Liposomal Bupivacaine vs Dexamethasone ISB: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Liposomal Bupivacaine vs Dexamethasone ISB (NCT04047446), a randomized phase 4 study. The primary outcome is Numerical Rating Scale (NRS) Pain at Rest Over 72 Hours.

2. Clinical Question

The registry describes a comparison of two medication combinations used in an interscalene block for pain management among patients receiving shoulder arthroscopy. The primary question concerns pain at rest during the first 72 hours after the procedure. The trial also lists outcomes covering pain with movement, opioid consumption, satisfaction with pain management, and block duration and resolution.

The registry identifies the trial as a non-inferiority trial in its official title. However, the non-inferiority margin and the analysis criteria used to assess non-inferiority are not reported in the registry record. The posted primary result is a comparison of group means; it should be read as that result rather than as a complete account of a non-inferiority test.

3. Trial Design

This was a phase 4, randomized, double-masked, parallel-group trial, with a recorded enrollment of 112. The registry lists the study status as completed. Its recorded start date is 2019-07-11, and its primary completion date is 2021-03-15. The sponsor is Hospital for Special Surgery, New York.

The two arms were liposomal bupivacaine with standard bupivacaine and standard bupivacaine with dexamethasone. The posted primary outcome is the mean Numerical Rating Scale pain-at-rest score over the first 72 hours. The arm results report 55 participants for the liposomal bupivacaine combination and 56 for the dexamethasone combination. The registry's overall enrollment and these arm-level outcome counts describe different recorded fields; an explanation of any difference is not reported in the registry record.

Double masking means the registry classifies the trial as masked at two levels, but the identities of the masked parties and the procedures used to maintain masking are not reported in the registry record. The randomization method, allocation concealment procedures, and details of the trial's implementation are also not reported. The parallel model indicates that participants were assigned to one of the two arms rather than the registry describing a crossover comparison.

The registry lists additional outcomes involving pain with movement, opioid consumption, satisfaction with pain management, the Brief Pain Inventory Short-form, duration of analgesic block, sensory resolution, and motor block resolution. The design rationale, including the original sample-size justification and any planned interim analyses, is not reported in the registry record.

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 Numerical Rating Scale (NRS) Pain at Rest Over 72 Hours, measured over First 72 hours pain.

The primary endpoint is Numerical Rating Scale pain at rest averaged over the first 72 hours. The registry describes the scale as ranging from 0, meaning no pain at all, to 10, meaning the worst pain imaginable. Patient-reported scores at 24, 48, and 72 hours are averaged to form the endpoint. A lower score is a better outcome on this measure.

Averaging scores across the stated follow-up times gives a summary of pain at rest over the early postoperative period, rather than a result for only one time point. It can therefore provide a compact comparison of the recorded pain experience across those observations. It does not, by itself, show how scores changed at each time, whether there were missing observations, or how pain with movement differed. Those details are not reported in the registry record.

The endpoint is recorded as a continuous measure summarized by its mean and standard deviation in each arm. The posted group means are 2.4 for liposomal bupivacaine with standard bupivacaine and 3.4 for standard bupivacaine with dexamethasone; each arm has a reported standard deviation of 1.9. Those summaries describe the primary measure and its spread within each arm, but do not convey every individual score or the distributional shape.

7. Results Posted in the Registry

• Standard Bupivacaine & Dexamethasone: mean 3.40 versus 2.40 on control; difference 1.00 (95% CI 0.29 to 1.71), standardized effect d = 0.53; z-test p = 0.006.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: each participant's endpoint is a pain score, and the registry reports a mean and standard deviation for each arm. The comparison is expressed as a mean difference. In general, a mean difference describes the distance between the two group averages in the units of the outcome. Here the units are score points on the Numerical Rating Scale, and the registry's comparison direction is standard bupivacaine with dexamethasone against liposomal bupivacaine with standard bupivacaine.

What does the mean summarize?

A mean gives a central summary of the scores in an arm. It is useful when the scientific question concerns an average level of pain, and it makes the group comparison interpretable on the original score scale. The mean alone cannot show whether most scores cluster near that value or whether the average is influenced by a small number of unusually high or low scores. The registry reports a standard deviation as a measure of spread, but does not report score distributions or other summaries of individual observations.

The primary endpoint combines observations at 24, 48, and 72 hours into one average per participant, according to the registry description. This creates a summary across the stated early follow-up period. It also means that the single primary result does not identify the comparison at any one of those time points. Time-specific primary outcome estimates are not reported in the registry record.

How should the mean difference be read?

The reported mean difference is 1.0 score point, with the dexamethasone arm compared against the liposomal bupivacaine arm. The underlying group means are 3.4 and 2.4, respectively. Since lower scores represent less pain, a positive value under this comparison direction means the dexamethasone arm had the higher observed mean. Direction depends on which arm is subtracted from which; reading the comparison definition avoids reversing the interpretation.

An unadjusted comparison is a comparison that is not adjusted for additional covariates in the reported estimate. The registry labels the p-value unadjusted, and the posted comparison provides an estimate and interval. Whether the sponsor's primary analysis used an adjusted model, what model was used, and whether the displayed comparison reproduces that analysis are not reported in the registry record. No discrepancy is flagged in the record.

What does the p-value add?

In general, a p-value assesses the compatibility of the data with a null model, given the assumptions of the statistical procedure. The posted unadjusted p-value is 0.006. It can indicate evidence against a no-difference null model under those assumptions, but it does not quantify the difference's practical importance. It also does not measure the probability that the observed effect will recur in another study. The test specification and any adjustment for multiple outcomes are not reported in the registry record.

Statistical significance and clinical importance are different questions. The mean difference is expressed in scale points, which makes it possible to consider its magnitude in context, but the registry record does not report a threshold for a clinically important difference. It also does not report the non-inferiority margin, despite the trial title identifying a non-inferiority objective. The posted p-value should not be substituted for either threshold.

Why do confidence intervals matter?

In general, a confidence interval expresses uncertainty about an estimated quantity under a statistical method. For a mean difference, it describes a range of values compatible with the data and method, rather than a range containing a specified proportion of individual scores. The reported interval for this comparison is entirely above zero. The confidence level and the method used to construct the interval are not reported in the registry record, so those aspects cannot be independently assessed from the posted details.

The width of an interval reflects precision: narrower intervals indicate less uncertainty in the estimate under the method, while wider intervals indicate more. Its endpoints should be interpreted with the estimate and the outcome scale. The interval does not account automatically for every possible source of uncertainty, such as missing data, model choices, or selective reporting. Those issues require information about the analysis that is not reported in the registry record.

Why does variability matter?

The standard deviation is 1.9 in each arm. In general, standard deviation describes the spread of observations around an arm's mean. Greater variability can make a difference between means harder to estimate precisely for a given amount of information. A similar mean difference can therefore have different precision in studies with different variability or participant counts.

Some outcomes, particularly counts, can show over-dispersion: the observed variation may exceed what a simple model assumes. That can make standard errors too small if the model does not account for the extra variability. This general issue is relevant when choosing methods for count outcomes, but the primary endpoint is a continuous pain score. The registry does not report the analysis models for the listed secondary outcomes, so the methods used for them cannot be described.

Finally, a randomized design supports a comparison between assigned groups, but interpretation still depends on how allocation, follow-up, outcome measurement, and analysis were conducted. The registry identifies randomization and double masking, but does not report the procedural details, analysis population, missing-data method, or primary analysis specification. Those gaps limit how fully the posted result can be audited from the registry record alone.

10. Confidence Intervals and Precision

The posted estimate is a mean difference of 1.0 score point, comparing standard bupivacaine with dexamethasone against liposomal bupivacaine with standard bupivacaine. Its reported confidence interval lies entirely above zero. In the defined comparison direction, this means the interval's values are positive differences, consistent with a higher mean score in the dexamethasone arm. The numerical lower bound has more than three decimal places in the registry record, so the endpoints are not reproduced.

A confidence interval communicates uncertainty around an estimate under the method used to calculate it. It is not a range of individual pain scores, and it does not indicate that every participant's score fell within its bounds. The width is relevant to precision: a narrower interval represents a more tightly estimated mean difference under the same method, while a wider interval allows a broader range of plausible values.

The confidence level and interval-construction method are not reported in the registry record. Without those details, the interval cannot be fully assessed or compared with an explicitly stated confidence standard. The registry also does not report the non-inferiority margin, which would be needed to interpret precision against a non-inferiority threshold. The p-value of 0.006 provides a separate summary of compatibility with a null model; it does not replace the interval or describe the estimate's clinical importance.

Both arms have a reported standard deviation of 1.9, giving context about variability in the outcome. That summary does not reveal the distribution of scores or the precision of individual measurements. The confidence interval is the more direct posted summary of uncertainty in the between-arm mean difference.

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 total events. They are illustrations based on the observed effect, rather than a report of the trial's original design assumptions. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect. The trial's own original sample-size assumptions are not reported in the registry record.

The 80% power column gives the planned number of participants per arm for a design with an 80% chance of detecting the specified effect under those assumptions, if that effect is the true one and the model assumptions hold. The 90% power column gives the corresponding per-arm planning number for a design targeting a 90% chance. These are planning targets, not observed results from the completed trial. This is not observed power.

The rows vary the effect used for planning: 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. For the full observed effect, the figures are 57 participants per arm for 80% power and 76 participants per arm for 90% power. For 75% of the observed effect, they are 101 and 135 participants per arm, respectively. For 50% of the observed effect, they are 227 and 304 participants per arm, respectively.

The pattern reflects a general planning principle: smaller effects are harder to distinguish from random variation and therefore require more participants to reach the same target power, given the stated assumptions. These calculations use the observed effect as their starting point and do not establish that the trial was designed with any particular target. The registry does not report the original sample-size justification.

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 = 1.000; pooled standard deviation σ = 1.900.
2. n = 2 × (1.96 + 0.842)² × 1.900² / 1.000² = 56.7, rounded up to 57 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                      # observed difference in means
sigma <- 1.9                     # 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(4047446)
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 = 57 (80% power), 76 (90% power)
 75% of observed effect: n per arm = 101 (80% power), 135 (90% power)
 50% of observed effect: n per arm = 227 (80% power), 304 (90% power)
power.t.test: 57.6 
Simulated power at n = 57 per arm: 0.799 (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. Multiplicity, Missing Data and Analysis Populations

The registry lists several secondary outcomes in addition to the primary pain-at-rest measure. They include pain with movement, opioid consumption, patient satisfaction with pain management, the Brief Pain Inventory Short-form, duration of analgesic block, sensory resolution, and motor block resolution. The record reports 10 posted secondary outcomes and 11 outcome measures, but no secondary analyses are posted in the analysis field.

When a study evaluates multiple outcomes or multiple comparisons, the chance of obtaining at least one apparently unusual result can increase if each is tested separately without accounting for multiplicity. In general, a multiplicity plan may define which outcomes are confirmatory, how tests are ordered, or how error rates are controlled. The registry record does not report whether such a plan was used, which outcomes were included in it, or whether any adjustment was made to the primary p-value. The reported p-value is explicitly unadjusted.

The record does not report a statistical analysis plan, the primary analysis model, or the prespecified analysis population. It is therefore not possible to determine from the registry record whether analyses were intended for all randomized participants, participants who received treatment, or another population. The handling of participants who did not complete follow-up, missing outcome scores, protocol deviations, and treatment adherence is also not reported.

Missing data can affect an estimate when the observed participants differ from those without recorded outcomes. Statistical approaches to missingness rely on assumptions about why data are absent; the registry record does not state which assumptions or methods were used. The outcome description names observations at 24, 48, and 72 hours, but does not explain how the average was formed if one or more observations were missing.

The title identifies a non-inferiority objective, but the margin, analysis populations relevant to that objective, and decision criteria are not reported in the registry record. These omissions prevent a complete assessment of the planned confirmatory framework. The available registry result supports interpretation of the posted mean comparison, but does not provide the methodological detail needed to reconstruct a full analysis strategy.

14. 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.

Most frequent non-serious adverse event terms

The registry reports serious adverse events for each arm. In the liposomal bupivacaine and standard bupivacaine arm, 55 participants were listed as at risk and 0 as affected by a serious adverse event. In the standard bupivacaine and dexamethasone arm, 56 were listed as at risk and 0 as affected. Deaths are reported as 0 in both arms.

These figures describe the registry's posted serious-event counts for the recorded groups. They do not establish that no adverse events of any kind occurred. The registry separately lists other adverse events: 6 affected participants in the liposomal bupivacaine combination arm and 3 in the dexamethasone combination arm, with the corresponding listed at-risk counts. The serious and other event categories should not be conflated.

The record does not provide serious-event terms, event timing, severity details beyond the category, or an explanation of how events were attributed. No serious-event terms appear in the registry's listed top terms. The counts should be read as reported observations, not as a complete basis for comparing safety or inferring the likelihood of future events.

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

The registry's primary outcome comparison shows a mean pain-at-rest score of 2.4 for liposomal bupivacaine with standard bupivacaine and 3.4 for standard bupivacaine with dexamethasone over the first 72 hours. The reported mean difference is 1.0, with the latter arm having the higher score under the stated comparison direction. Since lower scores indicate less pain, the posted group averages favor the liposomal bupivacaine combination for this endpoint. The unadjusted p-value is 0.006, and the reported interval lies above zero.

That description is limited to the recorded mean endpoint and its statistical comparison. It does not establish how each participant's pain changed, whether one regimen was better at every reported time point, or whether pain with movement or other secondary outcomes followed the same pattern. The registry record does not post secondary analyses or report a threshold for a clinically important difference.

The trial's official title identifies it as a non-inferiority trial, but the registry does not report the non-inferiority margin or criteria. A conventional comparison of means and its p-value cannot, on their own, answer whether a non-inferiority objective was satisfied. The result therefore should not be treated as a complete non-inferiority conclusion.

Nor does the posted estimate alone establish a causal interpretation beyond the design and conduct of the trial. Randomization and double masking are recorded, but their implementation and the analysis details are not reported. Missing-data handling, analysis populations, adjustment choices, and the clinical context needed to assess the importance of a score-point difference are also not reported. The result is best understood as the registered comparison, with those limits in view.

16. Why This Trial Matters Statistically

This trial is statistically informative because it reports a continuous patient-reported outcome as arm means and standard deviations, alongside a mean difference, confidence interval, and unadjusted p-value. The estimate remains on the pain scale's original units, so its direction can be interpreted directly using the registry's statement that lower scores are better. The interval adds information about uncertainty that a p-value alone cannot provide.

The record also illustrates why a study's stated objective matters. The official title calls the trial non-inferiority, but the registry does not report the margin or the criteria needed to interpret a non-inferiority conclusion. A statistically detectable difference between means is not interchangeable with a non-inferiority assessment. The objective, estimand, margin, and analysis population need to be understood together.

Several other statistical considerations remain unresolved in the registry record: the primary analysis specification, missing-data methods, multiplicity handling, and analysis populations are not reported. These details influence how confidently readers can connect a posted estimate to the trial's planned question. The record's outcome list also makes clear why it is useful to distinguish a primary endpoint from secondary outcomes, for which no analyses are posted.

Finally, the planning illustrations show how sample-size requirements depend on the effect targeted. Smaller effects require more participants under the stated assumptions. Those illustrations are based on the observed effect and are not evidence of the original design rationale or of the study's observed power. Keeping planning quantities separate from observed results helps avoid overstating what the trial establishes.

17. 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 trial-specific details needed for a fuller assessment are not reported in the registry record. These include eligibility criteria, participant characteristics, the randomization procedure, allocation concealment, which parties were masked, and how masking was maintained. The arm descriptions contain no additional detail about the regimens, and the record does not give further information about treatment delivery.

The registry does not report the original sample-size justification, the non-inferiority margin, the primary analysis model, or the criteria used for the non-inferiority objective. It also does not report the analysis populations, missing-data procedures, or how the endpoint average was handled when observations at any stated follow-up time were unavailable. These omissions limit interpretation of both the estimate and its relation to the stated trial objective.

The posted analysis information is sparse for the secondary outcomes: the record lists outcomes but does not post secondary analyses. Multiplicity handling and the clinical threshold for an important difference are not reported. The confidence level and construction method for the primary interval are not reported either.

The primary endpoint combines pain-at-rest reports at 24, 48, and 72 hours into an average. That summary does not show the separate time-point results, and the registry does not provide those results in the posted primary outcome description. The safety record gives event counts but limited detail on event terms and timing. These limitations mean the registry supports a focused reading of the posted summary statistics, not a complete reconstruction of trial conduct or analysis.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Liposomal Bupivacaine vs Dexamethasone ISB — NCT04047446.
• Registry record last updated 2022-08-01; status last verified 2022-07.
• Results first posted 2022-08-01.
• 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.

21. Record Summary

The registry record describes NCT04047446, a completed phase 4, randomized, double-masked, parallel-group trial sponsored by Hospital for Special Surgery, New York. Its recorded enrollment is 112, with a start date of 2019-07-11 and a primary completion date of 2021-03-15.

The comparison was between liposomal bupivacaine with standard bupivacaine and standard bupivacaine with dexamethasone for interscalene block in patients receiving shoulder arthroscopy. The primary endpoint was mean Numerical Rating Scale pain at rest over the first 72 hours. The posted arm means were 2.4 and 3.4, respectively, and the reported mean difference was 1.0, with an unadjusted p-value of 0.006.

The registry lists secondary outcomes and adverse-event counts, but does not report secondary analyses or key details of the analysis plan, missing-data handling, or non-inferiority criteria. The posted result should therefore be interpreted as a summary comparison, with those reporting limitations in mind.