Evaluation of the Efficacy and Safety of Locally Administered HTX-011 for Postoperative Analgesia Following Bunionectomy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of the Efficacy and Safety of Locally Administered HTX-011 for Postoperative Analgesia Following Bunionectomy (NCT02762929), a randomized phase 2 study. The primary outcome is Mean Summed Pain Intensity (SPI) Score Over 24 Hours.

2. Clinical Question

3. Trial Design

This was a Phase 2, randomized, double-masked, parallel-group, multicenter study. The registry record lists enrollment of 430 and a completed status. The recorded start was 2016-05, and primary completion was 2017-02. The brief summary describes an evaluation of locally administered HTX-011 for postoperative analgesia following bunionectomy.

The treatment groups included saline placebo and several active regimens: HTX-011A at 200 mg; HTX-011B at 30 mg, 60 mg, 120 mg, and 200 mg; HTX-002 at 60 mg, 120 mg, and 200 mg; HTX-009; and bupivacaine HCl at 50 mg. The arm descriptions specify injection for most regimens and injection or instillation for some HTX-011B regimens. HTX-011A and HTX-011B are described as bupivacaine/meloxicam formulations. More detailed procedures and the rationale for the different regimens are not reported in the registry record.

The primary endpoint was mean SPI over 0-24 hours. The posted arm summaries have different participant counts, ranging from 11 to 103 for this outcome. The registry record does not explain the differences between the endpoint counts and the overall enrollment, or identify the analysis population used for the summaries. No secondary outcomes are posted. The registry record does not report the original sample-size justification, planned analysis model, or details of how masking was maintained.

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.

Before assignment: Study HTX-011-208 included multiple study parts, various study drugs, formulations, and administration techniques. It was pre-specified in the SAP to pool different doses of the same study drug within study parts for Participant Flow, Baseline Characteristics, and AEs. We pooled different doses of the same study drug within study parts for Participant Flow, Baseline Characteristics, and AEs. However for Outcome Measures, different doses of study drugs were presented separately.

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.

Population: Study HTX-011-208 included multiple study parts, various study drugs, formulations, and administration techniques. It was pre-specified in the SAP to pool different doses of the same study drug within study parts for Participant Flow, Baseline Characteristics, and AEs. We pooled different doses of the same study drug within study parts for Participant Flow, Baseline Characteristics, and AEs. However for Outcome Measures, different doses of study drugs were presented separately.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Mean Summed Pain Intensity (SPI) Score Over 24 Hours, measured over 0-24 hours.

The primary endpoint was mean summed pain intensity (SPI) over 0-24 hours, reported in units on a scale. SPI is a continuous measure formed by combining pain intensity (PI) scores at scheduled assessment times. Each score is weighted by the scheduled time since the preceding PI assessment, so the resulting measure reflects both the recorded intensity and the time interval represented by that assessment.

The registry description gives a possible SPI range from 0, if PI is 0 at every time, to 240, if PI is 10 at every time. A lower SPI means a lower weighted sum of the recorded pain-intensity scores over the specified interval. The reported endpoint is a group mean, accompanied by a standard deviation in the arm summaries. A mean offers a compact description of the group’s scores, while the standard deviation describes variation among the individual scores.

A continuous, time-weighted measure can summarize repeated assessments across a defined period rather than treating one assessment as the full account of that period. It is important, however, to interpret SPI as the specific measure described in the registry, not as a direct measure of every aspect of postoperative experience. The registry record does not report a threshold for a clinically meaningful difference, or further details about the interpretation of changes in SPI.

7. Results Posted in the Registry

• HTX-011A: 200 mg: mean 69.16 versus 126.46 on control; difference -57.30 (95% CI -74.85 to -39.75), standardized effect d = -1.23; z-test p = <0.001.
• HTX-011B: 30 mg: mean 96.83 versus 126.46 on control; difference -29.63 (95% CI -54.57 to -4.69), standardized effect d = -0.62; z-test p = 0.020.
• HTX-011B: 60 mg: mean 83.38 versus 126.46 on control; difference -43.08 (95% CI -58.67 to -27.49), standardized effect d = -0.91; z-test p = <0.001.
• HTX-011B: 120 mg: mean 85.70 versus 126.46 on control; difference -40.76 (95% CI -53.85 to -27.67), standardized effect d = -0.91; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

Each arm’s primary-outcome result is reported as a mean and standard deviation. A mean is the arithmetic average of the measured SPI values in that arm. The standard deviation describes how spread out those individual values are around the mean. It is not the uncertainty in the mean itself: uncertainty in an estimated mean also depends on the number of observations. The outcome counts accompanying the arm summaries vary across groups.

How to read the mean differences

For each treatment group, the posted contrast is the treatment-arm mean minus the saline-placebo mean. A negative mean difference therefore means that the treatment arm’s estimated mean SPI is lower than the placebo group’s; a positive difference means it is higher. For example, the HTX-011A at 200 mg contrast is -57.3, with a 95% confidence interval from -74.85 to -39.75. This is a simple unadjusted recalculation from the posted arm summaries, rather than an analysis listed in the registry record. The registry record lists zero analyses.

These pairwise contrasts do not provide direct evidence about differences between two active treatments. For example, the estimates for two HTX-011B groups each use saline placebo as the comparator. Comparing those estimates with each other is not the same as estimating a direct treatment-versus-treatment contrast with its own uncertainty.

What the confidence interval conveys

General: a confidence interval expresses the uncertainty of an estimate under the calculation method used. In repeated use of the same method, intervals constructed in this way would cover the underlying parameter at the stated rate. A narrower interval indicates greater precision than a wider one, while an interval that includes zero leaves a zero mean difference among the values compatible with the interval. It does not give the probability that the true value lies within this particular interval.

The posted contrasts show intervals that exclude zero for HTX-011A and each HTX-011B dose group. The intervals for bupivacaine HCl, all three HTX-002 groups, and HTX-009 include zero. These are unadjusted intervals associated with the simple recalculations. The registry record does not report a multiplicity adjustment, so the intervals should not be interpreted as simultaneous coverage across every contrast.

What the p-values mean

General: a p-value measures how incompatible the observed data are with a specified null model, assuming that model and the calculation procedure. It is not the probability that the null hypothesis is true, and it does not measure clinical importance. The posted p-values are unadjusted: they apply to individual comparisons and do not account for the fact that several treatment groups were compared with placebo. The registry record does not report the sponsor’s inferential analysis, any prespecified significance threshold, or any correction for multiple comparisons.

It is useful to consider the estimated difference and its interval along with the p-value. A small p-value can accompany an estimate whose practical meaning is unknown, especially when no meaningful-difference threshold is reported. Conversely, a p-value that is not small does not prove that the groups are identical; a confidence interval may still include a range of differences.

Why variability and group size matter

General: the standard error describes the sampling uncertainty of an estimate. It tends to be larger when the observed data are more variable or when fewer observations contribute. That relationship helps explain why arm counts and the spread of SPI scores matter when assessing precision. The arm summaries list standard deviations, and the comparison calculations use pooled standard deviations. The registry record does not report a model-based adjustment or additional covariates for these contrasts.

General: over-dispersion arises when the observed variability exceeds what a statistical model expects. It can make standard errors too small if the model does not account for the extra variation. No over-dispersion assessment is reported in the registry record, and the posted endpoint is continuous; no claim about over-dispersion in this trial follows from the arm summaries alone.

The registry record also does not describe how missing outcome data were handled, whether all randomized participants contributed to the endpoint summaries, or which analysis population was used. Those omissions limit the ability to assess whether the posted summaries reflect the originally intended analysis.

10. Confidence Intervals and Precision

The confidence intervals around the unadjusted mean differences show how precisely each treatment-placebo contrast is estimated under the recalculation method. For HTX-011A at 200 mg, the estimated difference was -57.3, with a 95% confidence interval from -74.85 to -39.75. For HTX-011B at 30 mg, the estimate was -29.63, with an interval from -54.57 to -4.692. The intervals were -58.67 to -27.49 for 60 mg, -53.85 to -27.67 for 120 mg, and -94.3 to -60.16 for 200 mg.

The interval for bupivacaine HCl at 50 mg was -30.19 to 13.59. For HTX-002, intervals were -32.26 to 3.338 at 60 mg, -15.33 to 22.35 at 120 mg, and -55.59 to 18.31 at 200 mg. For HTX-009, the interval was -18.51 to 21.25. These latter intervals include zero, leaving zero among the mean differences compatible with the interval calculation. The HTX-011 intervals exclude zero, but that does not address the absence of a reported multiplicity adjustment.

General: an interval is not a guarantee that the true mean difference lies between its endpoints. It represents uncertainty under a particular calculation method and its assumptions. Wider intervals indicate less precision, and group size and outcome variability contribute to that uncertainty. The registry record does not post confidence intervals for the individual arm means. The displayed intervals are unadjusted recalculations rather than sponsor-reported analyses; the registry record does not report a different inferential analysis to compare with them.

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 describe participants per arm for 80% power and participants per arm for 90% power. They are not total event counts. The calculations are planning illustrations based on the observed effect, not the trial’s original design assumptions. The registry record does not report the original sample-size justification.

The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The planning rows therefore consider 100%, 75%, and 50% of the observed effect. The figures are recalculated planning illustrations and are not observed power.

In plain language, the 80% power column gives the estimated number of participants needed in each arm for the calculation to have an 80% chance of detecting the specified effect if that effect is present and the assumptions hold. The 90% power column applies the same idea with a higher target chance of detection, and generally requires more participants. These are planning targets, not statements about how likely a particular result is to be true.

Smaller effects are harder to distinguish from random variation, so the planning figures increase when the assumed effect is reduced from the observed estimate to a smaller fraction. The calculations are specific to each treatment-placebo contrast and its observed effect; they should not be treated as a single recommended sample size for the trial. They also do not account for unreported design features, such as any planned adjustment for multiple comparisons.

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 = -57.300; pooled standard deviation σ = 46.733.
2. n = 2 × (1.96 + 0.842)² × 46.733² / -57.300² = 10.4, rounded up to 11 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 <- -57.3                      # observed difference in means
sigma <- 46.7332833153051                     # 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(2762929)
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 = 11 (80% power), 14 (90% power)
 75% of observed effect: n per arm = 19 (80% power), 25 (90% power)
 50% of observed effect: n per arm = 42 (80% power), 56 (90% power)
power.t.test: 11.5 
Simulated power at n = 11 per arm: 0.778 (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 trial has multiple treatment arms, and the posted recalculations compare each arm with saline placebo. The resulting p-values are unadjusted. The registry record does not report a multiplicity strategy, such as a procedure to control the chance of false-positive findings across the set of comparisons. Consequently, the individual p-values should be read as results for separate contrasts, not as an overall test that accounts for all comparisons.

The registry record lists zero analyses. It does not identify a primary analysis population, say whether the endpoint results followed an intention-to-treat or per-protocol approach, or describe an analysis set for the reported outcome. It also does not report how missing SPI assessments or incomplete follow-up were handled. The endpoint counts vary between arms, but the reason for that variation is not reported in the registry record. Without participant-level information and an analysis description, it is not possible to determine from the posted summaries how missing observations may have affected the estimates.

The registered design is randomized, double-masked, and parallel-group, but the registry record does not specify the statistical model used for the original analysis, if one was conducted, or whether any covariates were included. It also does not report interim analyses, an analysis hierarchy among the treatment arms, or a planned significance threshold. These details should not be inferred from the unadjusted recalculations.

General: multiplicity matters because conducting multiple hypothesis tests can increase the chance of at least one apparently unusual result under a set of null hypotheses. A prespecified adjustment or testing hierarchy can address that issue, but none is described in the registry record. Missing-data methods and analysis populations also matter because estimates can depend on which participants and measurements are included. The available summaries do not resolve these uncertainties.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: impaired healing (3.3%), inflammation (3.3%), post procedural cellulitis (3.0%), postoperative wound infection (3.0%).

The registry safety record lists serious adverse events by group and gives the number at risk and the number affected. It lists one participant affected in HTX-011A, one in HTX-011B, none in bupivacaine HCl, none in saline placebo, none in HTX-002, and two in HTX-009. The listed numbers at risk were 33, 174, 25, 104, 64, and 30, respectively. No deaths are listed in any group.

These are counts, not adjusted comparisons, and the registry record does not report a statistical analysis of the safety differences. Serious adverse events are distinct from the separately listed other adverse events; those other-event counts are not described by the serious-event figures. The registry lists serious-event terms including impaired healing, inflammation, post procedural cellulitis, and postoperative wound infection, with each term’s percentage stated in the record. The record does not provide enough detail in these summaries to determine event timing, duration, severity beyond the serious-event classification, or whether events were judged related to treatment. The counts should therefore be read descriptively, not as evidence that one regimen caused or prevented an event.

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

The posted endpoint summaries show that mean SPI differed from the saline-placebo mean in the unadjusted recalculations for the HTX-011 groups, with negative estimated differences and intervals that exclude zero. The recalculated contrasts for bupivacaine HCl, HTX-002, and HTX-009 have intervals that include zero. These findings describe the posted group summaries over 0-24 hours; they do not establish a treatment effect beyond the limits of the analysis and record.

A statistical difference and a clinically meaningful difference are not interchangeable. The registry record does not report a threshold for a meaningful change in SPI, so the clinical importance of the numerical differences cannot be determined from these results alone. The comparisons are also unadjusted and the record does not describe a multiplicity procedure. The p-values cannot be interpreted as a trial-wide conclusion across all treatment arms.

These estimates do not directly compare the active treatments with one another. They do not establish how well the treatments perform outside the studied bunionectomy setting, nor do they resolve questions about outcomes beyond the primary 0-24 hour SPI measure. No secondary outcomes are posted in the registry record. The results also do not establish a causal explanation for any difference in group means; such interpretation depends on the full trial conduct, analysis plan, and available participant-level evidence.

The safety summaries list serious adverse-event counts and no deaths, but do not include an inferential comparison or detailed information about event attribution. They should be read as descriptive counts rather than as a basis for a conclusion about comparative safety. Taken together, the registry record supports a careful account of the posted means, contrasts, uncertainty, and safety counts, while leaving important analysis and clinical-interpretation details unreported.

16. Why This Trial Matters Statistically

This trial is statistically notable for its multi-arm structure and the range of observed group sizes. Several treatment regimens are compared with the same saline-placebo group, while the endpoint counts differ among arms. Those features make it important to distinguish the individual treatment-placebo estimates from direct comparisons between active regimens and to consider how multiplicity and unequal precision affect interpretation.

The primary measure combines repeated pain-intensity assessments over a defined 0-24 hour period into one time-weighted continuous score. That approach gives a summary across scheduled observations, but it also means that the definition and timing of assessments are central to interpreting the endpoint. The registry provides the scoring description and range, yet does not report a threshold for a clinically meaningful difference.

The posted arm means and variability allow simple unadjusted contrasts and confidence intervals to be recalculated. Those estimates make uncertainty more visible than a p-value alone, but they are not a substitute for a reported prespecified analysis. The registry record lists no analyses and does not describe adjustment for multiple comparisons, missing-data handling, or the analysis population.

For biostatisticians and clinical researchers, the key lesson is to separate what the numerical summaries can establish from what requires fuller reporting. The mean differences describe contrasts in observed group summaries; their intervals communicate estimation uncertainty under the recalculation method. Neither feature resolves the missing analysis-plan details or the clinical meaning of the score differences. Transparent reporting of the analysis population, missing-data methods, and multiplicity plan would be needed to assess the inferential context more fully.

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 contains no reported analyses, even though arm-level primary-outcome summaries and unadjusted recalculated contrasts are available. It does not report the original protocol’s sample-size rationale, the planned statistical model, analysis populations, interim analyses, missing-data methods, or any multiplicity adjustment. These absences limit assessment of whether the posted comparisons match the intended confirmatory analysis.

The arm counts for the primary endpoint vary, and the record does not explain the differences. The registry reports overall enrollment of 430, but the relationship between that enrollment and the endpoint counts is not described. The available summaries do not permit assessment of individual-level data, baseline balance, outcome distribution, or reasons for missing measurements.

The contrast calculations are unadjusted and based on posted arm summaries. They do not provide direct comparisons among active treatments. The record also does not report a clinically meaningful SPI threshold, secondary outcome results, or further details about the safety-event attribution and follow-up. These limitations are specific to the information documented in the registry record and should constrain interpretation of the numerical findings.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Evaluation of the Efficacy and Safety of Locally Administered HTX-011 for Postoperative Analgesia Following Bunionectomy — NCT02762929.
• Registry record last updated 2026-02-23; status last verified 2026-02.
• Results first posted 2023-10-04.
• 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 a completed Phase 2, randomized, double-masked, parallel-group, multicenter trial of locally administered treatments for postoperative pain following bunionectomy. Enrollment was 430, with a recorded start of 2016-05 and primary completion in 2017-02.

The primary endpoint was mean summed pain intensity over 0-24 hours. The posted summaries include saline placebo, several HTX-011 regimens, HTX-002, HTX-009, and bupivacaine HCl. Recalculated unadjusted contrasts versus placebo have confidence intervals excluding zero for the HTX-011 groups and including zero for the other listed active groups. The registry record lists no analyses and does not report multiplicity, missing-data, or analysis-population details. Safety summaries list serious adverse-event counts and no deaths.