Pharmacokinetics and Safety of Bupivacaine HCl Spinal Block and EXPAREL Local Infiltration in Total Knee Arthroplasty: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetics and Safety of Bupivacaine HCl Spinal Block and EXPAREL Local Infiltration in Total Knee Arthroplasty (NCT02284386), a na phase 4 study. The primary outcome is Maximum Plasma Concentration (Cmax).

2. Clinical Question

The study concerns the pharmacokinetic profile and safety of two bupivacaine formulations used together in adults undergoing primary unilateral total knee arthroplasty. Pharmacokinetics describes how drug concentrations change in the body over time. The registry record identifies maximum plasma concentration, or Cmax, as the primary endpoint and lists measurements spanning baseline through day 14.

This is a descriptive question about concentrations and safety in the studied group. It is not a randomized comparison of the combination against another treatment or against a control condition. As a result, the study design does not estimate a comparative treatment effect. The registry record does not report a numerical Cmax result, so the magnitude and precision of the observed concentration cannot be assessed from the listed endpoint description alone.

3. Trial Design

This is a Phase 4, multicenter, open-label, single-group study sponsored by Pacira Pharmaceuticals, Inc. The registry record lists the study as completed, with a start date of 2014-12 and primary completion in 2015-03. Enrollment is listed as 15. The study population was adults undergoing primary unilateral total knee arthroplasty.

Participants received a combination of bupivacaine HCl spinal nerve block and EXPAREL local infiltration into the surgical site. The arm description specifies spinal block with bupivacaine HCl 7.5 mg/mL and local infiltration of EXPAREL 266 mg. No separate control or comparison arm is described. Allocation is listed as not applicable, and the model is single group. The study is open label, so masking is listed as none.

The primary aim was to characterize the pharmacokinetic profile of total bupivacaine. The primary outcome is maximum plasma concentration, with measurements described at baseline, 15,30 min, 1,2,4,8,12,24,48,72 hours post dose, day 14. The outcome is specified as a mean with standard deviation. The registry record notes that one subject was removed as an outlier for the primary outcome; it does not describe the outlier rule, the reason for the decision, or how that decision was made.

There are six outcome measures listed in the registry record and no analysis entries. The record does not describe a randomized comparison, a separate control group, or a masking procedure. It also does not report the protocol’s sample-size justification, the intended timing of any interim analyses, or a detailed statistical analysis plan. The design supports description of observations in the study group; it does not by itself distinguish the effects of the two components or establish how the findings compare with another regimen.

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

Analysis population for the primary outcome, as defined in the registry: Of 15 subjects, one subject was removed as an outlier

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: Patients undergoing total knee arthroplasty

6. Primary Endpoint

The registry lists the primary outcome as Maximum Plasma Concentration (Cmax), measured over baseline, 15,30 min, 1,2,4,8,12,24,48,72 hours post dose, day 14.

The primary endpoint is maximum plasma concentration (Cmax), measured in ng/mL. It represents the highest measured concentration of total bupivacaine in plasma during the specified observation period. The registry record lists assessment at baseline, 15,30 min, 1,2,4,8,12,24,48,72 hours post dose, day 14, and describes the endpoint summary as a mean with standard deviation.

In pharmacokinetic studies, concentration measurements over time help characterize the timing and level of drug exposure in the body. Cmax is used to describe the peak concentration captured by the sampling schedule. It is a summary of concentration observations, not a direct measure of comparative benefit. The recorded value can be influenced by the schedule of blood collection: a peak occurring between scheduled assessments may not be captured as the measured maximum.

The registry record does not provide numerical Cmax values, standard deviations, confidence intervals, or results by measurement time. It therefore does not permit an assessment of the observed peak concentration or its precision. The outcome description also says that one subject was removed as an outlier, but the record does not explain the criterion used or provide enough information to determine the impact of that removal on the reported summaries.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies Cmax as a continuous primary outcome and specifies a mean and standard deviation as its summary measures. It also describes assessments at multiple times, from baseline through day 14. The following concepts are general explanations of the statistical methods relevant to this kind of outcome; the registry record does not provide a full analysis plan or numerical Cmax results.

What does a mean describe?

For a continuous variable, the mean is the arithmetic average of the observations included in the analysis. It gives a compact description of the group’s central concentration level. A mean can be influenced by unusually high or low observations, so it may not describe what a typical participant experienced when values are highly skewed. The registry record specifies a mean but does not provide the underlying values, a median, or a distribution plot in the registry record for the endpoint.

What does a standard deviation describe?

The standard deviation describes the degree of spread of observations around the mean. A larger standard deviation indicates more variability among the values, while a smaller one indicates that values are more closely clustered. It is a measure of variation among observations, not a measure of uncertainty in the mean itself. A confidence interval or standard error is commonly used to describe uncertainty about an estimated mean. No such uncertainty measure is reported for Cmax in the registry record.

Why use maximum plasma concentration?

Cmax summarizes the peak concentration observed during the sampling period. In pharmacokinetic work, concentration measurements at successive times help characterize the pattern of exposure. A maximum is interpretable as a summary of the highest observed level, but it depends on when samples are collected. If the true peak occurs between sampling times, the observed maximum may not coincide with that peak. The registry record lists a schedule extending from baseline to day 14, but does not report the actual concentration results at those assessments.

How should an outlier exclusion be considered?

An outlier is an observation that is unusually distant from other values according to some criterion. Whether to exclude one depends on the reason for the unusual value and on a prespecified, defensible analysis rule. Exclusion may change the mean and the standard deviation, and can change the apparent pattern of results. The primary outcome description states that one subject was removed as an outlier. The criterion, justification, timing, and sensitivity analysis are not reported in the registry record. Without results with and without that observation, readers cannot assess how consequential the exclusion was.

What does the single-group design allow?

A single-group study can describe measurements observed among participants receiving the study regimen. It cannot directly estimate a difference between that regimen and an unobserved or separate control condition. General statistical principle: a comparison requires observations under the conditions being compared, and random allocation can help make groups comparable in expectation. This study is listed as single group, with allocation not applicable and masking none. It therefore provides no randomized between-group contrast.

The registry record lists 15 enrolled subjects, but it does not give numerical primary outcome results or a detailed analysis population definition. The outcome description’s outlier note does not, by itself, establish the final number included in the analysis. No sample-size justification is reported in the registry record. Enrollment alone cannot establish the precision of the Cmax estimate; that would require the result and its variability, among other information.

Why do multiple assessment times matter?

Repeated measurements allow a concentration profile to be described over time, but they create multiple related observations. These measurements from the same participant are generally not independent, because an individual’s concentrations over time may be related. General statistical methods for repeated measurements account for that within-participant relationship when making combined inferences. The registry record lists the assessment schedule but does not report whether the analyses modeled repeated measurements jointly or summarized each time separately.

When many outcomes or time points are tested for statistical significance, the chance of at least one apparently notable result can increase. Methods for controlling multiplicity may be used when formal hypothesis tests are planned. The registry record does not report a multiplicity procedure, and it provides no analysis entries. It is therefore not possible to determine whether formal testing was conducted or how any multiple comparisons were handled.

General statistical principle: over-dispersion occurs when observed variation is greater than a statistical model assumes. If a model underestimates variability, its uncertainty estimates may be too small. The registry record describes a continuous endpoint summarized by a mean and standard deviation, but does not identify a model for the primary analysis. There is no basis in the registry information to say that over-dispersion was present or to assess how a model addressed it.

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("Bupivacaine SNB + EXPAREL Infiltration")
n   <- c(14)
m   <- c(408)
sp  <- c(161)
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  Bupivacaine SNB + EXPAREL Infiltration  14  408.000  161.000  315.041  500.959

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists six outcome measures, including maximum plasma concentration as the primary outcome. It provides a series of scheduled assessment times for that endpoint, from baseline to day 14. Considering multiple outcomes or time-specific results raises a general multiplicity issue: repeated testing can increase the chance of finding at least one apparently noteworthy result by chance. A prespecified hierarchy, adjustment, or other strategy can address that issue when appropriate. No multiplicity plan is reported in the registry record, and no analysis entries are listed.

The record does not report how missing concentration measurements were handled, whether any measurements were unavailable, or whether any imputation method was used. It does not define analysis populations such as an intention-to-treat or per-protocol population. The outlier note states that one subject was removed for the primary outcome, but the record does not explain how that subject was treated in other outcomes or how the decision relates to the analysis population.

These omissions limit assessment of the analysis process. Without the missing-data approach, readers cannot determine how incomplete measurements might have affected estimates. Without an analysis-population definition, it is not clear which observations were intended to contribute to each result. The registry record also does not describe interim analyses or a detailed statistical analysis plan. These items are not reported in the registry record; their absence from the record should not be taken to mean that any particular procedure was or was not used outside the information recorded there.

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.

Most frequent non-serious adverse event terms

The registry record reports serious adverse events for the Bupivacaine SNB + EXPAREL Infiltration group. Serious adverse events affected 0 of 15 subjects at risk. Other adverse events affected 12 of 15 subjects at risk. These are counts of subjects affected in the recorded group; they are not rates calculated and do not provide a comparison with another group.

The registry record does not list serious adverse event terms. The death count is not reported in the registry record. The other-adverse-event count does not identify event types, severity, duration, or whether an event was considered related to bupivacaine HCl, EXPAREL, the procedure, or another cause. It also does not give event timing or information about multiple events in the same subject.

Safety counts should be read in the context of the single-group design and the recorded risk-set size. With no comparator, the counts cannot establish whether the observed events were more or less common than under another treatment or background condition. They describe what the registry record reports for this study group, and do not establish causation.

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

This study is designed to characterize total bupivacaine pharmacokinetics and safety when bupivacaine HCl is given as a spinal nerve block with EXPAREL local infiltration in adults undergoing primary unilateral total knee arthroplasty. The registry record defines Cmax as the primary endpoint, gives its unit and summary type, and specifies a series of assessment times through day 14. It also records selected adverse-event counts for the single study group.

The record does not report numerical Cmax results, standard deviations, or confidence intervals. Consequently, it does not allow readers to determine the magnitude of the measured peak concentration or the precision of its estimate. The record notes removal of one subject as an outlier for the primary outcome, but does not give the exclusion rule or the effect of that decision on results.

The design does not answer whether the combination produces different concentrations or safety outcomes than another regimen, because no separate comparator group is described. It also cannot isolate the contribution of spinal bupivacaine HCl from that of local EXPAREL infiltration. The safety counts are descriptive and do not establish that any event was caused by either intervention.

General statistical principle: absence of a reported result is not the same as a result showing no effect, no variability, or no uncertainty. Here, the listed endpoint definition and the registry’s study description are not accompanied by numerical primary outcome findings in the registry record. Conclusions about the concentration profile or comparative effects would go beyond the information reported.

14. Why This Trial Matters Statistically

This study illustrates the distinction between a pharmacokinetic description and a comparative treatment evaluation. Its single-group design is suited to describing concentrations and safety observations in participants who received the specified combination. It does not create a direct contrast with a different regimen or a control condition. That distinction matters when readers interpret findings: a group summary is not itself an estimate of a between-treatment difference.

The endpoint also shows why measurement schedules matter. Cmax is the maximum concentration captured during observation, so its interpretation depends on the times when samples are taken. The registry record specifies assessments from baseline through day 14, but does not report numerical values. Without those values, the endpoint’s magnitude and variation cannot be judged.

The outlier note is another important statistical detail. A decision to exclude an unusual observation can affect a mean-based summary. Transparent reporting of the rule and results with and without the observation helps readers understand how dependent a finding is on that choice. Those details are not reported in the registry record.

Finally, the record’s safety counts need to be interpreted as descriptive counts in a single group. They do not provide a comparative risk estimate, and details about event types, attribution, and the death count are not reported. These features make the study a useful example of why study design, endpoint reporting, and analysis transparency all shape what a statistical result can support.

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 registry record does not report numerical results for the primary Cmax endpoint, including its mean, standard deviation, or confidence interval. This prevents evaluation of both the observed concentration level and the precision of its estimate. Although six outcome measures are listed, no analysis entries are listed, so the available record does not provide numerical outcome findings to interpret.

The study has a single-group, open-label design with allocation listed as not applicable. No separate comparator group is described. Thus, the record cannot support a randomized comparison or distinguish the effects of the spinal block and local infiltration from one another. The registry record also does not report a detailed statistical analysis plan, a sample-size justification, or an interim-analysis plan.

The primary outcome description states that one subject was removed as an outlier. The outlier definition, rationale, timing, analysis population, and results including that observation are not reported in the registry record. This limits assessment of the possible influence of the exclusion. The record also does not describe how missing measurements were handled or define the populations used for each analysis.

For safety, the record reports affected-subject counts but does not provide event descriptions or attribution details. No serious adverse event terms are listed, and the death count is not reported in the registry record. These gaps, along with the absence of a comparator, restrict interpretation of the safety findings to descriptive counts in the study group.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Pharmacokinetics and Safety of Bupivacaine HCl Spinal Block and EXPAREL Local Infiltration in Total Knee Arthroplasty — NCT02284386.
• Registry record last updated 2021-03-08; status last verified 2021-02.
• Results first posted 2016-06-28.
• 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, multicenter, open-label, single-group study sponsored by Pacira Pharmaceuticals, Inc. Enrollment is listed as 15, with a start date of 2014-12 and primary completion in 2015-03. Adults undergoing primary unilateral total knee arthroplasty received bupivacaine HCl spinal nerve block at 7.5 mg/mL and EXPAREL local infiltration at 266 mg.

The primary endpoint is maximum plasma concentration of total bupivacaine, in ng/mL, summarized as a mean and standard deviation over assessments from baseline through day 14. The endpoint description notes that one subject was removed as an outlier. Numerical primary endpoint results are not reported in the registry record.

Serious adverse events affected 0 of 15 subjects at risk, and other adverse events affected 12 of 15 subjects at risk. The death count is not reported in the registry record. No comparator group is described, and no analysis entries are listed.