Liposomal Bupivacaine Interscalene Nerve Block in Shoulder Arthroplasty: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Liposomal Bupivacaine Interscalene Nerve Block in Shoulder Arthroplasty (NCT03663283), a randomized phase 4 study. The primary outcome is Patient Pain Scores.

2. Clinical Question

The clinical question is about the measured pain scores for these two nerve-block regimens, not every possible aspect of recovery or pain control. Opioid consumption, time to cessation of nerve blockade, and satisfaction with pain control are listed as secondary outcomes. The registry record does not give their results in the information, so they cannot be used to broaden the interpretation of the primary comparison. The treatment descriptions indicate that dexamethasone accompanied both blocks; the comparison therefore concerns the block regimens as described, rather than a comparison of dexamethasone with no dexamethasone.

3. Trial Design

The registry identifies this as a randomized, parallel-group, phase 4 study, with a recorded enrollment of 104. The trial is marked completed. Its recorded start date is 2018-10-29 and its primary completion date is 2020-02-14. The official title describes a prospective randomized control trial and calls it single blinded, while the registry masking field lists quadruple masking. The record does not explain that difference or identify which people were masked.

The two groups were Liposomal Bupivacaine and Plain Bupivacaine. Each posted primary-outcome group contains 52 participants. Both descriptions specify an ultrasound-guided peripheral nerve block performed by an anesthesiologist and concomitant IV dexamethasone. The liposomal arm combined liposomal bupivacaine with plain bupivacaine; the comparator used standard bupivacaine hydrochloride. The registry’s arm descriptions end mid-sentence, so details beyond the wording recorded there are not reported in the registry record.

The primary outcome was patient pain scores over the first 72 hours post-operatively, measured by the Visual Analogue Scale. The registry lists opioid consumption, time to cessation of nerve blockade, and satisfaction with pain control using a satisfaction scale as secondary outcomes. It records four outcome measures and six analyses, but details of the additional outcome measure and the complete set of analyses are not reported in the registry record.

Random allocation can help balance groups on average, but the registry record does not report the sequence-generation method, allocation concealment, protocol deviations, or the analysis population. The original sample-size rationale and trial-specific planning assumptions are also not reported in the registry record. These gaps limit how fully the design and execution can be assessed from the posted information alone.

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

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 Patient Pain Scores, measured over 72 hours post-operatively.

The primary endpoint is the mean of patient pain scores over the first 72 hours after surgery. The score comes from a Visual Analogue Scale, with zero representing no pain and ten representing severe pain. The posted results describe the endpoint as a mean with standard deviation for each randomized arm. The reported values are 4.0 with a standard deviation of 2.57 in the Liposomal Bupivacaine group and 2.8 with a standard deviation of 1.88 in the Plain Bupivacaine group.

Using a continuous pain score preserves gradations in reported pain rather than reducing responses to a simple yes-or-no category. In general, a mean gives a group-level summary of the scores, while the standard deviation describes how much individual scores vary around that mean. Neither statistic shows the full distribution or reveals how each participant’s score changed over time. Although the timeframe covers the first 72 hours, the registry record does not specify whether the endpoint is an average across repeated measurements, a particular measurement within that period, or another summary of the score trajectory.

The endpoint is relevant to the stated study objective of comparing postoperative pain scores. The registry also names duration of nerve blockade, opioid consumption, and satisfaction as secondary outcomes, but the primary endpoint alone does not answer those separate questions. A group mean difference should therefore be interpreted as a contrast in the recorded pain-score summary, not as a complete account of analgesia, medication use, or patient experience.

7. Results Posted in the Registry

• Plain Bupivacaine: mean 2.80 versus 4.00 on control; difference -1.20 (95% CI -2.07 to -0.33), standardized effect d = -0.53; z-test p = 0.007.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a Wilcoxon (Mann-Whitney) superiority analysis for the primary comparison. It also supports a simple, unadjusted recalculation using the posted group means and standard deviations. These methods answer related but distinct statistical questions, and the output should be interpreted with that distinction in mind.

What does a comparison of means summarize?

For a continuous outcome, a group mean is the arithmetic average of the measured scores in that group. A mean difference expresses how far apart the two group averages are, with the sign depending on the order of subtraction. The posted comparison uses Plain Bupivacaine minus Liposomal Bupivacaine: its estimate is -1.2, based on group means of 2.8 and 4.0, respectively. The sign therefore indicates that the plain-bupivacaine group’s posted mean is lower under this ordering. The difference is expressed in the scale’s score units.

A mean is a compact description and can be useful for a continuous endpoint, but it does not describe every feature of the score distribution. Two groups can have similar means and different patterns of variation, or a mean can be influenced by extreme values. The posted standard deviations are 1.88 and 2.57. In general, a standard deviation describes the typical spread of individual observations around the group mean; it is not a confidence interval for the mean and does not show the range of individual scores.

What does the rank-based test assess?

The Wilcoxon (Mann-Whitney) method uses the ordering of observations across the two groups rather than relying only on the difference between their arithmetic means. In general, it evaluates whether values in one group tend to rank differently from values in the other group. It is not automatically a test of medians alone: interpreting it strictly as a median comparison requires additional assumptions about the shapes of the group distributions. The registry reports a superiority analysis and p = .0197, but the detailed test statistic, distribution summaries, and any additional model assumptions are not reported in the registry record.

The sponsor’s rank-based test and a mean-difference recalculation need not produce the same p-value, because they use the data differently and can target different aspects of the distributions. The posted recalculation gives p = 0.007. That value belongs to the unadjusted mean comparison, not to the Wilcoxon test. The registry record reports no discrepancy, but the sponsor’s method and result should still be identified separately from the recalculation.

How should the standardized effect be read?

The posted comparison gives a standardized effect estimate of -0.533 and a pooled standard deviation of 2.252. In general, standardizing a mean difference expresses it in units of a pooled measure of spread, which can help describe magnitude without using the original score units. Its sign follows the comparison’s subtraction order. Standardized effects do not replace the raw mean difference: the raw estimate is directly interpretable on the pain-score scale, while the standardized value is a relative measure whose interpretation depends on the variability in these groups.

The recalculation uses summary statistics and is unadjusted. It should not be confused with the trial’s own full analysis, and it cannot account for individual-level patterns that are not contained in group means and standard deviations. The registry does not report covariate adjustment for the primary comparison. It also does not give enough detail to determine whether repeated pain measurements were modeled jointly or how the 72-hour summary was formed.

What assumptions matter?

In general, a comparison of independent group means relies on an appropriate independent-groups setup and on the summary statistics accurately representing the outcome in each group. The precision of an estimate depends on both the observed spread and the number of observations contributing to it. A confidence interval conveys uncertainty in the estimated contrast rather than the range of individual participant scores. The posted limits are -2.065 and -0.335, but the confidence level and the precise interval method are not reported in the registry record.

For count outcomes, over-dispersion means that variation exceeds what a chosen model expects; ignoring it can make uncertainty estimates too small. That issue is not the stated basis of this continuous pain-score comparison, so it should not be assumed to have affected this analysis. More generally, the appropriateness of any model depends on the outcome, its distribution, and how the data were collected.

Randomization supports a comparison of the assigned groups, but the registry does not describe the randomization sequence or allocation concealment. It lists quadruple masking, while the official title describes a single-blinded trial; which participants or study personnel were masked is not reported in the registry record. Missing-data methods, analysis-population definitions, and multiplicity procedures are also not reported. Those details would help assess whether the reported result reflects the intended design and how robust its uncertainty estimate is.

10. Confidence Intervals and Precision

The posted mean difference is -1.2 on the pain-score scale, with an interval from -2.065 to -0.335. The interval describes uncertainty around the estimated group contrast under the assumptions of the calculation. In general, a confidence interval gives a range of effect values compatible with the data and method at a chosen confidence level; it is not a range containing a specified proportion of individual participants’ scores. The confidence level for this interval is not reported in the registry record, so it should not be assigned one based on convention.

The interval lies on the negative side of zero for the stated subtraction order, Plain Bupivacaine minus Liposomal Bupivacaine. That direction agrees with the posted group means of 2.8 and 4.0. The interval does not show the exact score difference for every participant, and it cannot establish that the same difference would occur in another population or setting. Its width reflects uncertainty in the mean comparison, not individual variability alone; the group standard deviations describe variability among scores.

The sponsor’s Wilcoxon analysis reports p = .0197, while the unadjusted mean-difference recalculation reports p = 0.007. Their distinction matters when judging precision: the interval is attached to the mean-difference comparison, while the reported p-value comes from a rank-based analysis. The registry does not report the confidence interval for the Wilcoxon result. The posted interval and the sponsor’s p-value therefore should not be presented as if they were all outputs from a single method.

Precision also depends on what was measured and how the endpoint was summarized. The record identifies a 72-hour postoperative period but does not explain the exact construction of the score summary within that period. Missing-data handling and the analysis population are not reported in the registry record. Those uncertainties limit how completely the interval can characterize the analysis.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total participants and not event counts. The assumptions stated for these illustrations are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is a stated fraction of the observed effect. The trial’s own original design assumptions and sample-size justification are not reported in the registry record.

For planning for 100% of the observed effect, the listed requirement is 56 participants per arm for 80% power and 74 participants per arm for 90% power. For planning for 75% of the observed effect, the corresponding figures are 99 and 132 participants per arm. For planning for 50% of the observed effect, they are 222 and 296 participants per arm. These are planning illustrations based on the observed effect, not the sample size selected for the original trial design.

In general, power is the chance that a specified study design will detect an effect of a particular size under its assumptions if that effect is present. The 80% column describes a planning target with an 80% chance of detection under those assumptions; the 90% column describes a higher target. Smaller effects are harder to distinguish from random variation, so planning to detect a smaller fraction of the observed effect requires more participants per arm. These calculations are not observed power.

The figures depend on assumptions that may not fully represent the trial’s outcome distribution, analysis method, or data completeness. They are useful for illustrating how the assumed effect size and desired power relate to planning, but they do not establish the precision or reproducibility of the result in another study.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -1.200; pooled standard deviation σ = 2.252.
2. n = 2 × (1.96 + 0.842)² × 2.252² / -1.200² = 55.3, rounded up to 56 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -1.2                      # observed difference in means
sigma <- 2.25158832826962                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(3663283)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 56 (80% power), 74 (90% power)
 75% of observed effect: n per arm = 99 (80% power), 132 (90% power)
 50% of observed effect: n per arm = 222 (80% power), 296 (90% power)
power.t.test: 56.2 
Simulated power at n = 56 per arm: 0.797 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Analyses Reported by the Sponsor

The registry’s own primary comparison is a Wilcoxon (Mann-Whitney) superiority analysis, with p = .0197. The separate recalculation uses the posted group means and standard deviations to estimate an unadjusted mean difference of -1.2, with an interval from -2.065 to -0.335 and p = 0.007. The comparison is defined as Plain Bupivacaine minus Liposomal Bupivacaine. The group means are 2.8 and 4.0, respectively.

These results come from different methods. A Wilcoxon analysis uses ranks, whereas the recalculation focuses on the difference in arithmetic means. A difference in their p-values is not, by itself, an arithmetic inconsistency: methods can yield different inferential results because they use different information and assumptions. The registry record marks the discrepancy flag as false. The sponsor’s own reported analysis should be treated as the trial’s primary reported analysis, while the recalculation is an additional unadjusted summary and not a replacement for it.

The registry does not give the sponsor’s test statistic, a confidence interval for the rank-based result, or full detail on how the test was implemented. It also does not report the confidence level for the recalculated interval. Therefore, the rank-based p-value and mean-difference interval should be kept distinct rather than combined as though they were outputs from a single analysis. Neither alone establishes the clinical importance of the measured difference.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists four outcome measures and six analyses. It identifies patient pain scores as the primary outcome and names opioid consumption, time to cessation of nerve blockade, and satisfaction with pain control using a satisfaction scale as secondary outcomes. The information in the registry record does not identify the additional outcome measure or provide results for all analyses. It also does not report whether all outcomes were prespecified in the same way or which analyses were considered confirmatory.

Multiplicity arises when several outcomes, time points, subgroups, or analyses are tested. In general, conducting many tests can increase the chance that at least one result appears statistically notable by chance. Methods such as prespecifying a primary outcome or adjusting the testing procedure can address this concern, but the registry record does not report a multiplicity plan or adjustment for this trial. It would therefore be inappropriate to assume that the posted p-values were adjusted, or that they were not, beyond the information explicitly recorded.

The registry does not report how missing pain scores were handled, whether all randomized participants contributed to the primary analysis, or whether an intention-to-treat or another analysis population was used. It does not describe reasons for missing data, withdrawals, exclusions from analysis, or sensitivity analyses. In general, missingness can affect both the estimated group means and their uncertainty, particularly when the probability of missing data is related to the outcome or treatment group. Without the handling details, the potential direction and size of any such effect cannot be assessed from the registry record.

The record also does not report a statistical analysis plan, interim analyses, or rules for stopping or selecting analyses. Those details are not to be inferred from the completed status or from the reported p-values. Their absence limits assessment of the prespecification and completeness of the analysis, but it does not establish that a particular procedure was or was not used.

These reporting gaps matter when interpreting a primary result alongside several listed outcomes. The pain-score comparison can be described as posted, while the evidence about secondary outcomes and the overall testing strategy remains incomplete in the registry record.

15. 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 0% reporting threshold.

The registry reports zero serious adverse events among 52 participants at risk in the Liposomal Bupivacaine group and zero among 52 participants at risk in the Plain Bupivacaine group. It also reports zero other adverse events among 52 at risk in each group, and zero deaths in each group. These are the adverse-event figures recorded for the trial.

A zero count means that no events of the specified category were recorded in the registry results for the listed group; it does not prove that the risk is absent. In general, the ability to detect uncommon events depends on the amount and duration of observation and on how events are collected and reported. The registry record does not give additional detail about adverse-event definitions, surveillance procedures, follow-up duration for safety, or event narratives. The top serious-event terms list is empty.

These figures should be interpreted as descriptive counts, not as evidence that the two regimens have identical safety profiles or that no adverse effects occurred outside the categories reported. They do not provide information about the severity or timing of any non-serious symptoms beyond the posted zero counts, and they do not establish long-term safety.

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

The primary result describes a difference in postoperative pain-score summaries between the two randomized groups. The posted mean was 4.0 in the Liposomal Bupivacaine group and 2.8 in the Plain Bupivacaine group. The unadjusted mean difference, calculated as Plain Bupivacaine minus Liposomal Bupivacaine, was -1.2, with an interval from -2.065 to -0.335. The sponsor’s rank-based superiority analysis reported p = .0197. These statistics characterize the posted primary outcome; they do not by themselves describe every dimension of treatment experience.

The result does not show the pain score for each individual or the way scores changed within each person over the first 72 hours. The registry does not explain exactly how the time-period summary was constructed. Group means and standard deviations cannot reveal all features of the distributions, and the mean contrast should not be read as a guaranteed difference for an individual participant.

The result also does not answer whether opioid consumption, time to cessation of nerve blockade, or satisfaction differed between groups. Those outcomes are listed as secondary measures, but their results are not reported in the registry record. Nor does the primary pain-score comparison establish a broader effect on recovery, longer-term pain, or other outcomes not listed as reported results.

The comparison applies to the specific nerve-block approaches described, including concomitant IV dexamethasone in both arm descriptions. It is not a comparison of dexamethasone with no dexamethasone. The registry’s descriptions specify the drug mixtures and ultrasound-guided administration but are truncated, so details not present in the record cannot be assumed.

Finally, statistical evidence and clinical importance are different questions. The interval and p-values address uncertainty under their respective statistical methods; the registry record does not provide a threshold for a clinically meaningful score difference. The observed figures should therefore be read as estimates for this trial’s stated endpoint, with the analysis and reporting limitations kept in view, rather than as a general conclusion about all patients or settings.

17. Why This Trial Matters Statistically

This trial illustrates why a clinical result should be read through both its endpoint and its analysis method. The primary outcome is a continuous pain score, summarized by group means and standard deviations, while the sponsor’s reported test is rank-based. The methods describe related contrasts but do not produce interchangeable statistics. Keeping the sponsor’s p-value separate from the unadjusted mean-difference recalculation avoids blending results from different approaches.

The direction of a difference depends on the order of subtraction. The posted mean difference is defined as Plain Bupivacaine minus Liposomal Bupivacaine and is -1.2. Stating that convention makes the negative sign interpretable alongside the group means. A number without its comparator order can easily be misunderstood, especially when the treatment names are similar.

The case also shows why estimates and uncertainty should be considered together. The mean difference and its interval convey the size and precision of the calculated contrast, while the standard deviations describe variability in the observed scores. Neither is a substitute for the other, and none of these summaries gives the complete distribution or individual experience.

Planning illustrations offer a separate statistical lesson: sample-size requirements depend on the effect a future study aims to detect and the desired power. The registry record does not report the trial’s original sample-size justification, so retrospective planning figures based on the observed effect should not be mistaken for the design basis of this trial.

Finally, interpretation depends on reporting beyond a p-value. The registry record does not report the missing-data approach, analysis population, or multiplicity plan, and its masking descriptions differ between the title and registry field. Recognizing those omissions helps keep conclusions tied to what the record actually documents.

18. 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 leaves important details about the primary endpoint’s construction unspecified. It states that pain scores were measured over the first 72 hours post-operatively using a Visual Analogue Scale, but it does not explain how measurements across that period were combined into the reported mean. The timing and frequency of assessments are not reported in the registry record.

The record does not describe eligibility criteria, the randomization procedure, allocation concealment, or the analysis population. It lists quadruple masking, while the official title describes the trial as single blinded; the roles of those masked and the reason for the difference are not reported. These gaps make it difficult to assess details of implementation from the registry entry alone.

The arm descriptions end mid-sentence, limiting the available account of the interventions. The posted information describes the nerve-block mixtures and concomitant IV dexamethasone, but additional procedural or treatment details are not reported in the registry record. The record also does not explain whether protocol deviations occurred.

Missing-data methods, reasons for missing observations, and sensitivity analyses are not reported. The record does not state whether the primary analysis included all randomized participants or how exclusions, if any, were handled. The multiplicity strategy and statistical analysis plan are also not reported, despite multiple outcomes and analyses being listed.

Finally, the primary comparison is available as group summaries and a rank-based p-value, but the sponsor’s test statistic and confidence interval are not reported. The confidence level for the recalculated interval is not given. Secondary-outcome results are not included in the registry information summarized for this analysis. These limitations constrain interpretation of the record; they do not establish that a particular unreported method or event occurred.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Liposomal Bupivacaine Interscalene Nerve Block in Shoulder Arthroplasty — NCT03663283.
• Registry record last updated 2021-02-21; status last verified 2021-02.
• Results first posted 2021-02-21.
• 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.

22. Record Summary

NCT03663283 is a completed randomized, parallel-group, phase 4 trial of nerve-block regimens in shoulder arthroplasty. The registry records enrollment of 104 and lists a start date of 2018-10-29 and primary completion date of 2020-02-14. The two arms were Liposomal Bupivacaine and Plain Bupivacaine, with 52 participants in each posted primary-outcome group.

The primary endpoint was patient pain scores over the first 72 hours post-operatively, measured on a Visual Analogue Scale. The posted means were 4.0 with standard deviation 2.57 and 2.8 with standard deviation 1.88, respectively. The unadjusted mean difference for Plain Bupivacaine minus Liposomal Bupivacaine was -1.2, with an interval from -2.065 to -0.335. The sponsor reported a Wilcoxon (Mann-Whitney) superiority analysis with p = .0197.

The registry lists opioid consumption, time to cessation of nerve blockade, and satisfaction with pain control as secondary outcomes. Their results, the missing-data approach, analysis population, and multiplicity plan are not reported in the registry record.