Liposomal Bupivacaine in Simultaneous Bilateral Total Knee Arthroplasty: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Liposomal Bupivacaine in Simultaneous Bilateral Total Knee Arthroplasty (NCT02349542), a na phase 4 study. The primary outcome is Adverse Events.

2. Clinical Question

In practical statistical terms, the record addresses two kinds of questions: whether adverse events were recorded during the stated follow-up window, and what bupivacaine levels were observed. The posted adverse-event data are descriptive counts for the single intervention group. They do not estimate how those counts compare with outcomes under an alternative treatment. The pharmacokinetic aim concerns drug concentration over time, but detailed concentration results and their analysis are not reported in the registry record. The clinical question is consequently narrower than a comparative effectiveness question: the available data describe recorded events in one group and identify a planned interest in plasma levels, without establishing a counterfactual outcome under another approach.

3. Trial Design

The registry identifies this as a Phase 4, completed study with a single-group model. Allocation is recorded as not applicable, and masking is recorded as none. These design features mean that the reported group is not one arm of a randomized comparison in the registry record. No control group is listed, so between-group treatment contrasts are unavailable.

The study title refers to liposomal bupivacaine in simultaneous bilateral total knee arthroplasty. Its brief summary describes evaluating bupivacaine serum levels, or pharmacokinetics, among patients receiving a standardized periarticular injection containing free and liposomal bupivacaine. The intervention listing names liposomal bupivacaine, and the arm description places its administration after the procedure. The registry record does not give additional details about administration beyond these descriptions.

The enrollment field records 20. The adverse-event data list 15 participants at risk for serious events and 15 at risk for other events. The record does not explain the relationship between the enrollment figure and the adverse-event denominators, so they should be read as distinct reported quantities rather than reconciled by assumption. The study start is recorded as 2015-01, primary completion as 2016-11-01, and status as completed.

The primary outcome is adverse events, measured as the number of participants with an event through 72 hours following injection. Plasma bupivacaine levels are listed as a secondary outcome. Although the record identifies the outcomes and study structure, it does not report a detailed protocol, eligibility criteria, schedule of blood sampling, analysis populations, or statistical methods. Those omissions limit interpretation of what was intended to be measured and how all available observations were handled.

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:

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 Adverse Events, measured over Up to 72 hours following injection.

The primary endpoint is the number of participants with adverse events during the period up to 72 hours following injection. It is a participant-level count outcome: each participant is classified according to whether an event was recorded in the specified period. The registry record distinguishes serious adverse events from other adverse events in the posted data. For each category, it reports the number at risk and the number affected.

Adverse-event outcomes are used in clinical studies to describe safety observations over a defined follow-up interval. A prespecified interval matters because the opportunity to observe an event depends on how long participants are followed. Here, the stated interval ends 72 hours after injection; the record does not establish whether events outside that interval were collected or reported elsewhere.

The posted figures report 0 affected participants for serious events and 0 for other events, with 15 at risk in each category. These are observed counts in the single listed group. They are not a comparative estimate and do not quantify the probability of an event beyond the participants represented in those rows. No confidence interval or inferential analysis is reported in the registry record.

The endpoint's use as a safety measure does not itself establish that all potential harms were captured. The record does not provide event definitions, collection procedures, severity criteria beyond the serious/other distinction, or information about missing follow-up. It also does not report the underlying plasma concentration results alongside the adverse-event counts. Therefore, these counts describe the posted safety data within the stated time frame, while leaving important details about ascertainment and the relationship to drug exposure unreported.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The main outcome is binary at the participant level: a participant either had a recorded event in the stated category and time window or did not. The registry reports counts of participants with events, rather than a continuous outcome such as a concentration measurement. For a binary outcome, a common descriptive summary is the number affected together with the number at risk. The posted data give these quantities separately for serious and other adverse events.

What does a count tell us?

A count tells how many participants in the reported group were recorded as having an event. The denominator indicates how many participants were considered at risk for that category. Together, these figures describe the observed data in that group. They do not, on their own, tell whether a risk is unusually high or low compared with a reference group. Such a comparison would require an appropriate comparator and a defined analysis, neither of which is reported for this single-group record.

When counts are converted into an event proportion, the numerator and denominator must come from the same outcome definition and analysis population. No new proportion is needed to interpret the posted counts, and none is reported in the registry record. The adverse-event denominators should not be replaced with the enrollment figure: the record lists enrollment as 20 but lists 15 at risk for each adverse-event category, without explaining the distinction.

Why does uncertainty matter when no events are observed?

Observed data are only one realization of a process that may vary across participants and settings. When no events are recorded in a group, the data still allow for a nonzero underlying event probability. A confidence interval is a statistical range that conveys uncertainty in an estimate, subject to the assumptions used to calculate it. It is not a guarantee that the true value lies in the range, nor does it correct limitations in outcome collection or study design. No such interval is reported for the adverse-event counts.

For rare outcomes, conventional approximations can behave poorly when event counts are sparse or zero. An exact method may be considered in some settings, but the registry record does not identify an interval method or report an interval. It would be inappropriate to attribute a particular statistical procedure to the study without that information.

What can a single-group design estimate?

A single-group study can describe what was observed among the people receiving the intervention. It cannot, without a comparator and suitable design assumptions, distinguish an intervention effect from other explanations for the observed outcomes. A comparative question asks what outcomes would have occurred under an alternative condition; the unobserved alternative outcome is not posted by a single group. The absence of a control group therefore limits causal interpretation, regardless of whether the observed count is zero or nonzero.

Allocation is recorded as not applicable, and masking as none. These labels do not document a random assignment process or blinded outcome assessment. The registry record does not report whether event reviewers were independent, whether a formal event-adjudication procedure was used, or how subjective events were classified.

How should the pharmacokinetic aim be understood?

Pharmacokinetics concerns how drug concentration changes over time in the body. The study summary says that serum levels were to be evaluated, and the secondary outcome is plasma bupivacaine levels. Concentration data would generally need an accompanying sampling schedule, units, summary method, and account of observations over time to be interpreted. Those details and the numerical results are not reported in the registry record. The adverse-event counts therefore cannot substitute for a pharmacokinetic analysis.

The record lists two outcome measures and identifies adverse events as primary and plasma bupivacaine levels as secondary. It does not report the statistical analysis plan, model specifications, handling of repeated concentration measurements, or a procedure for relating concentration to events. General statistical methods can be explained, but no specific one should be assumed to have been used.

What are planning calculations, and what are they not?

Any sample-size illustrations associated with these results are planning scenarios, not observed study results and not the trial's original design justification. The stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a fraction of the observed effect. Those assumptions describe hypothetical future planning, not the single-group study design recorded. A planning sample size is not observed power, and it does not alter the evidence represented by the reported adverse-event counts. The registry record does not report the trial's own sample-size justification.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Liposomal Bupivacaine")
n      <- c(15)
events <- c(0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Liposomal Bupivacaine  15  0  0.0  0.0  21.8  0.0  20.4  0.2  20.6

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies adverse events as the primary outcome and plasma bupivacaine levels as a secondary outcome. It does not report a statistical analysis plan describing how these outcomes were to be analyzed, whether there were additional outcome definitions, or whether any adjustment for multiple comparisons was planned. With multiple outcomes or repeated assessments, testing many hypotheses can increase the chance of at least one apparently notable result by chance. Whether that issue arose cannot be determined from the record, because no inferential analyses are reported.

The registry record does not report an analysis population or explain how participants with incomplete data were handled. Although enrollment is recorded as 20, the adverse-event rows list 15 at risk in each category; the record does not describe why those denominators differ. Missing outcome data, exclusions after enrollment, and the completeness of follow-up are not reported in the registry record. It is not possible to infer whether data were missing or how any such data were treated.

The record also does not state whether all participants completed the stated follow-up period, how adverse events were elicited, or whether events were independently reviewed. For the secondary pharmacokinetic outcome, the timing and completeness of plasma measurements and the treatment of measurements below assay limits are not reported in the registry record. These omissions matter because missingness or selective reporting can affect the interpretation of both event counts and concentration summaries.

No interim analyses or stopping rules are reported in the registry record. Their presence or absence should not be inferred. The available material therefore supports a descriptive reading of the posted adverse-event counts, but not conclusions about multiplicity control, missing-data assumptions, or the planned analysis population.

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 serious adverse-event row reports 0 affected participants among 15 at risk. The other adverse-event row also reports 0 affected participants among 15 at risk. Both rows concern the liposomal bupivacaine group, and the primary outcome timeframe is up to 72 hours following injection. These figures describe the posted counts within the specified outcome categories and follow-up period.

A reported count of zero does not demonstrate that the underlying risk is zero. It means no affected participants are recorded in that row. The record does not provide an uncertainty interval, event ascertainment details, or an explanation for why the adverse-event denominators are 15 while the enrollment field is 20. Those limitations prevent a fuller assessment of the precision and completeness of the safety information.

The serious-event terms are not listed, and the death field is not reported. A missing death count should not be interpreted as a count of zero. The record also does not describe event severity criteria, relatedness assessment, or whether events beyond the stated timeframe were collected. The posted figures should therefore be read as limited descriptive safety data, not as a complete characterization of all possible adverse outcomes.

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

The posted results document 0 participants with serious adverse events and 0 with other adverse events in the corresponding rows, each of which lists 15 participants at risk. The primary outcome is defined over the period up to 72 hours following injection. These results describe what is recorded for the single liposomal bupivacaine group in the registry.

They do not show what would have happened to similar patients under an alternative intervention, because no comparator group is listed. Without that contrast, the results cannot estimate a relative treatment effect. They also do not establish that the intervention caused any particular outcome, or that no events could occur in a different population or under different circumstances. The record lacks the detailed methods needed to assess event detection and follow-up completeness.

The enrollment field records 20, but the adverse-event data use a denominator of 15 for each category. Since the registry record does not explain this, the safety counts should be interpreted using their stated denominators rather than assuming that all enrolled participants contributed to those rows. The record does not state whether the discrepancy reflects exclusions, missing follow-up, or another reason.

The study's stated pharmacokinetic aim is not resolved by the adverse-event counts. Plasma bupivacaine levels are listed as a secondary outcome, but numerical levels and their analysis are not reported in the registry record. Consequently, the data do not establish a relationship between drug concentration and adverse events.

The most defensible interpretation is narrow: no affected participants are recorded in the two adverse-event categories for the listed group and reporting window. The counts do not quantify uncertainty, establish comparative safety, or provide a complete account of pharmacokinetics. The record is informative as a description of the submitted observations, with substantial limits on how broadly those observations can be interpreted.

14. Why This Trial Matters Statistically

This study illustrates why study design is essential to statistical interpretation. A single-group safety record can document events observed after an intervention, but it cannot provide the same information as a controlled comparison. Without a comparator, the observed counts cannot show whether event occurrence differs from what would have been expected under another treatment or care approach.

It also highlights the difference between zero observed events and zero risk. The posted adverse-event rows record no affected participants, but a finite set of observations cannot establish that an event is impossible. Uncertainty estimates help communicate how much the data can say about an underlying event probability. No such estimate is reported in the registry record, so the degree of precision is not quantified.

Denominators are equally important. The registry records enrollment of 20 but lists 15 participants at risk for each adverse-event category. Readers need a clear account of who contributed data to each outcome and why. Without that explanation, the endpoint counts remain interpretable as posted, but the route from enrollment to analyzed population is unclear.

Finally, the record separates an adverse-event question from a pharmacokinetic aim. The two are scientifically related in concept, but the listed adverse-event counts do not reveal plasma concentrations or how those concentrations varied over time. Reporting both outcome data and their analysis methods is necessary to understand whether exposure patterns correspond to clinical observations. This record offers a useful case study in distinguishing descriptive safety counts from comparative evidence and in recognizing when registry reporting leaves key statistical questions unresolved.

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.

Several limitations specific to this record constrain interpretation. The design is listed as single group, with allocation not applicable and no masking. No control group is recorded, so the adverse-event counts have no concurrent comparator. The study cannot answer a comparative question from these data alone.

The reported enrollment is 20, whereas each adverse-event category lists 15 participants at risk. The registry record does not explain this difference or identify the analysis population. It also does not report whether all participants completed follow-up, whether any outcome data were missing, or how incomplete observations were handled. The stated adverse-event timeframe is up to 72 hours following injection, but event collection and follow-up procedures are not described.

The event data are limited to counts in serious and other categories. Serious-event terms are not listed, and the death field is not reported. Definitions, severity assessment, relatedness judgments, and ascertainment procedures are not reported in the registry record. No confidence intervals or inferential analysis accompany the counts.

The study summary describes a pharmacokinetic purpose, and plasma bupivacaine levels are identified as a secondary outcome. However, concentration values, units, sampling times, and analytical methods are not reported in the registry record. The relationship between drug levels and adverse events therefore cannot be assessed from the posted information.

The record does not report eligibility criteria, participant characteristics, the original sample-size justification, or detailed statistical methods. It also does not report whether interim analyses, stopping rules, or multiplicity procedures were planned. These gaps should not be filled by assumptions. They limit reproducibility and restrict the conclusions to a descriptive account of the posted outcomes.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Liposomal Bupivacaine in Simultaneous Bilateral Total Knee Arthroplasty — NCT02349542.
• Registry record last updated 2017-08-31; status last verified 2017-08.
• Results first posted 2017-08-02.
• 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 identifies NCT02349542 as a completed Phase 4, single-group study of liposomal bupivacaine in simultaneous bilateral total knee arthroplasty. It records enrollment of 20, no masking, and a study start of 2015-01, with primary completion on 2016-11-01.

The primary outcome is the number of participants with adverse events up to 72 hours following injection. The adverse-event data list 0 serious events among 15 at risk and 0 other events among 15 at risk. Plasma bupivacaine levels are listed as a secondary outcome, consistent with the stated pharmacokinetic aim.

No comparator, inferential analysis, uncertainty interval, or explanation of the adverse-event denominators is reported in the registry record. The results therefore support a descriptive reading of the recorded events, but not a comparative treatment-effect conclusion or a detailed interpretation of plasma exposure.