Lopinavir/Ritonavir (Kaletra) PK in Children: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Lopinavir/Ritonavir (Kaletra) PK in Children (NCT00810108), a randomized phase 4 study. The primary outcome is Lopinavir Area Under the Curve (AUC).

2. Clinical Question

This is a pharmacokinetic question, not a comparison of clinical outcomes. AUC describes drug exposure over the sampling interval; it does not by itself establish whether either administration method changes symptoms, disease progression, or other patient outcomes. The registry’s stated hypothesis was that exposure would be lower after crushed tablets mixed with pudding or yogurt than after tablets swallowed whole. That is the investigators’ hypothesis, not a conclusion that should be treated as established merely because it was stated in advance.

The crossover design means participants received both administration methods, in different orders. This allows the study to compare exposure under each condition within the same participant, if the analysis accounts for the paired observations appropriately. The registry does not describe the details of such an adjustment. The posted results therefore need to be read as pharmacokinetic summaries and a reported ratio analysis, with the available information about how those results were analyzed kept in view.

3. Trial Design

The registry describes a randomized, open-label, crossover study in pediatric patients who were already taking lopinavir/ritonavir tablets as part of their clinical care. The study was Phase 4, enrolled 12 participants, and is listed as completed. Its stated objective was to compare lopinavir pharmacokinetics when tablets were taken whole or crushed.

Participants were assigned to one of two sequences. One sequence took whole tablets at Study Visit 1 and crushed tablets at Study Visit 2; the other took crushed tablets at Study Visit 1 and whole tablets at Study Visit 2. Thus, the intended comparison involved both administration conditions in each sequence rather than separate groups assigned permanently to one condition. Randomization refers to assignment to these sequences. The registry does not report the randomization procedure or the details of any period or sequence adjustment in the analysis.

The study was open label, with no masking reported. Participants and study staff therefore were not described as blinded to whether tablets were whole or crushed. This does not alter the laboratory definition of AUC, but awareness of the administration condition is part of the design context. The registry does not report additional procedures intended to reduce possible measurement or operational effects of that awareness.

Pharmacokinetic sampling was scheduled before dosing and at 1, 2, 4, 6, 8, and 12 hours after dosing. The primary outcome was lopinavir AUC, reported in mg*hr/L. The primary population description refers to subjects who completed the pharmacokinetic sampling visits with whole tablet administration. The registry gives 12 participants for each administration summary, but further detail on participant flow, completeness of the paired measurements, or exclusions is not reported in the registry record.

The registry lists the study start as 2006-06 and primary completion as 2009-05. A more detailed protocol, sample-size justification, and fuller statistical analysis plan are not reported in the registry record. The posted analysis method is described as a two-sided t-test for the crushed-to-whole tablet AUC ratio, with a 90% confidence interval.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All subjects who completed the pharmacokinetic sampling visits with whole tablet administration were analyzed

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 Lopinavir Area Under the Curve (AUC), measured over pre-dose, 1,2,4,6,8, and 12 hours post-dose.

The primary endpoint is lopinavir area under the plasma concentration–time curve, or AUC. It combines concentration measurements across the scheduled sampling period into a measure of drug exposure over time. In this study, sampling was planned before dosing and at 1, 2, 4, 6, 8, and 12 hours after dosing. The AUC unit is mg*hr/L.

AUC is used in pharmacokinetic studies because it summarizes exposure across multiple measurements rather than relying on a concentration at a single time point. For a comparison of administration methods, it can describe whether the overall concentration profile differs between conditions. It is an exposure measure, not a direct measure of clinical benefit, safety, or disease control. Interpreting it clinically would require evidence and context beyond the AUC comparison reported in this record.

The registry identifies the endpoint summary as a median with an inter-quartile range. For whole tablets, the median AUC was 144 mg*hr/L, with an inter-quartile range of 101 to 202. For crushed tablets, the median was 92 mg*hr/L, with an inter-quartile range of 79 to 103. These are summaries of the posted observations; the inter-quartile range describes the middle half of the distribution, not the uncertainty in the estimated median.

The registry also reports a separate analysis of the ratio of crushed-tablet AUC to whole-tablet AUC. That ratio analysis is not the same summary as comparing the two medians. Its interpretation depends on the analysis method and the underlying participant-level data, which are not described in detail in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical results combine descriptive summaries of AUC with an inferential analysis of a ratio. These serve different purposes. The medians and inter-quartile ranges describe the observed distributions for each administration condition. The ratio estimate, confidence interval, and p-value summarize a specific comparison under the reported testing approach. Keeping those roles separate helps avoid treating a descriptive statistic as if it were the test result.

What does the median describe?

The median is the middle value when observations are ordered. It is less affected by unusually high or low observations than the arithmetic mean, so it can be a useful way to summarize a distribution that is skewed. The whole-tablet median AUC was 144 mg*hr/L and its inter-quartile range was 101 to 202. The crushed-tablet median was 92 mg*hr/L and its inter-quartile range was 79 to 103. These summaries do not show the full shape of the distributions or the connection between each participant’s two observations.

An inter-quartile range describes the central spread of observed values. It is not a confidence interval around the median and does not directly express how precisely a treatment contrast has been estimated. In a crossover study, the distribution of within-participant differences or ratios can be especially relevant, because each participant contributes observations under both administration conditions. Those participant-level contrasts are not reported in the registry record.

How should the ratio be read?

The reported parameter is the ratio of crushed-tablet AUC to whole-tablet AUC. A value of 1 would represent equal values on the ratio scale; values below 1 indicate a lower estimate for the numerator condition relative to the denominator condition. The posted estimate is 0.55. This is a relative comparison, not an absolute AUC value, and it should not be conflated with the two separate medians.

The registry reports a 90% confidence interval from 0.45 to 0.69. In general, a confidence interval is a range generated by a statistical procedure that, under its assumptions and repeated use, has the stated coverage. For a single study, it indicates the precision of the estimate in relation to that procedure; it does not mean there is a 90% probability that the fixed ratio lies inside this particular interval. The interval reflects sampling uncertainty under the analysis, not uncertainties in unreported protocol details or the applicability of the results to other populations.

What does the p-value contribute?

The posted p-value is <0.05 for a two-sided t-test. In general, a p-value measures how unusual the observed test statistic, or one more extreme, would be if the null hypothesis and the test assumptions held. It is not the probability that the null hypothesis is true. Nor does it tell readers whether an observed difference is clinically important. The estimate and confidence interval are needed to understand the direction and precision of the reported comparison.

The registry states that the test is a t-test, but does not report whether the calculation used paired data, a particular transformation, a period effect, or another crossover-specific model. A t-test applied to paired observations and a t-test treating observations as independent do not encode the same dependence structure. The exact test implementation is therefore not recoverable from the registry description alone.

Why does crossover structure matter?

In a crossover design, the participant serves as their own comparison across treatment conditions. This can account for stable differences between participants when the analysis uses the pairing. At the same time, treatment order and time period can matter: an observation in one visit may be affected by circumstances related to that period, and sequence assignment can affect how the conditions are encountered. A crossover analysis may need to address such features, but the registry does not report the details needed to determine whether they were modeled or how.

More generally, over-dispersion means that variation in observed data is greater than a statistical model assumes. When a model understates variability, its uncertainty estimates can be too narrow and tests can appear more decisive than warranted. This is a general statistical concern, not a finding reported for this study. The registry does not provide enough information to assess whether over-dispersion was evaluated or relevant to the ratio analysis.

What can planning illustrations establish?

Sample-size planning illustrations are not observed power and do not describe what the trial was designed to detect unless they come from the original protocol. The planning assumptions described for the illustrations use a two-sided significance level of 0.05, equal allocation, a normal approximation, and effects set as a stated fraction of the observed effect. The record does not report that these were the original design assumptions or provide a sample-size justification. Such illustrations are hypothetical planning exercises based on an observed result, not evidence that the study had adequate power for a prespecified target.

The registry does not report an interim-analysis plan, multiplicity adjustment, or detailed analysis plan. Those omissions limit how much can be inferred about whether the reported p-value was the sole primary test, how endpoint testing was organized, or whether any decisions were made during the study based on accumulating data. These details should not be assumed from the test label or the fact that a primary endpoint is identified.

Finally, a reported confidence interval and p-value are conditional on the analysis and the data included. The registry’s primary-population description refers to participants completing the pharmacokinetic sampling visits with whole-tablet administration. It does not fully describe missing observations, exclusions, or handling of incomplete paired measurements. Such information is important in a crossover study because the comparison may depend on having usable measurements under both conditions.

10. Analyses Reported by the Sponsor

The registry reports the analysis as a two-sided t-test of the crushed-to-whole tablet AUC ratio. The estimate is 0.55, with a 90% confidence interval from 0.45 to 0.69 and a p-value of <0.05. The arm-level summaries are medians with inter-quartile ranges: 144 mg*hr/L for whole tablets and 92 mg*hr/L for crushed tablets. These are not interchangeable forms of the same statistic; the reported ratio analysis should be read as its own result.

No discrepancy is recorded between the sponsor’s reported analysis and a recalculated result. That does not supply unreported methodological details: the registry does not explain exactly how the t-test handled the crossover pairing or how the ratio was constructed. The posted sponsor analysis is the inferential result to cite, while the medians describe the separate AUC distributions. A reader should not reconstruct a ratio test from the two medians alone, because medians do not contain the participant-level pairing information needed for that analysis.

The registry does not report a prespecified equivalence or non-inferiority margin. Therefore, the ratio estimate, confidence interval, and p-value should not be taken as establishing a formal equivalence or non-inferiority conclusion without additional protocol information. The numerical results describe the reported analysis; their interpretation remains bounded by the method details and study information available in the registry record.

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary outcome measure and one reported analysis. It does not report whether additional statistical tests were conducted but not posted, whether there was an adjustment for multiple comparisons, or whether any outcomes were selected after examining the data. Multiplicity procedures and analysis plans are not reported in the registry record. Without that information, the p-value should be interpreted as the result of the posted test, rather than as evidence that the study-wide chance of a false-positive finding was controlled by a particular procedure.

The record reports a primary-analysis population described as all subjects who completed the pharmacokinetic sampling visits with whole-tablet administration. It also lists 12 participants in each administration summary and an enrollment of 12. The registry does not describe whether all participants contributed complete paired measurements, how incomplete sampling was handled, or whether any participants were excluded from the ratio analysis. A count in each condition does not, by itself, specify the completeness or linkage of individual crossover observations.

Missing-data methods are not reported in the registry record. In general, missing measurements can affect a crossover estimate if the likelihood of missingness is related to treatment condition, measurement values, or participant characteristics. Different handling approaches make different assumptions, so the absence of a description prevents assessment of those assumptions. It does not establish that data were missing, nor that a particular method was used.

The registry does not report an interim-analysis plan or stopping rules. It also does not report the original sample-size justification or a complete statistical analysis plan. Planning illustrations based on the observed effect are not a substitute for a prespecified design calculation and must not be read as observed power. The available record consequently supports interpretation of the posted endpoint summaries and reported test, but not a full reconstruction of the study’s analysis decisions or missing-data process.

12. 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 0% reporting threshold.

The safety summary lists 13 subjects at risk and zero subjects with serious adverse events. It also lists 13 subjects at risk and zero subjects with other adverse events. No serious adverse-event terms are listed. These figures describe the registry’s posted safety counts; they do not provide event rates by treatment condition or establish that no events occurred outside the listed categories or observation period.

The safety denominator of 13 differs from the trial enrollment of 12. The registry does not explain this difference or describe how the safety population was defined. The result should therefore be reported with the denominator as posted, without assuming why it differs from enrollment. Deaths are not reported in the registry record; the deaths entry does not give a count.

Zero reported events in these categories is a count, not proof that the administration methods have no safety risks. The record does not provide event timing, severity detail beyond the serious-event category, exposure duration for safety reporting, or a treatment-specific breakdown. The registry’s safety information is limited to the counts and categories.

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

The principal statistical result is a reported crushed-to-whole tablet AUC ratio of 0.55, with a 90% confidence interval from 0.45 to 0.69 and a two-sided p-value of <0.05. The arm summaries likewise show different median AUC values: 144 mg*hr/L for whole tablets and 92 mg*hr/L for crushed tablets. These results describe pharmacokinetic exposure in the study’s observed participants and under the reported analysis.

They do not establish a clinical effect. AUC is a drug-exposure endpoint, not a direct measure of symptoms, disease status, or treatment success. The registry does not report a clinical outcome comparison that links the AUC findings to those outcomes. It also does not report enough information to interpret the result against a prespecified clinical threshold or a formal equivalence or non-inferiority margin.

The estimate applies to a small crossover study of pediatric patients already taking lopinavir/ritonavir tablets as part of clinical care. The registry does not report the age range or other participant characteristics needed to judge how closely the enrolled group resembles a broader population. The results should not be generalized beyond the studied context without additional evidence.

Precision is conveyed by the reported confidence interval, but it depends on the statistical procedure and available data. Details of the t-test implementation, paired-data handling, missing observations, and full analysis plan are not reported in the registry record. Those gaps do not erase the posted estimate, but they limit independent evaluation of how it was obtained.

The safety counts report zero serious and zero other adverse events among 13 subjects at risk in each category, while the enrollment is 12. The reason for this denominator difference and a fuller safety description are not reported. These counts should be understood as the registry’s limited safety summary, not as evidence that no safety concern is possible.

14. Why This Trial Matters Statistically

This trial illustrates how a crossover design can frame a pharmacokinetic comparison. Each participant was assigned to a sequence that included both whole and crushed tablet administration. When properly analyzed, within-participant comparisons can separate treatment-condition differences from stable differences between individuals. The registry’s description, however, does not give enough detail to establish exactly how the reported test used that pairing.

It also illustrates the distinction between descriptive summaries and an inferential contrast. Separate medians describe the AUC distribution in each condition; the ratio analysis estimates a relative comparison using the analysis specified in the registry. These summaries should not be substituted for one another. Understanding what each statistic represents is essential when communicating a result from a small pharmacokinetic study.

The record also makes visible the importance of specifying the analysis. The test is identified as a two-sided t-test, but details of the crossover model, missing-data handling, multiplicity, and sample-size justification are not reported. Those omissions are relevant to precision and reproducibility, especially when a study’s primary comparison depends on repeated measurements from the same participants.

Finally, a pharmacokinetic endpoint answers a focused question about exposure. It does not by itself answer a clinical-outcome question. Keeping the endpoint’s scope clear prevents a statistical comparison of AUC from being mistaken for a broader conclusion about patient outcomes. The study is therefore useful as an example of reading an exposure ratio, confidence interval, and p-value alongside design and reporting limitations.

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 study enrolled 12 participants, which limits the amount of information available for estimating variability and for evaluating the stability of a crossover comparison. The registry does not report participant characteristics beyond the pediatric population already taking lopinavir/ritonavir tablets as part of clinical care. The age range and other details needed to assess representativeness are not reported in the registry record.

The study was open label, with no masking reported. The primary endpoint is a pharmacokinetic measurement, but the registry does not describe laboratory procedures, assay characteristics, or quality-control methods. Those details are not reported in the registry record, so the precision and reproducibility of measurement cannot be independently assessed from the available description.

The registry reports a two-sided t-test for the crushed-to-whole ratio but does not specify how the crossover design was represented in the analysis. The treatment sequence and study visits are described, but adjustment for period, sequence, or within-participant correlation is not reported. A full statistical analysis plan is also not reported. This leaves uncertainty about the exact model behind the interval and p-value.

The primary population description refers to subjects completing pharmacokinetic sampling visits with whole-tablet administration. Although 12 participants are listed for each administration summary, participant-level completeness and handling of incomplete sampling are not described. Missing-data methods, exclusions, and a detailed participant flow are not reported in the registry record.

The record does not report an original sample-size justification, an interim-analysis plan, a multiplicity strategy, or a prespecified equivalence or non-inferiority margin. It also does not report clinical outcome data connecting the exposure contrast to patient outcomes. Safety reporting lists 13 subjects at risk, although enrollment is 12; the reason for this difference is not reported. These limitations constrain interpretation of the estimate and its broader relevance without changing the numerical result as posted.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Lopinavir/Ritonavir (Kaletra) PK in Children — NCT00810108.
• Registry record last updated 2012-07-06; status last verified 2012-06.
• Results first posted 2012-07-06.
• 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.

19. Record Summary

The registry record describes a completed Phase 4 randomized, open-label crossover study with 12 enrolled pediatric patients already taking lopinavir/ritonavir tablets. Participants followed one of two sequences, receiving whole and crushed tablets at separate study visits. Pharmacokinetic sampling was scheduled before dosing and at 1, 2, 4, 6, 8, and 12 hours after dosing.

The primary endpoint was lopinavir AUC in mg*hr/L. The reported median was 144 mg*hr/L for whole tablets, with an inter-quartile range of 101 to 202, and 92 mg*hr/L for crushed tablets, with an inter-quartile range of 79 to 103. The reported crushed-to-whole AUC ratio was 0.55, with a 90% confidence interval from 0.45 to 0.69 and a two-sided p-value of <0.05.

The safety summary lists zero serious and zero other adverse events among 13 subjects at risk in each category. Detailed crossover analysis procedures, missing-data handling, multiplicity, and the original sample-size justification are not reported in the registry record. The results address pharmacokinetic exposure and should not be read as clinical-outcome findings.