Pharmacokinetics of Entospletinib in Adults With Normal and Impaired Liver Function: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetics of Entospletinib in Adults With Normal and Impaired Liver Function (NCT02521376), a non-randomized phase 1 study. The primary outcome is Pharmacokinetic (PK) Parameter: AUCtau of ENTO.

2. Clinical Question

3. Trial Design

This was a Phase 1, open-label, non-randomized, parallel study of entospletinib pharmacokinetics in adults with normal or impaired hepatic function. The registry record gives enrollment as 56 and status as completed. The study began on 2015-11-16, and primary completion was 2017-10-25. Gilead Sciences is listed as the sponsor.

The impaired-function cohorts were classified as mild, moderate, and severe hepatic impairment. A healthy-control group was also included. Entospletinib was administered twice daily on Days 1-4 and as one morning dose on Day 5 in each of the three impaired-function cohorts. The registry record does not give a dose amount in the information. It describes no masking, so participants and investigators were not blinded to treatment assignment.

The design is parallel rather than crossover: participants were grouped according to hepatic-function category rather than described as receiving multiple study conditions in sequence. Allocation was non-randomized. Consequently, comparisons across hepatic-function groups should be read as observational contrasts within the study, not as randomized treatment effects. The registry record explicitly notes that the arms are not a like-for-like control comparison.

The primary analysis population consisted of participants who received at least one dose and had at least one evaluable pharmacokinetic concentration reported by the laboratory. The record says available data were analyzed and that healthy controls might participate in more than one cohort. This detail matters when interpreting comparisons: control observations may be reused across cohort contrasts rather than being independent, wholly separate control groups. How that feature was handled analytically is not reported in the registry record.

The study also listed secondary outcomes covering treatment-emergent adverse events and treatment-emergent laboratory abnormalities. The registry record lists four outcome measures and eight analyses, but does not provide the full analysis specifications or results for the primary pharmacokinetic endpoint in the information. No recruitment or enrollment by individual cohort beyond the safety counts is stated as a separate design summary.

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: 102 participants were screened.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants in the PK Analysis Set (all enrolled participants who received at least one dose of ENTO and had at least one evaluable PK concentration data value reported by the PK lab) with available data were analyzed. Healthy control participants may participate in more than one cohorts.

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 randomized participants who received at least one dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Pharmacokinetic (PK) Parameter: AUCtau of ENTO, measured over 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 84, and 96 hours postdose on Day 5.

The primary endpoint was the mean AUCtau of entospletinib, with units of h*ng/mL. AUCtau is defined in the registry record as the area under the concentration-versus-time curve over the dosing interval. It summarizes drug concentration across time rather than relying on a concentration measured at a single sampling moment. This makes it a pharmacokinetic measure of exposure across the interval between doses.

The endpoint was assessed using concentration measurements scheduled from 0 (predose) through 96 hours postdose on Day 5, at the time points specified in the record. AUCtau is relevant to this study because the central question is whether exposure differs between participants with impaired hepatic function and matched healthy controls. The record specifies the mean as the summary parameter and standard deviation as the measure of dispersion.

A mean describes the central value of the observations, while a standard deviation describes how spread out individual observations are around that mean. Those summaries can characterize the observed exposure in each group, but they do not by themselves establish the precision of a between-group contrast. Confidence intervals or other inferential results would help show the range of differences compatible with the data. Such primary endpoint estimates and uncertainty measures are not reported in the registry record. Therefore, the endpoint definition and sampling schedule can be described, but the magnitude and precision of the observed pharmacokinetic findings cannot be assessed from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation depends on distinguishing the endpoint, the summaries used for it, the group comparisons, and the uncertainty around those comparisons. The registry record identifies a continuous pharmacokinetic endpoint: mean AUCtau, measured in h*ng/mL. It specifies standard deviation as the dispersion measure. It does not give the AUCtau values or the inferential procedures used to compare groups, so the methods below explain the concepts relevant to reading this design rather than claiming that a particular unreported method was used.

What does AUCtau represent?

AUCtau is the area under a concentration-versus-time curve over the dosing interval. In general, integrating concentration across time summarizes exposure over an interval, whereas a single concentration measurement describes only one sampling time. The record lists blood sampling from predose through 96 hours postdose on Day 5, including the specified intervening time points. The exact method used to derive each participant's AUCtau from those measurements is not reported in the registry record. The endpoint definition states the conceptual measure, not the computational details.

The registry record specifies a mean and standard deviation. In general, the mean is an arithmetic summary of observed values, while the standard deviation describes how much individual values vary around the mean. A standard deviation is not the same as a confidence interval: it describes variability among observations, while a confidence interval expresses uncertainty about an estimated quantity. Neither the group standard deviations nor confidence intervals for AUCtau are reported in the registry record.

How should group comparisons be understood?

The study compares participants by hepatic-function group and healthy-control status. Because allocation was non-randomized, these contrasts are not randomized treatment comparisons. In general, random assignment can help balance measured and unmeasured characteristics across groups, while a non-randomized comparison may retain differences associated with group membership. Here, hepatic-function status defines the cohorts; the record does not establish that other characteristics were balanced.

The study summary says impaired-function participants were stratified by smoking status as appropriate and describes healthy controls as matched. Matching can make groups more comparable on selected characteristics, but the record does not identify the matching variables, matching process, or analysis used to account for matched observations. It is therefore not possible to determine how much comparability was achieved or what statistical consequences matching had. The record also says healthy controls may participate in more than one cohort. In general, reusing a control group can make comparisons statistically dependent; whether and how the analysis accounted for this is not reported in the registry record.

The endpoint is continuous, so analyses might describe means, differences, ratios, or transformed values in general statistical practice. However, the registry record identifies only mean AUCtau and standard deviation in the endpoint description; it does not specify a model, transformation, adjustment set, or contrast scale. None should be inferred. The actual estimates and statistical tests are also not reported in the registry record, so the direction and precision of any contrast remain unknown.

What is the role of uncertainty?

General statistical explanation: a confidence interval gives a range of values compatible with the data and the method's assumptions. A narrow interval indicates greater precision than a wide interval, but interpretation also depends on the endpoint and the question being asked. A p-value, when reported, addresses compatibility of the data with a specified null model; it does not convey effect magnitude by itself. Neither confidence intervals nor p-values for the primary AUCtau comparisons are reported in the registry record. Statistical significance, precision, and practical importance therefore cannot be evaluated from the primary results.

The reported standard deviation would help describe variability in observed individual AUCtau measurements, but not the uncertainty in a group contrast by itself. For a group comparison, uncertainty depends on the observed data and analysis structure, including any matching or shared controls. Since group-level AUCtau results and analysis details are absent, no valid uncertainty statement can be reconstructed from the endpoint description.

Why does over-dispersion matter?

General statistical explanation: over-dispersion occurs when observed variability is greater than a statistical model assumes. If it is ignored, standard errors may be too small and confidence intervals too narrow, making the evidence appear more precise than it is. This concept is most often discussed for outcomes such as counts, but the broader lesson is that a model's variability assumptions need to suit the data. The registry record does not report a model or evidence of over-dispersion for the continuous pharmacokinetic endpoint, so no claim about its presence or treatment is warranted.

For continuous pharmacokinetic measurements, the distribution of individual values and the influence of unusually high or low observations can affect the mean and the uncertainty of a comparison. General methods may use transformations or robust approaches when justified by the data, but the record does not state that any such approach was used. It would be inappropriate to assign one to this trial without a reported analysis plan or results.

What does the planning illustration mean?

The planning illustration is described as using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It considers effects stated as fractions of the observed effect. These are assumptions for a planning calculation, not a description of the study's original enrollment design. The record does not report the original sample-size justification, and the illustration does not represent observed power. Sample-size values are planning illustrations rather than observed outcomes. No illustration values are repeated in this explanation.

In general, planning calculations depend on the target effect, variability, significance level, allocation, and statistical method. A calculation based on an observed effect is conditional on that effect estimate; it does not establish the probability that the completed study detected a real effect. The registry record does not include the primary AUCtau estimates needed to assess the observed effect in this explanation, nor does it report the original assumptions used to plan the study.

The central methodological limitation is thus not a technical detail of a known model but the lack of reported primary results and analysis specifications. The endpoint and design are described, but the reader cannot assess the actual estimates, uncertainty, adjustments, or sensitivity analyses from the registry record.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Cohort 1: Moderate Hepatic Impairment Smoking", "Cohort 1: Moderate Hepatic Impairment Non-smoking", "Cohort 1: Healthy Control Matched to Smoking", "Cohort 1: Healthy Control Matched to Non-smoking", "Cohort 2: Severe Hepatic Impairment", "Cohort 2: Healthy Control")
n   <- c(9, 9, 9, 9, 7, 7)
m   <- c(1788.9, 7490, 4081.5, 3318, 7036, 3402.7)
sp  <- c(771.3, 3805.03, 2464.77, 1788.9, 2814.95, 1771.79)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Cohort 1: Moderate Hepatic Impairment Smoking  9  1788.900  771.300  1196.026  2381.774
CARM  Cohort 1: Moderate Hepatic Impairment Non-smoking  9  7490.000  3805.030  4565.195  10414.805
CARM  Cohort 1: Healthy Control Matched to Smoking  9  4081.500  2464.770  2186.910  5976.090
CARM  Cohort 1: Healthy Control Matched to Non-smoking  9  3318.000  1788.900  1942.930  4693.070
CARM  Cohort 2: Severe Hepatic Impairment  7  7036.000  2814.950  4432.605  9639.395
CARM  Cohort 2: Healthy Control  7  3402.700  1771.790  1764.068  5041.332

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists four outcome measures and eight analyses. It identifies AUCtau as the primary endpoint and lists secondary outcomes concerning treatment-emergent adverse events and treatment-emergent laboratory abnormalities. It does not report how the analyses were organized across those outcomes or whether any formal multiplicity procedure was used.

General statistical explanation: when several outcomes or comparisons are examined, the chance of at least one apparently unusual result can increase if each is assessed separately without accounting for the collection of tests. A prespecified hierarchy, adjustment procedure, or clearly defined primary contrast can help readers understand which findings were confirmatory and which were exploratory. The registry record does not describe such a strategy, so it is not possible to tell how multiplicity was handled.

The record says the primary pharmacokinetic analysis used available data from participants in the PK Analysis Set: participants who received at least one dose and had at least one evaluable pharmacokinetic concentration reported by the laboratory. It does not report the number with complete AUCtau data, the extent or pattern of missing concentrations, reasons for missing data, or any imputation method. It also does not explain how participants with incomplete sampling contributed to endpoint estimation. The record therefore does not support an assessment of whether missingness could have affected the primary result.

Healthy controls may participate in more than one cohort, but the record does not say how this reuse was handled in the analysis. Details of covariate adjustment, matching, smoking-status stratification, sensitivity analyses, and the statistical model are not reported in the registry record. These gaps constrain interpretation of both the primary comparison and the secondary outcomes.

12. 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 non-serious adverse event terms

The safety figures distinguish serious adverse events, other adverse events, and deaths. In the severe hepatic impairment group, 0 of 7 participants at risk were affected by a serious adverse event, and 1 of 7 had another adverse event. In the moderate hepatic impairment group, 0 of 18 had a serious adverse event, and 4 of 18 had another adverse event. In the mild hepatic impairment group, 0 of 10 had a serious adverse event, and 3 of 10 had another adverse event. Among healthy controls, 0 of 20 had a serious adverse event, and 6 of 20 had another adverse event. Deaths were 0 in every group.

These are participant counts, not event counts, and the figures should be read as descriptive observations during the period covered by the registry results. The record lists no serious adverse-event terms. The counts do not establish that groups had equivalent safety outcomes or that any difference was caused by entospletinib. The study was non-randomized, and no uncertainty estimates or comparative safety analysis are reported in the registry record. The listed other-event figures should also not be assumed to represent the full detail of the secondary laboratory-abnormality outcome.

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

This study was designed to characterize entospletinib pharmacokinetics in adults with impaired hepatic function relative to healthy controls. Its primary endpoint, AUCtau, is an exposure measure over the dosing interval. The record documents the endpoint definition and collection schedule, and it describes the relevant cohorts and dosing schedule. Those details establish the question the study set out to address.

They do not establish the answer. The registry record does not report the primary AUCtau results, so the relative exposure in the impaired-function groups cannot be quantified from the information. No group means, standard deviations, contrasts, confidence intervals, or p-values for that endpoint are reported. Accordingly, the evidence available in the record does not show whether observed exposure was higher, lower, or similar across groups, or how precise any comparison was.

The design also limits causal interpretation. Participants were not randomized to hepatic-function status, and the record notes that the arms are not a like-for-like control comparison. The study summary refers to matched controls and smoking-status stratification as appropriate, but the matching and analysis details are not reported. Controls could participate in more than one cohort, which may matter for the independence of comparisons. These features do not invalidate the study's pharmacokinetic purpose, but they require caution when interpreting group contrasts.

The safety counts show no serious adverse events and no deaths in the listed groups, alongside the reported counts of other adverse events. They are descriptive and do not prove that the groups have the same safety profile, particularly without uncertainty estimates or a reported comparative analysis. The study's listed safety outcomes should be interpreted within the information available in the registry record.

The planning illustration is not an observed-power result and is not evidence that the study was designed around the illustrated assumptions. It is a planning aid based on a stated fraction of the observed effect. The original sample-size justification is not reported in the registry record. Overall, the available record describes the study question and design, but does not provide the primary numerical results needed to judge effect size or precision.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of a pharmacokinetic question that depends on comparing continuous exposure measures across clinically defined groups. AUCtau summarizes concentration over a dosing interval, making it more informative about interval exposure than any single concentration measurement alone. The study also documents repeated concentration sampling on Day 5, providing the measurement framework for its primary endpoint.

The design illustrates why the allocation method matters. Hepatic-function categories were not assigned at random, so comparisons are observational. The registry record describes matched healthy controls and smoking-status stratification as appropriate, but does not give the details needed to judge how effectively these features addressed differences between groups. The possibility that healthy controls participated in more than one cohort adds a further consideration: comparisons may share control observations, and the analysis approach to that dependence is not reported.

The record is also a reminder to separate an endpoint definition from an endpoint result. Naming the mean AUCtau and its standard deviation does not provide the estimated exposure or the uncertainty around a contrast. Without those primary results, statistical precision and the direction or magnitude of group differences remain unknown. The safety counts can be read descriptively, but they do not fill that gap or establish equivalence between groups.

Finally, planning calculations based on fractions of an observed effect should not be confused with the study's original design justification or observed power. The registry record does not report the original sample-size rationale. Readers can therefore distinguish the study's stated pharmacokinetic objective from what can actually be concluded from the results available in the registry record.

15. 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 most consequential limitation for interpretation is that the registry record does not report the primary AUCtau estimates or the inferential results. The endpoint definition and sampling schedule are available, but the group means, standard deviations, contrasts, and uncertainty measures are not. The primary pharmacokinetic finding therefore cannot be evaluated for direction, magnitude, or precision.

The study was non-randomized and the registry record specifically cautions that the arms are not a like-for-like control comparison. The matching criteria for healthy controls are not reported, nor are the details of any adjustment for group differences. The brief summary mentions stratification by smoking status as appropriate, but the statistical implementation is not described. Healthy controls may have participated in more than one cohort; how any dependence created by shared controls was handled is not reported.

The record does not report the original sample-size justification, the statistical model for the primary endpoint, a multiplicity strategy, or sensitivity analyses. It also does not describe the amount, pattern, or handling of missing pharmacokinetic measurements beyond defining the analysis population as eligible participants with available data. Without these details, robustness and potential sources of analysis-related bias cannot be assessed.

The safety information is limited to participant counts for serious and other adverse events and deaths. No serious-event terms are listed, and comparative uncertainty estimates are not reported. These descriptive counts cannot establish equivalence or attribute events to treatment. The posted record also does not provide the detailed laboratory-abnormality results named among the secondary outcomes in the information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Pharmacokinetics of Entospletinib in Adults With Normal and Impaired Liver Function — NCT02521376.
• Registry record last updated 2019-07-26; status last verified 2019-05.
• Results first posted 2019-07-26.
• 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.

19. Record Summary

The registry record describes NCT02521376, a completed Phase 1, open-label, non-randomized, parallel study sponsored by Gilead Sciences. It enrolled 56 participants and examined entospletinib pharmacokinetics in mild, moderate, and severe hepatic impairment relative to healthy controls. The primary endpoint was mean AUCtau, with standard deviation, measured over the dosing interval using the specified Day 5 sampling schedule.

Entospletinib was administered twice daily on Days 1-4 and as one morning dose on Day 5 in the impaired-function cohorts. The record lists secondary outcomes for treatment-emergent adverse events and laboratory abnormalities. Serious adverse events and deaths were reported as 0 in each group; other adverse-event counts were 1 of 7, 4 of 18, 3 of 10, and 6 of 20, respectively, for severe impairment, moderate impairment, mild impairment, and healthy controls.

The primary AUCtau results and key statistical analysis details are not reported in the registry record. Comparisons therefore cannot be assessed for effect size or precision from the record.