Phase 2 Herniorrhaphy Study for Opioid Elimination: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 2 Herniorrhaphy Study for Opioid Elimination (NCT03695367), a non-randomized phase 2 study. The primary outcome is Percentage of Subjects Receiving no Opioid Rescue.

2. Clinical Question

The endpoint concerns opioid rescue after surgery, rather than pain intensity alone. Other listed outcomes include total postoperative opioid consumption in IV morphine milligram equivalents, the percentage receiving no opioid rescue, and severe pain defined using a numeric rating scale. The registry record lists the no-opioid-rescue outcome more than once among the secondary outcomes, and describes the severe-pain threshold as a score >7 on a scale of 0-10. These endpoint descriptions identify what was intended to be measured; they do not establish what participants experienced. Because the cohorts were not randomized and differed by the addition of ketorolac, even complete cohort results would require cautious interpretation as a comparison of treatment strategies rather than an isolated estimate of ketorolac's effect.

3. Trial Design

This was a completed Phase 2, open-label study of HTX-011 in a multimodal analgesic regimen after unilateral open inguinal herniorrhaphy. The registry record lists nonrandomized allocation, no masking, and a sequential model. Enrollment was 63. The recorded study start was 2018-10-01, and primary completion was 2018-11-20.

The first cohort received HTX-011, described as bupivacaine/meloxicam at 300 mg/9 mg via instillation, with a non-opioid multimodal analgesic regimen. The second received the same described HTX-011 dose and regimen plus IV ketorolac. The safety record lists 33 participants at risk in the first cohort and 30 in the second. These figures describe the recorded safety groups; they do not supply primary endpoint results.

Sequential, nonrandomized allocation means participants were not assigned at random between the two cohorts, and the groups are not a randomized control comparison. The addition of ketorolac is a regimen difference, but the record does not establish that it is the only systematic difference between cohorts. No masking means the study was open-label. These design features matter when interpreting any apparent group contrast: cohort differences could reflect factors other than the regimen distinction.

The registry record identifies a 72-hour primary endpoint timeframe and the Safety Population. Further detail about eligibility, treatment assignment procedures, follow-up beyond the stated timeframe, protocol deviations, or the rationale for the sequential cohorts is not reported in the registry record. A sample-size justification and the trial's statistical analysis plan are also not reported in the registry record. The record marks the study completed, but completion alone does not indicate that all planned analyses or results were posted.

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:

Analysis population for the primary outcome, as defined in the registry: Safety Population

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 Percentage of Subjects Receiving no Opioid Rescue, measured over 72 hours.

The primary endpoint is the percentage of participants receiving no opioid rescue during the 72-hour timeframe. It is a binary participant-level outcome: each participant either received opioid rescue during the defined period or did not. The registry record labels the measurement unit as participants and identifies the Safety Population.

This endpoint can be useful because it expresses opioid rescue as an interpretable participant outcome, rather than only reporting a group total of opioid use. It addresses whether rescue medication was used within the specified period; it does not, by itself, describe pain intensity, timing of rescue, or the amount of opioid consumed among participants who received it. The registry record lists total postoperative opioid consumption and pain-related outcomes separately, reflecting that these measures address different aspects of postoperative experience.

The registry record does not report the number or percentage receiving no opioid rescue in either cohort. It also does not report a confidence interval, a test result, or a between-cohort estimate for this primary endpoint. Consequently, the endpoint's definition and timeframe are available, but its observed result and precision cannot be evaluated from the posted registry results.

In general, a binary endpoint is summarized by counts and proportions, with uncertainty intervals used to show how precisely the underlying proportion is estimated. Those quantities are not reported for this primary outcome in the registry record. The endpoint should therefore be read as the stated outcome of interest, not as evidence about the observed level of opioid rescue.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The design and endpoint descriptions allow several statistical concepts to be explained, but the registry record does not report the analysis plan or primary outcome results. General explanations below should not be mistaken for methods confirmed as having been used in this study.

What does a binary endpoint represent?

In general, a binary endpoint classifies each participant into one of two outcome categories. For this study's primary endpoint, the categories are receiving no opioid rescue during the 72-hour timeframe or not meeting that description. A group result would ordinarily include the number of participants in each category and the relevant denominator. A percentage is easier to interpret when its denominator is clear; counts help readers understand how many observations support that percentage.

The registry record identifies the measurement unit as participants and the population as the Safety Population. It does not report the cohort counts for the endpoint, percentages, or denominators used in an outcome analysis. The safety group sizes cannot be substituted for outcome counts: knowing how many participants were at risk does not tell a reader how many received no rescue.

What does a confidence interval add?

In general, a confidence interval describes uncertainty around an estimated effect or proportion. It reflects the fact that an estimate based on a finite group of participants can vary across samples. An estimate alone can conceal substantial uncertainty, especially when the amount of information is limited. The interval's width and location help readers judge precision and the range of values compatible with the analysis. A confidence interval is not itself a guarantee that the true value lies within a particular reported interval.

No confidence interval for the primary endpoint is reported in the registry record. As a result, its precision cannot be assessed. The record also contains no posted inferential analyses for the primary endpoint. No conclusion about statistical significance or the evidence for a cohort difference follows from the endpoint definition alone.

Why does allocation affect a cohort contrast?

In general, random allocation helps balance measured and unmeasured participant characteristics across study groups, on average. It supports a more credible causal comparison when other design and analysis requirements are met. This study used nonrandomized, sequential allocation, so that protection is absent. Cohort comparisons may be affected by baseline differences or by changes over time. The record does not report details that would establish whether these concerns were addressed through adjustment or other methods.

The two cohorts also received different regimens: the second included IV ketorolac, while both included HTX-011 and a non-opioid multimodal regimen. A difference in outcomes, if reported, could not automatically be attributed to ketorolac. The study design and any adjustment methods would need to support that interpretation; the statistical plan and such methods are not reported in the registry record.

Why can over-dispersion matter?

In general, over-dispersion occurs when observed variability in count data is greater than assumed by a statistical model. If a model assumes less variability than is present, standard errors may be too small and uncertainty may be understated. This is a general issue for some count outcomes, including opioid-consumption measures, depending on their distribution and analysis. The registry record does not report the distribution of opioid consumption or the methods used to analyze it. There is no basis to say whether over-dispersion was assessed or whether it affected any result.

The primary endpoint is binary, not a count of repeated opioid doses. General methods for binary outcomes and methods for count outcomes are not interchangeable. The record's listing of total opioid consumption as a separate outcome does not establish the statistical model used for that measure.

What can planning calculations tell readers?

In general, sample-size calculations describe how many participants a hypothetical design might require under stated assumptions about the effect to detect, significance level, allocation, and statistical method. Such calculations are planning illustrations, not results from enrolled participants and not observed power. A planning calculation based on an observed effect is especially dependent on that effect estimate and should not be treated as a prospective justification for this trial.

The registry record does not report the trial's own sample-size justification or statistical analysis plan. It gives no primary endpoint effect estimate on which to base an interpretation of planning illustrations. Therefore, no conclusion about whether enrollment was adequate for the primary question can be drawn from the registry record alone.

In general, observed power calculated after a study is complete is not a substitute for reporting the estimated effect and its uncertainty. Readers learn more from the outcome estimate and confidence interval than from a retrospective power label. No such primary endpoint estimate or interval is reported in the registry record.

These explanations describe statistical principles rather than confirmed trial procedures. The available registry information establishes the study's nonrandomized, open-label structure, its cohorts, and its 72-hour primary endpoint; it does not establish the detailed model, adjustment strategy, uncertainty method, or decision rules used in an analysis.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Cohort 1: HTX-011 + MMA Regimen", "Cohort 2: HTX-011 + MMA Regimen + Ketorolac")
n      <- c(33, 30)
events <- c(30, 27)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Cohort 1: HTX-011 + MMA Regimen  33  30  90.9  75.7  98.1  76.4  96.9  76.3  96.7
ARM  Cohort 2: HTX-011 + MMA Regimen + Ketorolac  30  27  90.0  73.5  97.9  74.4  96.5  74.2  96.4

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists multiple outcomes, including total postoperative opioid consumption in IV morphine milligram equivalents, the percentage of participants receiving no opioid rescue, and severe pain measured using an NRS-R pain-intensity score. The primary endpoint is the percentage receiving no opioid rescue during 72 hours. The record also repeats the no-opioid-rescue wording among secondary outcomes. Listing multiple outcomes raises a general multiplicity issue: when many hypotheses are tested, the chance of at least one apparently unusual result can increase. In general, a prespecified testing hierarchy or multiplicity adjustment can help define how results should be interpreted.

The statistical analysis plan, any prespecified testing hierarchy, and any multiplicity adjustment are not reported in the registry record. The record does not report inferential results for the primary endpoint, and it lists no analyses. It is therefore not possible to determine how multiplicity was handled or to assess a family of statistical claims from the posted results.

Missing-data procedures are not reported in the registry record. The record does not describe whether outcome data were missing, how missing observations were handled, or whether any sensitivity analyses were planned or performed. The named NRS-R outcome specifies Windowed Worst Observation Carried Forward in its description, but that wording does not establish how missing data were handled for the primary endpoint or other outcomes.

The endpoint population is identified as the Safety Population, but further details of its definition, participant exclusions, or analysis-population rules are not reported in the registry record. The record's enrollment and safety group sizes do not establish the endpoint denominators. Without outcome counts and missing-data details, readers cannot evaluate the influence of incomplete observations on the primary result.

12. 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 non-serious adverse event terms

The safety record lists serious adverse events for the two cohorts. In Cohort 1, 0 of 33 participants at risk were recorded with a serious adverse event; in Cohort 2, 0 of 30 participants at risk were recorded with a serious adverse event. The record also lists 0 deaths in each cohort. These are counts in the registry record, not estimates of comparative risk.

For other adverse events, the record lists 5 participants in Cohort 1 and 7 in Cohort 2. It does not provide the event terms in the available safety summary, so the kinds of events represented by those counts cannot be described. The record lists no serious adverse-event terms. It also does not give further information about event timing, severity beyond the serious classification, relatedness, or participant-level overlap among events.

In general, safety counts need to be interpreted in relation to the population observed and the way events were collected and classified. A count of zero recorded events does not demonstrate that an event is impossible or that two regimens have equivalent safety. Here, allocation was nonrandomized and sequential, so a comparison between cohort counts would not by itself establish a treatment effect. The registry record does not report a statistical comparison of adverse events.

These figures describe the reported safety record only. They do not establish a broader safety profile or resolve uncertainty beyond the participants and events recorded.

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

The registry record establishes that a completed Phase 2, open-label, nonrandomized, sequential study evaluated HTX-011 in multimodal analgesic regimens after unilateral open inguinal herniorrhaphy. It specifies a primary endpoint of receiving no opioid rescue during 72 hours and identifies the Safety Population. It also distinguishes a cohort receiving the regimen with IV ketorolac from one without the listed ketorolac addition.

What the record does not establish is the primary endpoint result. No cohort counts or percentages for receiving no opioid rescue are reported, and no comparison estimate, confidence interval, or test result is available. Thus, the posted registry data do not show the observed frequency of rescue or the precision of an estimate. This is not evidence of a positive result, a negative result, or no difference; the outcome information required to make those distinctions is missing from the registry record.

The design also limits what a cohort comparison could mean. Because allocation was nonrandomized and sequential, the groups cannot be treated as randomized counterparts. The second regimen included IV ketorolac, but an observed difference, if one were reported, would not necessarily represent the causal effect of adding ketorolac. Other cohort differences and time-related factors may matter, and the record does not report enough detail to evaluate them.

The safety summary reports no serious adverse events or deaths in either cohort and lists other adverse events in both. These descriptive counts do not establish that one regimen is safer, and the registry record does not report event terms for the other adverse events.

Overall, the record supports a description of the study design, intended endpoint, and limited safety counts. It does not support a quantitative conclusion about the primary outcome, comparative effectiveness, or a causal treatment effect. The absence of a posted result should not be read as a finding that the endpoint was not met or that no difference existed.

14. Why This Trial Matters Statistically

The study addresses an outcome that is distinct from pain intensity: whether participants received opioid rescue during a defined postoperative period. For statistical interpretation, that distinction matters. A binary measure of rescue use, a total opioid-consumption measure, and a pain rating describe different features of the postoperative course; no one measure automatically substitutes for the others.

The record also illustrates why trial design is essential to reading group results. The cohorts were nonrandomized and sequential, and the second regimen added IV ketorolac to the stated combination. Those details determine how strongly a cohort contrast could support a causal interpretation. Even when an outcome is clinically interpretable, an estimate's meaning depends on how groups were formed and what sources of bias remain plausible.

Another statistical issue is transparency of results. The registry record states the primary endpoint and timeframe, but does not report the outcome counts, percentages, or uncertainty estimates. Without these, readers cannot assess the magnitude or precision of the primary result. A completed study record can therefore leave the central statistical question unanswered when results are not posted.

The safety counts provide a further example of why descriptive data should not be over-interpreted. Event counts can help characterize what was recorded, but they do not establish equivalence or comparative risk in a nonrandomized study. The record's lack of adverse-event terms also limits clinical interpretation of the other-event counts.

Statistically, the most important distinction is between a defined endpoint and a reported finding. The endpoint description makes clear what was intended to be measured; it does not reveal the observed data. This distinction prevents unsupported conclusions about opioid rescue, pain, or comparative regimen effects.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several limitations specific to this study follow directly from the registry record. First, the primary endpoint result is not reported: there are no cohort counts or percentages for participants receiving no opioid rescue during the 72-hour timeframe. The record also does not report a comparison estimate or its uncertainty. This prevents quantitative interpretation of the main endpoint.

Second, the study used nonrandomized, sequential allocation and no masking. The cohorts therefore are not a randomized control comparison. Any apparent difference between regimens could be influenced by characteristics of participants or by factors associated with the sequential design. The registry record does not provide enough information to assess the extent of such influences.

Third, the cohorts differed in the listed regimen because IV ketorolac was included in the second cohort. The record does not establish that all other aspects were identical or provide an analysis capable of isolating the contribution of ketorolac. A cohort contrast would therefore need cautious interpretation.

Additional limitations include the absence of a reported sample-size justification, statistical analysis plan, multiplicity strategy, and primary-endpoint missing-data procedures. Further definitions of the Safety Population and endpoint denominators are not reported in the registry record. The registry record lists several outcomes but does not provide results that would allow readers to compare or reconcile them.

The safety summary reports counts but no terms for the other adverse events. It does not provide detailed event descriptions or a statistical comparison. These omissions limit interpretation of the safety information as well as of the primary outcome.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase 2 Herniorrhaphy Study for Opioid Elimination — NCT03695367.
• Registry record last updated 2026-03-02; status last verified 2026-02.
• Results first posted 2021-07-02.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT03695367 is a completed Phase 2, open-label study of HTX-011 in a multimodal analgesic regimen following unilateral open inguinal herniorrhaphy. The registry record lists nonrandomized allocation, no masking, and a sequential model. Enrollment was 63; the recorded start was 2018-10-01 and primary completion was 2018-11-20. The sponsor was Heron Therapeutics.

The two cohorts received HTX-011, described as bupivacaine/meloxicam at 300 mg/9 mg via instillation, with a non-opioid multimodal analgesic regimen; the second cohort also received IV ketorolac. The primary endpoint was the percentage of participants receiving no opioid rescue during 72 hours in the Safety Population.

The registry record does not report the primary endpoint results or a statistical comparison. It lists 0 serious adverse events and 0 deaths in each cohort, with other adverse-event counts of 5 and 7, respectively. The nonrandomized, sequential design and missing outcome results limit interpretation of comparative effects.