EXPAREL for Minimally Invasive Supracervical Hysterectomies: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for EXPAREL for Minimally Invasive Supracervical Hysterectomies (NCT03769714), a randomized phase 4 study. The primary outcome is Pain at 12 Hours.

2. Clinical Question

The registry describes the study aim as reducing postsurgical pain and potentially reducing requests for additional opioid analgesia. However, the posted primary outcome is pain at 12 hours; it does not itself measure opioid use, adverse events related to opioids, recovery experience, or economic effects. The primary comparison is therefore narrower than the broader aims described in the study summary.

The result is an estimate of the difference in average pain scores between the two randomized groups. It should be read alongside its confidence interval, which shows the range of differences compatible with the posted data and analysis. The registry record does not report a more detailed primary analysis population or additional outcome results for the broader aims.

3. Trial Design

This was a Phase 4, randomized, parallel-group pilot study with quadruple masking, listed as completed. Maimonides Medical Center is named as the sponsor. The recorded start date is 2018-10-01 and the primary completion date is 2019-06-30. The registry lists enrollment as 60.

Participants were assigned to saline solution for injection or EXPAREL. The arm descriptions state that Group A received 20ml of saline while prepping, with the syringe covered to disguise its contents. Group B received 20ml of liposomal bupivacaine into the cervical stroma at the 4 and 8 o’clock positions. The registry labels the study placebo-controlled and double-blinded in its official title, and lists masking as quadruple; it does not report which specific roles were masked.

The arm descriptions give n=26 for each group. For the posted primary outcome, the saline group has a reported n of 27 and the EXPAREL group a reported n of 28. The registry record does not explain the difference between the arm-description counts and the outcome-summary counts. These figures should be read in their respective contexts rather than treated as interchangeable.

The primary outcome is pain at 12 hours after surgery, reported as a mean and standard deviation. The record describes a combined faces and numerical rating scale, with scores from 0 to 10. It lists two outcome measures but posts no secondary outcome results. Although the study is described as a pilot study, the registry record does not report its original sample-size justification, detailed protocol, or trial-specific statistical plan.

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 Pain at 12 Hours, measured over 12 hours after surgery.

The primary endpoint is pain measured 12 hours after surgery. The registry describes showing participants a card combining a visual analogue faces scale with a numerical scale from 0, meaning no pain, to 10, meaning the worst pain imaginable. The posted result summarizes scores as a group mean and standard deviation.

A mean provides a measure of the group’s average score, while the standard deviation describes variation among scores around that average. Reporting both makes it possible to compare the groups’ average pain ratings while also seeing that individual ratings varied. A single mean does not describe every participant’s experience, and it does not show how many people reported any particular score.

A pain score at a fixed postoperative time is used to quantify pain at that particular time point. It is distinct from cumulative pain over a period, requests for additional analgesia, opioid consumption, adverse events, or recovery experience. Those broader outcomes appear in the study summary as aims or possible consequences, but the registry record does not post results for them.

The scale’s endpoints give the numerical score direction: higher values correspond to worse pain, while lower values correspond to less pain. The group comparison therefore describes the difference in average reported score at 12 hours. It does not, by itself, establish how pain changed over time or whether other aspects of recovery differed.

7. Results Posted in the Registry

• Exparel: mean 3.70 versus 3.90 on control; difference -0.20 (95% CI -1.79 to 1.39), standardized effect d = -0.07; z-test p = 0.805.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a continuous score summarized by a group mean and standard deviation. The posted comparison is a difference in means, with the EXPAREL group compared against the saline group. The reported estimate is -0.2, with a confidence interval from -1.788 to 1.388 and an unadjusted p-value of 0.805. The registry record does not give a detailed account of the method used by the sponsor for the primary analysis.

What does a difference in means describe?

In general, a difference in means subtracts one group’s average score from the other group’s average score. Here, the stated comparison is EXPAREL minus saline. A value below zero indicates a lower average score in the EXPAREL group; a value above zero indicates a higher average score. Because the scale runs from no pain at 0 to the worst pain imaginable at 10, the direction can be interpreted in terms of lower or higher average reported pain. The estimate describes a group-level average, not a guaranteed change for any individual.

The mean is useful for summarizing a continuous outcome, but it does not convey the full distribution. The standard deviations of 3.1 in the saline group and 2.9 in the EXPAREL group describe the spread of scores around the respective means. In general, a standard deviation is not a confidence interval and does not say precisely where every participant’s score falls. Overlap in the ranges of individual scores is also not, by itself, a test of the difference between group means.

What does the confidence interval add?

In general, a confidence interval presents a range of values compatible with the observed data under the assumptions of the analysis. The interval from -1.788 to 1.388 includes zero and values on both sides of zero. This means the reported estimate alone does not precisely determine whether the underlying mean difference is negative or positive. The interval is an uncertainty statement about the mean difference, not a range containing a specified proportion of individual pain scores.

A confidence interval can be more informative than a p-value because it displays the size and direction of differences that remain compatible with the data. It does not show the probability that a particular value is true. Its interpretation also depends on the statistical model and analysis assumptions; the registry record does not report enough detail to assess all of those assumptions for the sponsor’s analysis.

How should the p-value be read?

In general, a p-value describes how unusual data at least as incompatible with a specified null hypothesis would be if that hypothesis and the analysis assumptions were correct. The unadjusted p-value of 0.805 is not the probability that the null hypothesis is true, nor is it the probability that the result occurred “by chance.” It does not measure the size or clinical importance of a difference. A large p-value can occur when the observed estimate is close to zero, when estimates are imprecise, or for both reasons.

The registry explicitly labels the value unadjusted. The record does not report whether any multiplicity adjustment was applied elsewhere, nor does it give a complete analysis plan. There are two outcome measures listed but no secondary results posted. The primary comparison should therefore be described using the reported unadjusted value without implying that it accounts for every possible analysis or outcome.

Why does variability matter?

In general, greater variability makes it harder to estimate a group mean precisely when other aspects of the design are held fixed. The posted standard deviations are large in relation to the difference in means, and the confidence interval spans negative and positive values. This combination makes the direction and size of the underlying difference uncertain. Variation in pain ratings is expected in a patient-reported measure, but the registry record does not report individual scores or distributional diagnostics.

Over-dispersion is a general concern when observed variation is greater than a statistical model anticipates. If a model understates variability, its uncertainty estimates can be too narrow. The registry record does not report an over-dispersion assessment or indicate that a model requiring such an assessment was used. It would be inappropriate to infer a specific model or diagnosis from the summary statistics alone.

What does “recalculated” mean?

In general, a recalculated result is an unadjusted calculation based on the posted summary statistics rather than a reproduction of a sponsor’s individual-level analysis. The mean difference, confidence interval, and unadjusted p-value posted for this comparison are the statistics used in the interpretation. The registry record does not report a sponsor analysis that can be compared with a separate recalculation, and the discrepancy flag is false. Summary-statistic calculations cannot recover adjustments or details that are not posted in the registry.

Randomization is intended in general to support a fair comparison by assigning participants to groups rather than choosing groups based on expected outcomes. However, the posted summary does not establish how randomization was generated or concealed; those details are not reported in the registry record. Likewise, the record’s masking label gives the stated masking level but not the roles masked or an assessment of whether masking was maintained.

10. Confidence Intervals and Precision

The estimated mean difference in 12-hour pain score was -0.2 points for EXPAREL relative to saline. Its confidence interval extends from -1.788 to 1.388. Because the interval includes zero and reaches into both negative and positive values, the posted data are compatible with a range of possible directions and magnitudes for the mean difference.

Precision concerns how tightly the data estimate a quantity. A narrow confidence interval would indicate greater precision than a wide interval, all else equal. The interval in this comparison is broad relative to the point estimate, so the exact size and direction of the difference are uncertain. The point estimate should not be treated as the only plausible value, and the interval should not be interpreted as a range for individual patients’ scores.

The standard deviations, 3.1 for saline and 2.9 for EXPAREL, show that scores varied within both groups. The posted outcome counts are n=27 for saline and n=28 for EXPAREL. The registry arm descriptions instead list n=26 in each group; the record does not explain the difference. The confidence interval belongs to the posted comparison, and its uncertainty should not be detached from the data and analysis that produced it.

In general, a confidence interval is not proof that every value inside it is equally likely, and it does not assign a probability to the true difference. Nor does an interval that includes zero demonstrate equivalence. Establishing equivalence would require a defined equivalence margin and an analysis designed for that purpose; neither is reported in the registry record.

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 sample-size figures are planning illustrations based on the observed effect, not the trial’s original design assumptions. They give participants per arm for the stated target power, rather than a total across arms or a count of events. The planning assumptions listed 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 80% power column gives the illustrated number of participants per arm for a design with 80% power to detect the specified effect under those assumptions. The 90% power column gives the corresponding number per arm for a design with 90% power. In general, power is the chance of detecting an effect of a specified size under the assumptions of a study when that effect is present. These columns do not describe the power achieved by the completed trial.

The illustrations use 100%, 75%, and 50% of the observed effect. The listed participants per arm for 80% power are 3,532, 6,279, and 14,126, respectively; for 90% power they are 4,728, 8,405, and 18,911, respectively. In this set of planning calculations, smaller effects require more participants per arm to detect with the stated power. The very small observed mean difference is the basis for these planning illustrations, so their large figures should not be mistaken for a recommended design for a future trial.

The curve is a visual companion to the planning figures and should be interpreted under the same assumptions. These values are not observed power, and they do not reveal what sample-size calculation, if any, informed the original trial. The registry record does not report the trial’s original sample-size justification or its design assumptions.

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 = -0.200; pooled standard deviation σ = 3.000.
2. n = 2 × (1.96 + 0.842)² × 3.000² / -0.200² = 3,531.5, rounded up to 3,532 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 <- -0.2                      # observed difference in means
sigma <- 2.99977986613735                     # 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(3769714)
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 = 3,532 (80% power), 4,728 (90% power)
 75% of observed effect: n per arm = 6,279 (80% power), 8,405 (90% power)
 50% of observed effect: n per arm = 14,126 (80% power), 18,911 (90% power)
power.t.test: 3532.4 
Simulated power at n = 3,532 per arm: 0.801 (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

Multiplicity arises when a study evaluates multiple outcomes, time points, groups, or analyses. In general, conducting many statistical tests can increase the chance of obtaining at least one apparently notable result even when no underlying difference exists. A prespecified plan can clarify which outcomes and comparisons are primary and whether adjustments are intended. The registry record lists two outcome measures, but posts no secondary outcome results. It does not report a detailed multiplicity plan or adjustment for the primary comparison.

The posted p-value is explicitly unadjusted. It should therefore be described as the unadjusted result, not as a value known to account for all testing in the study. The registry record has zero analysis entries, and it does not provide a complete statistical analysis plan. It is not possible to determine from the record whether other analyses were conducted or how their results were handled.

Missing-data methods matter because participants without a recorded endpoint may differ from those with an observed score. In general, analysis choices about missing outcomes can affect both estimates and uncertainty. The registry record does not report missing-data handling, the number of participants with missing 12-hour pain scores, or the reasons for any missingness. It also does not report whether imputation or sensitivity analyses were used. No assumptions about missing observations should be inferred from the posted arm counts.

An analysis population defines which participants contribute to a result, for example whether all randomized participants are included or whether a subset is used. The registry record does not describe the primary analysis population or state how participants were handled after randomization. The outcome summaries report n=27 for saline and n=28 for EXPAREL, while the arm descriptions state n=26 for each group; the record does not explain these differing counts.

These omissions do not demonstrate that a particular method was or was not used. They limit what can be established from the registry record. The displayed comparison can be described as posted, but its full relationship to a protocol-defined analysis, missing-data strategy, and multiplicity plan is not reported.

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.

The registry reports serious adverse events, other adverse events, and deaths separately for the saline and EXPAREL groups. For each group, 30 participants are listed as at risk for serious adverse events and 0 as affected. For other adverse events, 30 are listed as at risk and 0 as affected. Deaths are listed as 0 in both groups.

These are the adverse-event figures posted in the registry; they are not the same counts as the primary pain-outcome summaries or the arm-description counts. The record does not explain the different denominators across these entries. It also does not post any serious adverse-event terms, and no event terms are listed in the serious-event summary.

In general, a zero count in a registry summary means that no events were reported in that category for the stated group and risk count. It does not establish that an event is impossible or that the study can rule out uncommon harms. The registry record does not provide further detail about event definitions, collection procedures, follow-up, or whether events were assessed as related to an intervention. These figures should be read as the reported counts, not as a complete characterization of safety.

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

The posted primary result is a small estimated difference in average pain score at 12 hours: -0.2 points for EXPAREL compared with saline. The confidence interval, from -1.788 to 1.388, includes zero and spans differences in both directions. The unadjusted p-value is 0.805. Taken together, these statistics show that the posted comparison does not estimate the direction or size of a difference precisely.

The result does not establish equivalence between the groups. A failure to find a statistically notable difference is not the same as demonstrating that any difference is small enough to be unimportant. The registry record does not report an equivalence margin or an equivalence analysis. Nor does the result establish that EXPAREL has a particular effect: the point estimate is one estimate among a range of values compatible with the reported interval.

The endpoint captures a reported pain score at one postoperative time point. It does not answer whether cumulative pain over 24 hours differed, whether participants requested additional analgesia, how much opioid medication was used, or whether opioid-related adverse events differed. Those outcomes are mentioned in the study summary, but results for them are not reported in the registry record. Recovery experience and economic effects are also not reported as results.

The adverse-event summary records zero affected participants for serious and other adverse events in each group and zero deaths. These registry counts do not settle the broader safety question; the record does not give further information about event definitions, collection, or follow-up.

Overall, the registry supports a careful description of the posted mean pain scores and their uncertainty, but not a firm conclusion about the broader aims in the study summary. Missing details about the analysis population, missing data, and original statistical plan further limit what can be inferred. The result should be understood as an imprecise comparison at the stated endpoint, rather than as a definitive answer about pain management or other outcomes.

16. Why This Trial Matters Statistically

This trial is statistically instructive because the estimated difference in the primary outcome is close to zero while the uncertainty interval is broad. A point estimate alone might draw attention to the direction of the mean difference, but the interval shows that the data do not tightly locate the underlying difference. Considering both the estimate and its precision is essential for a balanced interpretation.

The posted standard deviations are large relative to the mean difference. This illustrates a general issue in clinical research: patient-reported outcomes can vary substantially across participants, making a group average an incomplete description of individual experience. The mean and standard deviation provide useful summaries, but the registry does not post individual-level distributions or additional summaries of the pain ratings.

The planning illustrations also demonstrate how sample-size calculations depend on the effect a future study aims to detect. Under the listed assumptions, planning for smaller fractions of the observed effect requires more participants per arm. Those calculations are illustrations based on the observed estimate, not evidence of the original design rationale or the completed trial’s observed power.

Finally, the registry’s varying counts across arm descriptions, outcome summaries, and adverse-event summaries underline why denominators and analysis populations need to be read in context. The record does not explain the differences, so they should not be reconciled by assumption. Clear reporting of analysis populations, missing-data handling, and planned comparisons would make the relationship between design and reported estimates easier to assess.

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.

The registry record does not report the original sample-size justification, the detailed statistical analysis plan, or the randomization method. It identifies the trial as randomized and quadruple-masked, but does not specify which roles were masked or provide information about how masking was maintained.

The arm descriptions list n=26 in each group, while the posted primary outcome summaries give n=27 for saline and n=28 for EXPAREL. The adverse-event entries list 30 at risk in each group. The registry record does not explain these differences, so the specific populations underlying each summary cannot be clarified from the record alone.

The record does not report the primary analysis population, missing-data handling, or the number and reasons for any missing pain scores. It also does not provide individual-level score distributions, so the mean and standard deviation are the available summaries for understanding the 12-hour outcome.

Although the study summary describes broader aims involving cumulative pain, additional analgesia, opioid consumption, adverse events, recovery experience, and possible economic benefit, the registry posts no secondary outcome results. The posted primary endpoint is a pain score at 12 hours, and the adverse-event summary provides counts without further detail about event definitions, assessment, or follow-up. These reporting limits constrain interpretation of both the efficacy-related aims and the safety information.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: EXPAREL for Minimally Invasive Supracervical Hysterectomies — NCT03769714.
• Registry record last updated 2024-01-09; status last verified 2024-01.
• Results first posted 2024-01-09.
• 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 describes a completed Phase 4 randomized, parallel-group pilot study of EXPAREL versus saline for minimally invasive supracervical hysterectomy. It lists quadruple masking, enrollment of 60, and Maimonides Medical Center as sponsor. The primary endpoint is mean pain score 12 hours after surgery on a combined faces and numerical scale from 0 to 10.

The posted mean scores were 3.9 for saline and 3.7 for EXPAREL. The estimated mean difference was -0.2, with a confidence interval from -1.788 to 1.388 and an unadjusted p-value of 0.805. The interval includes zero and does not precisely establish the direction or size of the difference.

The registry posts no secondary outcome results and does not report the original sample-size justification, analysis population, or missing-data methods. Its arm descriptions and posted summaries give differing counts, which the record does not explain. Adverse-event entries report zero affected participants in each group for serious and other events, and zero deaths.