establish how results were prioritized beyond the named primary endpoint.

10. Multiplicity, Missing Data and Analysis Populations

The registry record names AUC[0-inf] as the primary endpoint and lists secondary pharmacokinetic measures, including AUC from zero to the last quantifiable concentration, time to maximum concentration, lag time, apparent oral clearance, apparent terminal-phase volume of distribution, terminal-phase rate constant, and terminal-phase half-life. It also lists the number of participants with abnormal ECG findings. There are 27 outcome measures in the record. The registry lists zero analyses, so it does not provide numerical outcome analyses for these measures.

Multiplicity arises in general when several outcomes or comparisons are tested: the chance of at least one apparently notable finding can increase as more tests are considered. Statistical plans may address this with a prespecified hierarchy or adjustment, but whether this study used such an approach is not reported in the registry record. The record does not report a multiplicity strategy, analysis hierarchy, or interim analyses.

The record defines a PK Parameter Population consisting of participants with valid and evaluable pharmacokinetic parameters. It does not report the number in that population, missing-data counts, reasons for missing samples, rules for handling values below quantification, or imputation methods. It also does not report whether all enrolled participants contributed to safety summaries or how missing safety information was handled. Those omissions limit assessment of potential selection or missing-data effects.

The planned enrollment was 48, and 25 participants were enrolled. The reasons for the difference, group-specific enrollment, and any effect on analysis populations are not reported in the registry record. Without endpoint estimates, uncertainty intervals, and analysis details, the record does not allow an assessment of multiplicity-adjusted evidence or missing-data sensitivity.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: death (11.1%).

The safety counts are reported separately for participants with normal hepatic function, moderate hepatic impairment, and severe hepatic impairment. Serious adverse events affected 1 of 9 participants in the normal-function group, 0 of 8 in the moderate-impairment group, and 0 of 8 in the severe-impairment group. Other adverse events affected 3 of 9, 2 of 8, and 4 of 8 participants, respectively. The record lists 1 death in the normal-function group and none in the impairment groups.

The registry also identifies Death as a serious adverse-event term at 11.1%. That entry is a reported event term; the record does not give a causal assessment. It does not establish whether the death was related to study treatment, hepatic function, or another cause. The relationship between the event-term listing and the participant-level counts is not explained in the registry record.

These are descriptive figures from small, non-randomized groups, not a controlled comparison of safety risk. The group sizes and event counts should not be interpreted as evidence that one group had safer treatment. The registry record does not report event timing, individual clinical details, seriousness criteria, or causality assessments. The counts describe what was recorded, not what caused the events.

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

The record describes a study designed to characterize gepotidacin pharmacokinetics after a single oral 1500 mg dose in adults with normal hepatic function or hepatic impairment. Its primary measure, AUC[0-inf], is a measure of plasma exposure, and the study also lists other pharmacokinetic and safety outcomes. The posted information therefore identifies a relevant question about exposure across hepatic-function groups.

However, the numerical primary-endpoint findings are not reported in the registry record. There are no posted group estimates, measures of uncertainty, or statistical comparisons. The record cannot establish whether exposure differed between groups, the direction or size of any difference, or its precision. Nor does the endpoint alone establish clinical outcomes or a dosing recommendation.

The design was non-randomized and open-label, and the registry cautions that the arms are not a like-for-like control comparison. This matters when interpreting any group contrast: hepatic-function groups may differ in other ways, and the record does not provide matching details or adjusted analyses. The group-specific enrollment and the number of participants contributing evaluable PK data are also not reported in the registry record.

Safety information is limited to selected participant counts. The record lists serious adverse events, other adverse events, and deaths by group, but does not establish causality. These descriptive counts cannot be used to infer a comparative safety effect.

The record also states that 48 participants were planned and reports 25 enrolled, without explaining the difference. The apparent overlap in Child-Pugh ranges for the moderate and severe groups is not resolved. These uncertainties, together with absent numerical PK results and analysis details, mean the record supports understanding the study's purpose and design, but not a conclusion about exposure differences or the implications of those differences.

13. Why This Trial Matters Statistically

This study illustrates how pharmacokinetic research asks a different question from a conventional efficacy comparison. The focus is exposure after a specified dose, measured using concentration-time data, rather than whether a treatment changes a clinical outcome. AUC[0-inf] is the named primary measure, while the additional listed outcomes describe other aspects of concentration and disposition.

It also highlights the importance of distinguishing a planned comparison from a randomized comparison. Participants were grouped by hepatic function, and the study was non-randomized. The normal-function participants were intended to be matched with impaired participants, but the matching details and analysis are not reported in the registry record. The registry's own caution that the arms are not like-for-like is important: an observed difference, if reported, would need interpretation in light of design and participant comparability.

Clear reporting of the analysis population and uncertainty is essential in pharmacokinetic studies. The record defines who could contribute valid and evaluable PK parameters, but does not state how many participants met that definition or report exposure estimates and precision. Without these details, readers cannot assess how much information underlies the primary endpoint or how precisely it was estimated.

The discrepancy between planned enrollment of 48 and reported enrollment of 25 also makes trial conduct relevant to interpretation. The record does not explain the difference or report enrollment by group. In a study intended to compare several hepatic-function categories, group-specific information is necessary to understand the scope and precision of the resulting evidence.

Finally, safety counts require careful separation from causal conclusions. The record reports events by group but does not provide causality assessments, and the non-randomized design does not support a simple treatment-risk comparison. These features make transparent reporting of results and methods particularly important for readers evaluating what the study can establish.

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 of the registry record is that it specifies the primary endpoint but does not report its numerical results. Group estimates, variability, confidence intervals, and statistical comparisons are absent. Although the endpoint is defined as a geometric mean with geometric coefficient of variation, those summaries cannot be interpreted without their values.

The reported enrollment is 25, whereas the brief summary says 48 participants were planned. The record does not explain why enrollment was lower than planned, provide enrollment by group, or state how many participants contributed evaluable PK parameters. This restricts assessment of the information available for each hepatic-function category.

The study is non-randomized and open-label. The registry says normal-function participants were matched with participants with impairment, but matching criteria, completion, and analytical handling are not reported. The record itself warns that groups are not a like-for-like control comparison. No baseline characteristics or adjusted analyses are reported to address group comparability.

The group definitions also contain an unresolved inconsistency: both the moderate-impairment and severe-impairment descriptions give a Child-Pugh score of 7 to 9. The record does not clarify the intended range for severe impairment. It also does not report whether the optional mild-impairment group was enrolled or whether the stated conditions for proceeding to Part 2 were met.

Analysis methods beyond the endpoint summary are not reported. The record does not describe handling of missing samples, values below quantification, multiplicity, interim analyses, or a sample-size justification. Safety information is limited to event counts, without event timing or causality assessments. These are limitations of what the registry record reports; they do not establish how the study was conducted beyond the recorded details.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Pharmacokinetics (PK) Study of Gepotidacin (GSK2140944) in Adult Subjects With Varying Degrees of Hepatic Impairment and in Matched Control Subjects With Normal Hepatic Function — NCT03562117.
• Registry record last updated 2021-04-12; status last verified 2021-03.
• Results first posted 2019-12-17.
• 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

This completed Phase I study evaluated pharmacokinetics, safety, and tolerability after a single oral dose of gepotidacin, 1500 mg, in adults with normal hepatic function or hepatic impairment. It was open-label, non-randomized, and parallel, with a planned two-part structure. The registry reports 25 enrolled participants and states that 48 were planned.

The primary endpoint was plasma AUC[0-inf], summarized in the registry plan as a geometric mean with geometric coefficient of variation. The PK Parameter Population included participants with valid and evaluable PK parameters. Numerical primary results, analysis estimates, and uncertainty measures are not reported in the registry record.

Selected adverse-event counts are reported for normal, moderate-impairment, and severe-impairment groups. The record does not establish causality. It also cautions that the arms are not a like-for-like control comparison. Reasons for the enrollment difference, group-specific PK population sizes, matching details, and several analysis methods are not reported in the registry record.