Pharmacokinetics of Efavirenz in HIV-1 Infected Subjects With Hepatic Impairment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetics of Efavirenz in HIV-1 Infected Subjects With Hepatic Impairment (NCT00162097), a non-randomized phase 1 study. The primary outcome is Maximum Plasma Concentration (Cmax).

2. Clinical Question

3. Trial Design

The registry describes a completed phase 1, nonrandomized, unmasked, parallel study. Its stated purpose was to assess steady-state pharmacokinetics of efavirenz in HIV-1 infected subjects taking stable antiretroviral regimens containing efavirenz, with selected degrees of hepatic impairment or normal hepatic function. The listed enrollment is 21. The record gives a start date of 2004-11 and a primary completion date of 2008-03.

Four dosed groups are identified: participants with mild, moderate, or severe hepatic impairment, and participants with normal hepatic function. Each group description specifies EFV600mg. A separate group is labelled “Not Dosed.” The registry also lists efavirenz-containing antiretroviral regimens as interventions. Detailed arm descriptions beyond their labels are not reported in the registry record.

Because allocation was nonrandomized, the groups should be read as observed categories rather than randomized treatment arms. Differences between them could reflect differences in participant characteristics or other factors, not only hepatic-function status. The registry itself cautions that the arms are not a like-for-like control comparison. It does not describe a protocol for assigning participants to hepatic-function groups.

The primary outcome is maximum plasma concentration, or Cmax, measured in micrograms (mcg)/mL. The registry says it was obtained directly from concentration-time data and that the analysis was performed per protocol. Although the study is marked completed, the primary outcome values and reported inferential analyses are not reported in the registry record. The registry lists secondary safety outcomes, but does not provide corresponding numerical results in the registry record for this analysis.

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: 21 participants were enrolled in the study; 5 discontinued prior to study drug administration (1 adverse event, 1 enrollment completed, 1 screen failure, 1 no longer met study criteria and 1 withdrew consent).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analysis was performed per protocol.

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 Maximum Plasma Concentration (Cmax), measured over Blood samples were collected at time 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours post-dose, relative to administration of PM or AM dose..

Cmax is the highest plasma concentration recorded over the specified sampling period. It is one measure of drug exposure: it describes the peak concentration observed after a dose, rather than the full concentration-time profile or total exposure across time. The registry states that Cmax was obtained directly from concentration-time data and reports the unit as micrograms (mcg)/mL.

Blood sampling was scheduled at time 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours post-dose, relative to administration of the PM or AM dose. Those collection times provide the observations used to identify the maximum in the measured profile. The record does not specify further details about how samples were handled or how missing measurements affected endpoint estimation.

The planned summary is a geometric mean with full range. In general, a geometric mean summarizes values on a multiplicative scale and can be useful for positive measurements whose variation is better described proportionally than additively. The full range describes the observed span, not the precision of an estimated group mean. The actual Cmax estimates and ranges are not reported in the registry record, so the magnitude and variability of the endpoint cannot be assessed from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does Cmax represent?

Cmax is the maximum measured concentration in a concentration-time profile. In this study, the registry says it was derived directly from the concentration-time data. Sampling was scheduled from the pre-dose measurement through 24 hours post-dose, with observations at the listed intervening times and relative to administration of a PM or AM dose. The endpoint is therefore a peak observed within the scheduled sampling profile; it is not, by itself, a measure of total exposure or the time at which the peak occurred.

As a general statistical point, an observed maximum can depend on the sampling schedule. A peak occurring between scheduled collection times may not be captured exactly. The registry record gives the collection schedule but does not report how closely observed maxima corresponded to the underlying concentration curve, or whether any modeling beyond direct extraction was used. It specifically states that Cmax was obtained directly from concentration-time data.

Why report a geometric mean?

The registry specifies a geometric mean and full range for the primary outcome. In general, a geometric mean is calculated on a logarithmic scale and transformed back to the original measurement scale. It is appropriate for positive measurements when multiplicative variation is a useful way to describe differences. For example, proportional changes can be more meaningful than equal absolute changes across a range of concentrations. This is a general explanation of the summary statistic, not a claim about the observed distribution in this study.

The full range is a descriptive summary of the observed extremes. It shows the span of values but is sensitive to extreme observations and does not quantify the precision of the estimated geometric mean. Neither the geometric mean nor the range is reported numerically for the study in the registry record. Standard errors, confidence intervals, and participant-level measurements are also not reported there.

What can a confidence interval tell a reader?

In general, a confidence interval expresses statistical uncertainty around an estimate under the assumptions of the method used to construct it. A narrower interval indicates greater precision under those assumptions; a wider interval indicates less precision. It does not remove bias from nonrandom allocation, incomplete data, or inappropriate modeling. The registry record does not report confidence intervals for Cmax, so the precision of the primary endpoint estimates cannot be judged from those intervals.

A statistical test and an interval answer related but different questions. A test assesses compatibility of data with a specified null hypothesis under a model, while an interval shows a range of values compatible with the data and method at a stated confidence level. The registry does not report a test, p-value, confidence level, or interval for the primary endpoint. No inferential claim about differences between the hepatic-function groups can be drawn from the posted record.

Why does the design matter?

Allocation is recorded as nonrandomized, masking as none, and the model as parallel. In general, nonrandomized groups may differ in measured and unmeasured characteristics. Randomization, when used, helps balance such characteristics on average; it is not a feature of this study. Consequently, descriptive differences between the groups would not by themselves show that hepatic impairment caused a difference in Cmax. The registry explicitly says the arms are not a like-for-like control comparison.

The parallel designation means the registry records separate groups rather than a crossover arrangement. It does not supply details about assignment, matching, adjustment, or the timing of measurements beyond the stated sampling schedule. Those design and analysis details are not reported in the registry record. The study population is described as HIV-1 infected subjects on stable efavirenz-containing regimens, with selected hepatic-function categories; the record does not support extending results to populations or regimens not described.

What does per-protocol analysis imply?

The primary outcome analysis is identified as per protocol. Generally, a per-protocol analysis includes participants who satisfy specified protocol requirements, but the exact rules vary by study. It can be informative about outcomes among participants who followed the protocol, while potentially excluding participants with deviations or incomplete observations. The record does not identify the analysis criteria, explain exclusions, or state how many participants contributed Cmax data in each group. Thus the analysis denominator and the effect of exclusions cannot be evaluated.

The registry lists enrollment of 21 and also identifies a not-dosed group. These are record details, but enrollment should not be assumed to equal the number analyzed for Cmax. The number contributing to each endpoint group is not reported in the registry record. Nor does the record describe imputation or another method for handling missing concentration measurements.

What is not available for evaluating the analysis?

The registry record does not report a statistical analysis plan, model specification, adjustment variables, hypothesis tests, confidence intervals, or numerical Cmax outcomes. It also lists zero analyses in the record details. Without those details, readers cannot assess whether comparisons were prespecified, how uncertainty was estimated, or whether the analysis accounted for potential differences among nonrandomized groups. These gaps concern the report available in the registry and do not establish what analyses may or may not have been conducted elsewhere.

General statistical principles remain relevant: estimates should be read alongside their uncertainty, group comparisons should account for the study design, and missing outcome data can affect interpretation if missingness is related to concentration or participant characteristics. Over-dispersion is a concern for count outcomes when variability exceeds a model's assumptions, but the primary outcome is a concentration summary, not a count. No evidence about over-dispersion or a fitted model is reported for this endpoint.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures, including the primary Cmax outcome and secondary safety outcomes. It does not report how many were tested statistically, which outcomes were designated as confirmatory, or whether any adjustment for multiple comparisons was planned or used. The registry also lists zero analyses. The multiplicity strategy is therefore not reported in the registry record.

As a general statistical principle, evaluating many outcomes or group contrasts can increase the chance of finding an apparently notable result by chance if each is interpreted without regard to the others. Multiplicity adjustment is one possible approach, but whether it is needed and how it should be applied depend on the study questions and analysis plan. No multiplicity method can be attributed to this study from the registry information.

The primary outcome population is described as per protocol. The registry does not report the criteria defining that population, the number analyzed in each group, or the handling of protocol deviations. Although enrollment is listed as 21 and a not-dosed group appears in the adverse-event listing, neither fact establishes how many participants had evaluable Cmax measurements. Missing data methods, reasons for missingness, and any imputation procedures are not reported in the registry record.

These omissions matter because endpoint denominators and missingness can affect both the estimated summaries and their precision. Without group-specific analysis counts or a description of exclusions, readers cannot determine whether the reported population represents all enrolled participants or a subset. The registry does not provide the information needed to assess that issue.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: oesophageal candidiasis (20.0%), aids related complication (20.0%), hyponatraemia (20.0%).

The registry lists serious adverse event figures by group. No serious adverse events are recorded among the dosed groups with mild, moderate, or severe hepatic impairment, or among participants with normal hepatic function. The not-dosed group is listed with one serious adverse event among five at risk. These are the registry's recorded figures; they do not establish a causal relationship between efavirenz and an event.

The record lists the serious terms OESOPHAGEAL CANDIDIASIS, AIDS RELATED COMPLICATION, and HYPONATRAEMIA, each at 20.0%. It does not identify the group attribution for these terms in the registry record, so they should not be assigned to a particular hepatic-function group. Death counts are null in the group records; deaths are therefore not reported in the registry record rather than confirmed as absent.

These figures are descriptive. The groups are small as listed and were not randomized, and the registry cautions that they are not like-for-like control groups. A comparison of their event counts cannot establish relative safety or quantify a causal treatment effect. The record also lists other adverse events and several additional safety outcome categories, but their numerical results are not reported in the registry record.

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

This study was designed to assess steady-state efavirenz pharmacokinetics among HIV-1 infected subjects taking stable efavirenz-containing antiretroviral regimens, across selected hepatic-function categories. Its primary outcome was Cmax, the maximum plasma concentration, with a geometric mean and full range specified as the summaries. That description establishes what the study set out to measure, not what the measured values were.

The registry record does not report numerical Cmax results, group-specific ranges, or inferential comparisons. It therefore cannot support a conclusion about the direction or size of any difference between participants with hepatic impairment and those with normal hepatic function. It also cannot establish that there was no difference. Missing results are not equivalent to a null result.

The nonrandomized design is important to the meaning of any potential group contrast. The registry itself says the arms are not a like-for-like control comparison. Group differences, if reported, would need to be interpreted as observational and in light of possible differences between participants. The record does not report an adjusted analysis that could address such differences, and no statistical analysis plan is reported.

The record does provide some descriptive context: the study was phase 1 and completed; the primary outcome analysis was per protocol; and the listed safety groups include serious adverse event counts. However, it does not provide the Cmax analysis denominators, detailed missing-data handling, or numerical results for the listed secondary safety outcomes. Those gaps limit assessment of both precision and completeness.

Accordingly, the result that can be interpreted from this record is limited to the study's stated aim, design, and endpoint definition. It does not establish pharmacokinetic equivalence, a clinically meaningful change, or a treatment effect. Those conclusions would require outcome estimates and appropriate analysis details that are not reported in the registry record.

13. Why This Trial Matters Statistically

This trial is statistically useful as an example of why a clearly named endpoint and a completed study record do not, by themselves, permit interpretation of a result. The registry identifies Cmax, its measurement unit, its summary form, and the concentration sampling schedule. Yet without the numerical estimates, readers cannot assess the observed peak concentrations or their variability. Transparent reporting of estimates and uncertainty is essential for drawing conclusions from a quantitative endpoint.

The record also illustrates the distinction between a group description and a randomized comparison. The groups are defined by hepatic-function status, but allocation was nonrandomized, and the registry cautions that they are not like-for-like controls. Statistical contrasts in such a design require careful attention to potential confounding and to the limits of causal interpretation. A group label alone does not make the groups exchangeable.

Specifying a geometric mean and full range also highlights that summaries answer different questions. The geometric mean describes a central value on a multiplicative scale, while the range describes observed extremes. Neither replaces an interval expressing uncertainty, and neither can be evaluated without the actual values and analysis counts.

Finally, the per-protocol designation and listed not-dosed group show why population definitions matter. Readers need to know who contributed data to each outcome and how exclusions or missing measurements were handled. Those details are not reported in the registry record. This study therefore underscores the importance of reporting estimates, denominators, uncertainty, and analysis decisions alongside an endpoint definition.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main limitation for interpreting the primary endpoint is that the registry record does not report any numerical Cmax result. No group estimates, ranges, confidence intervals, or test results are available in the record described. Consequently, the magnitude, variability, and precision of the pharmacokinetic measurements cannot be evaluated.

The nonrandomized design limits causal interpretation. The registry explicitly warns that the arms are not a like-for-like control comparison. It does not report how participants entered each hepatic-function group or whether analyses adjusted for participant characteristics. Potential group differences beyond hepatic function therefore cannot be assessed.

The primary outcome population is described as per protocol, but the registry does not provide the criteria for that population, group-specific analysis counts, or reasons for excluding observations. The enrollment figure does not identify the endpoint denominator. A not-dosed group is recorded, but its relationship to the primary endpoint analysis is not described. Missing-data handling is not reported in the registry record.

The registry lists 13 outcome measures but does not state the multiplicity approach, statistical model, or hypothesis-testing plan. It also gives no numerical results for the listed secondary safety outcomes in the registry record for this analysis. Serious adverse event figures are descriptive and do not permit causal comparison, particularly given the nonrandomized design. Death values are null and are not reported as counts.

Finally, the arm descriptions contain little detail beyond the hepatic-function category and EFV600mg label. Additional regimen characteristics and protocol specifics are not reported in the registry record. These limitations concern what can be established from the registry record; they do not establish whether additional information exists elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Pharmacokinetics of Efavirenz in HIV-1 Infected Subjects With Hepatic Impairment — NCT00162097.
• Registry record last updated 2010-09-14; status last verified 2010-09.
• Results first posted 2010-08-25.
• 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, nonrandomized, unmasked, parallel study of efavirenz pharmacokinetics in HIV-1 infected subjects on stable efavirenz-containing antiretroviral regimens. It lists enrollment of 21, a start date of 2004-11, and a primary completion date of 2008-03.

The primary endpoint was maximum plasma concentration (Cmax), summarized as a geometric mean with full range and analyzed per protocol. The registry specifies collection from pre-dose through 24 hours post-dose. The numerical Cmax results and statistical comparisons are not reported in the registry record.

Groups are described by hepatic-function category, with a separate not-dosed group in the safety listing. Allocation was nonrandomized, and the registry cautions that the arms are not like-for-like controls. Serious adverse event counts are recorded by group, but the record does not support causal safety comparisons.