Phase 2 Dose-Ranging Study of SKY0402 for Prolonged Postoperative Analgesia in Subject Undergoing Hemorrhoidectomy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 2 Dose-Ranging Study of SKY0402 for Prolonged Postoperative Analgesia in Subject Undergoing Hemorrhoidectomy (NCT00529126), a randomized phase 2 study. The primary outcome is Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) at Rest (NRS-R) Pain Intensity Scores From 0 Through 72 Hours.

2. Clinical Question

The clinical question is about pain intensity over time, rather than a single pain rating. The NRS asks participants to rate current pain on a scale from 0 to 10, where 0 means no pain and 10 means the worst possible pain. The AUC combines measurements across the stated interval into a single measure with units of scale*hrs.

The registry describes a randomized, triple-masked, parallel-group study and lists postoperative pain as the condition. The record does not report the detailed enrollment criteria, the actual timing or frequency of pain assessments, or the specific protocol for administering the study treatments. It also does not report the original statistical comparison plan. Those missing details limit how specifically the posted group summaries can be connected to the intended clinical question.

3. Trial Design

This was a Phase 2, randomized, triple-masked, parallel-group, active-control, dose-ranging study. The official title describes it as multicenter. The study status is completed, and the registry lists enrollment of 100. The recorded start was 2007-09, and primary completion was 2007-12.

The study evaluated a single administration of SKY0402 at three dose levels: 300mg, 225mg, and 75mg. The active-control group received bupivacaine HCl; the brief summary describes the comparison as against 75 mg of bupivacaine HCl. The registry does not report the bupivacaine dose in the arm description itself. The listed group sizes for the primary outcome are 25.0, 25.0, 24.0, and 26.0, respectively.

The primary outcome was the AUC of NRS pain intensity at rest from 0 through 72 hours. The registry describes participants resting in a position that did not worsen postoperative pain and remaining in that position for at least 5 minutes before responding to the pain question. The outcome is reported as a mean with a standard deviation.

The record lists two outcome measures, including a secondary outcome concerning participants with adverse events through 72 hours or serious adverse events through 30 days. One secondary outcome is posted. The registry record does not report the allocation concealment method, the exact masking roles, detailed treatment procedures, the original sample-size justification, or the full analysis populations. It also does not report a sponsor analysis among the outcome analyses; the recalculated comparisons are not a substitute for an analysis plan or results that are not 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

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 Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) at Rest (NRS-R) Pain Intensity Scores From 0 Through 72 Hours, measured over 0 to 72 hours.

The primary endpoint is the area under the curve of pain intensity at rest, based on Numeric Rating Scale ratings collected from 0 through 72 hours after treatment. The scale asks how much pain a participant is having at that moment, with response anchors of 0 for no pain and 10 for the worst possible pain. Participants were to rest in a position that did not exacerbate postoperative pain for at least 5 minutes before responding.

An AUC represents accumulated measurements across a specified period. In general, it can capture both the level of a measure and how that level evolves over time, rather than relying on one assessment alone. For this endpoint, the reported unit is units on a scale*hrs. A larger AUC corresponds to more accumulated pain-rating burden across the assessment interval, assuming the measurement process was applied consistently across groups.

The registry reports the mean and standard deviation for each group. A mean is a summary of the group’s observed values; the standard deviation describes how spread out individual values are around that mean. These summaries do not show the pattern of scores at each assessment time or how much individual participants’ pain changed. The registry record does not report the actual assessment schedule, the handling of missing pain ratings, or a fuller definition of the endpoint calculation.

Rest pain is distinct from pain during movement or activity. The endpoint is therefore specific to the resting-position assessment described in the registry and should not be read as a complete measure of every aspect of postoperative pain or recovery.

7. Results Posted in the Registry

• SKY0402 225mg: mean 172.00 versus 175.00 on control; difference -3.00 (95% CI -91.74 to 85.74), standardized effect d = -0.02; z-test p = 0.947.
• SKY0402 75mg: mean 225.00 versus 175.00 on control; difference 50.00 (95% CI -50.38 to 150.38), standardized effect d = 0.28; z-test p = 0.329.
• Bupivacaine HCl: mean 331.00 versus 175.00 on control; difference 156.00 (95% CI 60.48 to 251.52), standardized effect d = 0.90; z-test p = 0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous: each participant’s pain ratings over time are represented by an AUC value, and the registry reports a mean and standard deviation for each group. A continuous outcome can take a range of values, so analysis often focuses on differences in group means. Such a difference is easiest to interpret when the endpoint’s direction is clear. Here, a larger AUC means a larger accumulated pain-intensity score, while a smaller AUC means a smaller one.

What does a mean difference represent?

A mean difference compares the average endpoint value in one group with the average in a reference group. The posted recalculated estimates use SKY0402 300mg as the reference. The estimate of -3.0 for SKY0402 225mg is the difference between its mean and the reference mean, as reported in the recalculation. The estimates for SKY0402 75mg and bupivacaine HCl are 50.0 and 156.0, respectively. A positive estimate indicates a higher mean in the named comparison group than in the reference group; a negative estimate indicates a lower mean. These are unadjusted estimates, not adjusted treatment effects.

What do the standard deviations describe?

The standard deviation describes variation among observed participant values within a group. The reported standard deviations are 173.0 for SKY0402 300mg, 146.0 for SKY0402 225mg, 185.0 for SKY0402 75mg, and 175.0 for bupivacaine HCl. They indicate that individual AUC values vary around the group means. A standard deviation is not the same as a standard error or a confidence interval: it describes the spread of observations, while uncertainty in a mean or mean difference depends on both the spread and the amount of information in the analyzed group.

How should the p-values be read?

A p-value describes how compatible the observed data are with a specified null hypothesis under the assumptions of the analysis. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The recalculated unadjusted p-values are 0.947 for SKY0402 225mg, 0.329 for SKY0402 75mg, and 0.001 for bupivacaine HCl, each compared with SKY0402 300mg. The record does not report a multiplicity adjustment, so these should not be interpreted as adjusted results from a prespecified family of comparisons.

Why do confidence intervals matter alongside p-values?

A confidence interval gives a range of values compatible with the data and the assumptions used to calculate it. It conveys the uncertainty in an estimate and shows which effect sizes remain consistent with the observed information. The intervals for the SKY0402 dose comparisons include no difference and also include effects in either direction. The bupivacaine HCl interval is entirely above no difference. A confidence interval does not indicate that every value inside it is equally likely, and it cannot account for biases or design limitations not represented in the calculation.

What is the role of the reference group?

Interpretation depends on which group is treated as the reference. In the posted recalculations, SKY0402 300mg is the control reference. The trial description separately identifies bupivacaine HCl as the active control, which is not the same reference used for these recalculated estimates. This distinction affects the wording and direction of each mean difference. The registry record does not report a sponsor analysis that resolves this difference in framing.

What can randomization and masking contribute?

Randomization is intended to make treatment groups comparable on average with respect to factors known and unknown at enrollment. Masking can reduce the influence of treatment knowledge on participant reports and study assessments. The registry labels the study randomized and triple-masked, but the specific roles masked and the randomization procedures are not reported. General statistical reasoning therefore supports recognizing these design features without assuming details about how they were implemented or whether masking was maintained.

What is not captured by these summaries?

Group means and standard deviations do not describe the full distribution of AUC values, changes within individuals, or the time course of pain ratings. They also do not explain how missing measurements, additional analgesia, protocol deviations, or exclusions were handled. These details are not reported in the registry record. In general, over-dispersion matters when outcome variability is greater than the analysis assumes, because uncertainty estimates can then be too small. The record does not provide an over-dispersion assessment for this endpoint, and no claim about that issue can be made from the posted summaries alone.

10. Confidence Intervals and Precision

The recalculated mean difference for SKY0402 225mg versus SKY0402 300mg is -3.0, with a confidence interval from -91.74 to 85.74. The interval is wide relative to the point estimate and includes both a lower AUC and a higher AUC than the reference. The estimate is therefore not precise enough to identify the direction or size of the difference from the posted summary statistics.

For SKY0402 75mg versus SKY0402 300mg, the estimated mean difference is 50.0, with a confidence interval from -50.38 to 150.4. This interval also includes no difference and values in either direction. For bupivacaine HCl versus SKY0402 300mg, the estimate is 156.0, with a confidence interval from 60.48 to 251.5. That interval lies above no difference, while still spanning a range of possible effect sizes.

A confidence interval describes uncertainty under the calculation’s assumptions. It does not show the range containing most individual participants’ outcomes, and it does not correct for bias, missing data, or unreported design features. The registry record does not state the confidence level used for these intervals, so one should not infer a level that is not reported.

The standard deviations also indicate substantial variation in individual AUC values: 173.0, 146.0, 185.0, and 175.0 across the groups in the order reported. The recalculated comparisons use the posted group summaries and do not incorporate an adjusted model. Taken together, the estimates should be read as uncertain group-level comparisons rather than precise predictions for individual participants or proof of equivalence between groups.

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 justification. They assume a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. For each comparison, the assumed effect is the stated fraction of the observed effect: 100%, 75%, or 50%. The figures are participants per arm, not total participants or total events.

The 80% power column gives an illustrative number of participants per arm for a design with an 80% chance of detecting the assumed effect under the stated planning assumptions, if that effect and those assumptions were correct. The 90% power column gives the corresponding illustration for a 90% chance. These are planning probabilities, not guarantees about what a future study will find. This is not observed power.

Smaller assumed effects require more participants per arm to detect under the same planning framework. For the SKY0402 225mg comparison, planning for 100% of the observed effect gives 44,691 participants per arm for 80% power and 59,829 for 90% power; planning for 75% gives 79,451 and 106,362, and planning for 50% gives 178,763 and 239,313. The very small observed difference is reflected in these large illustrations.

For SKY0402 75mg, the corresponding figures are 202 and 270 for 100%, 358 and 479 for 75%, and 805 and 1,078 for 50%. For bupivacaine HCl, they are 20 and 27 for 100%, 35 and 47 for 75%, and 79 and 105 for 50%. These figures are comparison-specific; they are not a proposed design for a new trial. The original study’s own sample-size assumptions and justification are not reported in the registry record.

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 = -3.000; pooled standard deviation σ = 160.070.
2. n = 2 × (1.96 + 0.842)² × 160.070² / -3.000² = 44,690.6, rounded up to 44,691 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 <- -3                      # observed difference in means
sigma <- 160.070297057262                     # 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(529126)
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 = 44,691 (80% power), 59,829 (90% power)
 75% of observed effect: n per arm = 79,451 (80% power), 106,362 (90% power)
 50% of observed effect: n per arm = 178,763 (80% power), 239,313 (90% power)
power.t.test: 44691.6 
Simulated power at n = 44,691 per arm: 0.797 (20000 replicates)

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

13. Multiplicity, Missing Data and Analysis Populations

The posted results include several comparisons involving the primary endpoint, but the registry record does not report a multiplicity strategy. When multiple hypotheses are tested, the chance of at least one false-positive finding can increase if each test is treated independently at the same significance threshold. Adjustments or a prespecified hierarchy can address this concern, but no such procedure is described in the record. The recalculated p-values are unadjusted, so they should be interpreted as unadjusted comparisons rather than as family-wise conclusions.

The registry lists two outcome measures and one posted secondary outcome concerning participants with adverse events through 72 hours or serious adverse events through 30 days. It reports no outcome analyses. Details such as whether the primary endpoint was designated before study completion, whether secondary outcomes were tested formally, and how outcomes were prioritized are not reported in the registry record.

Missing-data handling is also not reported. The group sizes listed for the primary endpoint may identify the records contributing to the posted summaries, but the registry does not explain whether all randomized participants were analyzed, how incomplete pain-rating records were handled, or whether any participants were excluded from the endpoint calculation. No assumptions about imputation, censoring, or analysis population should be inferred.

The record does not report an intention-to-treat population, a per-protocol population, or a safety population definition. It also does not provide a participant flow description or reasons for any difference between enrolled, treated, and analyzed participants. Those omissions matter because analysis choices can affect both the estimate and its uncertainty. The available recalculations are simple, unadjusted comparisons of posted summary statistics and cannot replace a prespecified analysis that is absent from the registry record.

More generally, a complete appraisal of missingness considers how much outcome information is absent, why it is absent, and whether missingness may differ across groups or relate to pain. Without those details, the direction and magnitude of any missing-data effect cannot be determined.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

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: rectal hemorrhage (4.2%).

The safety summary reports the number at risk and the number affected for serious adverse events and other adverse events. For serious adverse events, the record lists 0 affected among 25 at risk in the SKY0402 High Dose group, 0 among 25 in the SKY0402 Middle Dose group, 1 among 24 in the SKY0402 Low Dose group, and 0 among 26 in the Bupivacaine HCl group. These are counts, not comparative risk estimates.

For other adverse events, the listed affected counts are 0 among 25 in the SKY0402 High Dose group, 7 among 25 in the SKY0402 Middle Dose group, 7 among 24 in the SKY0402 Low Dose group, and 10 among 26 in the Bupivacaine HCl group. The registry also lists rectal hemorrhage as a top serious adverse event term with 4.2%. The record does not provide the context needed to link that percentage to a particular group or to establish its denominator.

Deaths are not reported in the registry record. The safety outcome refers to adverse events through 72 hours and serious adverse events through 30 days, but further detail on event severity, relatedness, timing, and ascertainment is not available in the posted summary. Counts alone do not show whether an event was treatment-related or whether groups differ in safety.

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

The results describe group-level pain AUC values after a single administration of SKY0402 or bupivacaine HCl in a Phase 2 dose-ranging study. The means show lower recorded AUC values in the SKY0402 300mg and 225mg groups than in the SKY0402 75mg and bupivacaine HCl groups. The recalculated comparison estimates quantify differences relative to SKY0402 300mg, not relative to bupivacaine HCl.

The uncertainty varies across comparisons. The intervals for SKY0402 225mg and 75mg versus the SKY0402 300mg reference include no difference and values in either direction. The interval for bupivacaine HCl versus the reference lies above no difference. These results describe the posted data and their recalculated uncertainty; they do not establish that one treatment is clinically preferable, nor do they demonstrate equivalence or non-equivalence between treatments.

The endpoint measures resting pain intensity accumulated across 0 through 72 hours. It does not directly measure pain during activity, long-term outcomes, overall recovery, or every aspect of analgesic use. The registry record does not report the pain-assessment schedule, the impact of additional pain medication, or the handling of missing assessments. Those omissions limit the interpretation of what the AUC means for the full postoperative experience.

The safety counts are descriptive and cover the stated adverse-event windows. They are not adjusted comparisons and do not establish causation. The record also does not report a detailed analysis plan, full participant flow, or sponsor analyses. As a result, the posted findings should be understood as a limited statistical account of one completed Phase 2 trial, not a comprehensive assessment of treatment effects or safety.

16. Why This Trial Matters Statistically

This trial illustrates how the choice of reference group shapes interpretation. The clinical study description identifies bupivacaine HCl as the active control, while the recalculated mean differences use SKY0402 300mg as the reference. A reader can misread a comparison if the reference is not made explicit. Statistical summaries are meaningful only when their direction and comparator are clear.

The endpoint also demonstrates the distinction between an individual assessment and a summary across time. An AUC combines repeated pain ratings into one quantity, which can be useful for describing accumulated symptom burden across a defined interval. At the same time, it conceals the timing of pain and variation among individuals. Means and standard deviations provide useful summaries but do not reproduce the full course of pain ratings.

Precision is another important lesson. The recalculated estimates for the two lower SKY0402 doses have intervals that encompass both lower and higher AUC values than the reference. A nonsignificant p-value does not establish that groups are the same, and a point estimate should not be interpreted without its uncertainty. The planning illustrations further show how sample-size requirements depend on the effect size one aims to detect; they are not evidence of the trial’s achieved power or original design rationale.

Finally, the registry record distinguishes what is available from what remains undocumented. Randomization and masking are listed, but implementation details, missing-data procedures, multiplicity handling, and sponsor analyses are not reported. These are central to interpreting clinical trial results, especially when analyses are recalculated from summary statistics rather than presented as the trial’s own statistical analysis.

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 offers limited information about the conduct of the trial and the analysis. It does not report detailed eligibility criteria, recruitment procedures, the allocation method, how masking was implemented, or whether masking was maintained. The official title describes a multicenter study, but site-level information is not included in the available record.

The primary endpoint summary does not show pain values at individual assessment times. The registry record does not report the number or schedule of ratings, how the AUC was calculated from those ratings, or how missing ratings were handled. It also does not describe rescue analgesia or other factors that could influence observed pain reports. The endpoint therefore cannot be interpreted as a full account of pain experience across recovery.

The posted comparisons are unadjusted recalculations from summary statistics, and the registry lists no outcome analyses. The original analysis plan, multiplicity approach, analysis populations, and sample-size justification are not reported. The recalculated comparisons also use SKY0402 300mg as their reference, rather than presenting the active-control comparison with bupivacaine HCl as the reference.

The safety record provides counts but limited event-level detail. It does not report treatment relatedness, group-specific context for the listed serious adverse event term percentage, or death counts; deaths are not reported in the registry record. These limitations mean that the summaries support description of posted values, but not a complete evaluation of efficacy or safety.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Phase 2 Dose-Ranging Study of SKY0402 for Prolonged Postoperative Analgesia in Subject Undergoing Hemorrhoidectomy — NCT00529126.
• Registry record last updated 2021-03-04; status last verified 2021-02.
• Results first posted 2013-08-06.
• 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

NCT00529126 is a completed Phase 2, randomized, triple-masked, parallel-group, active-control dose-ranging study of SKY0402 after hemorrhoidectomy. The registry lists enrollment of 100 and describes a single administration of three SKY0402 dose levels alongside bupivacaine HCl. The study period is recorded as starting in 2007-09, with primary completion in 2007-12.

The primary outcome is the mean AUC of NRS pain intensity at rest from 0 through 72 hours. Posted group means range from 172.0 for SKY0402 225mg to 331.0 for bupivacaine HCl. Recalculated unadjusted comparisons use SKY0402 300mg as the reference. The registry lists one secondary outcome and does not report outcome analyses, the original sample-size rationale, or key details of missing-data and multiplicity handling.

Safety counts are posted for serious and other adverse events. These counts and the recalculated pain comparisons are descriptive evidence from the registry record and should be interpreted in light of the missing methodological and analysis details.