A Study of Tapentadol Immediate-Release in the Treatment of Patients With Acute Pain From Bunionectomy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Tapentadol Immediate-Release in the Treatment of Patients With Acute Pain From Bunionectomy (NCT01516008), a randomized phase 3 study. The primary outcome is Sum of Pain Intensity Differences (SPID) Over 48 Hours.

2. Clinical Question

3. Trial Design

This was a phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study of tapentadol immediate-release for acute pain after bunionectomy. The record describes it as a bridging study for Korea. The study was completed. Its start is recorded as 2012-01, and its primary completion as 2013-02.

Participants were assigned to placebo, tapentadol immediate-release 50 mg, or tapentadol immediate-release 75 mg. The posted primary analysis included an intent-to-treat population defined as randomized participants who received at least 1 dose. The primary outcome used last-observation-carried-forward imputation for missing values. Further details of randomization procedures, treatment duration, dose timing, adherence, and the original analysis plan are not reported in the registry record.

The primary endpoint was SPID over 48 hours. The registry also lists outcomes including time to first rescue medication use, pain-intensity reduction and response rates at specified time points, SPID and pain-relief measures over other intervals, and Patient Global Impression of Change at 72 hours. Results for those secondary outcomes are not included in the posted outcome figures, so their estimates cannot be evaluated from this record.

The reported primary analyses used ANCOVA to compare each tapentadol group with placebo. The registry reports the group sizes, mean SPID values, standard deviations, adjusted mean differences, confidence intervals, and p-values. It also provides counts for serious and other adverse events. Details of the trial's own sample-size rationale and any interim analyses are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: 353 participants were randomly allocated to the 3 treatment arms. 352 participants received at least 1 dose of the study drug and were included in the intent-to-treat (ITT) analysis set.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-treat (ITT) analysis set, which included all randomized participants with at least 1 dose of study medication. Last-observation-carried-forward imputation method used for missing values.

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 Sum of Pain Intensity Differences (SPID) Over 48 Hours, measured over 48 hours.

The primary endpoint, sum of pain-intensity differences over 48 hours (SPID48), combines repeated pain ratings into a time-weighted measure. Pain intensity was recorded on an 11-point numerical rating scale, from 0=no pain to 10=pain as bad as you can imagine. At each assessment, pain-intensity difference was the baseline rating minus the current rating. The time-weighted sum of those differences formed SPID48.

The stated scale ranges from -480, described as worst, to 480, described as best. A higher SPID indicates greater pain relief. Because the endpoint incorporates ratings over time, it represents both the direction and persistence of change across the assessment interval rather than a single pain rating at one time point.

General statistical context: a repeated-measure summary can provide a single outcome for comparing groups over a defined interval, but it also depends on the measurement schedule and the way missing ratings are handled. In this trial, the registry specifies last-observation-carried-forward imputation for missing values in the intent-to-treat analysis set. The record does not report further details of the assessment schedule or sensitivity analyses for missing data.

7. Results Posted in the Registry

• Tapentadol IR 50 mg: mean 131.70 versus 65.30 on control; difference 66.40 (95% CI 37.10 to 95.70), standardized effect d = 0.58; z-test p = <0.001.
• Tapentadol IR 75 mg: mean 154.50 versus 65.30 on control; difference 89.20 (95% CI 57.60 to 120.80), standardized effect d = 0.73; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: SPID48 is a score rather than a count of events or a binary response. The registry reports group means and standard deviations, then presents ANCOVA estimates of the mean difference between each active-treatment group and placebo. A mean difference expresses the contrast in the endpoint's original score units. A positive difference favors the tapentadol group for this endpoint because higher SPID indicates greater pain relief.

What does ANCOVA contribute?

General statistical context: analysis of covariance (ANCOVA) estimates a group contrast while accounting for other variables included in the model. This can make the reported contrast differ from a simple subtraction of the two displayed group means. The registry identifies ANCOVA as the method and labels its estimates as net mean differences. It does not identify the covariates or give enough model detail to reconstruct the adjusted estimates independently. The adjusted values and their confidence intervals should therefore be read as the registry's reported analysis, not as calculations from the group means alone.

How should the recalculations be understood?

The recalculated mean differences use the posted means and standard deviations to form simple, unadjusted comparisons of each dose with placebo. They are useful as a check on the direction and approximate scale of the posted group summaries, but they do not reproduce the ANCOVA analysis. The recalculated intervals quantify uncertainty under that unadjusted approach. They should not be presented as the sponsor's estimates, nor should differences between the adjusted and unadjusted results be attributed to a particular cause when the model details are not reported. The record does not flag a discrepancy.

What does a p-value say?

General statistical context: a p-value measures how incompatible 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 registry reports p < 0.001 for both ANCOVA comparisons and for the unadjusted recalculations. These values indicate strong statistical evidence against a zero difference under the respective analyses, but do not describe the full range of plausible effect sizes. The confidence intervals help convey that range.

Why does variability matter?

The standard deviations describe how spread out individual SPID scores were within each group. The posted values are 121.0 for placebo, 107.2 for tapentadol immediate-release 50 mg, and 124.0 for tapentadol immediate-release 75 mg. General statistical context: greater variability makes a group mean less precise when the amount of information is otherwise similar. Differences between group means must be interpreted alongside this spread and the number of observations contributing to each group estimate.

General statistical context: over-dispersion is especially relevant to count outcomes when observed variation exceeds what a simple count model expects. The primary endpoint is a continuous score, not a count, so that count-data issue is not the central modeling concern. Relevant considerations include the distribution of the score, the covariates used in ANCOVA, and the handling of missing measurements; the registry does not report all details needed to assess these points.

How does the analysis population affect interpretation?

The registry defines the primary intent-to-treat analysis set as randomized participants with at least 1 dose of study medication. This is not a record of every randomized participant regardless of treatment receipt. The number analyzed in each group is reported alongside the endpoint values. The registry says missing values were handled with last-observation-carried-forward imputation. General statistical context: this method carries a participant's most recent observed outcome forward to fill a later missing assessment. It can preserve observations in the analysis, but it relies on an assumption that the carried-forward value is a reasonable substitute for the unobserved value. The record does not report sensitivity analyses that would show how alternative missing-data assumptions affect the findings.

Overall, the reported ANCOVA estimates are the principal adjusted results, while the recalculations are unadjusted checks based on summary data. Both approaches yield positive mean differences and p-values below 0.001 for the two dose-versus-placebo comparisons. Their distinct methods should remain clear when discussing the estimates.

10. Confidence Intervals and Precision

The registry reports 95% confidence intervals for the ANCOVA mean differences. For tapentadol immediate-release 50 mg versus placebo, the adjusted mean difference is 76.35, with an interval from 51.0 to 101.7. For 75 mg versus placebo, the adjusted mean difference is 90.60, with an interval from 65.1 to 116.1. Both intervals lie above zero, in keeping with the positive estimated differences and reported p-values of <0.001.

General statistical context: a confidence interval gives a range of estimates compatible with the observed data under the analysis and its assumptions. It conveys uncertainty around an estimate, rather than guaranteeing that the true effect lies within a particular interval. The width reflects both the amount of information and the variability in the outcome, as well as features of the model. These intervals concern mean differences on the SPID48 scale; they are not intervals for individual participants' outcomes.

The recalculated, unadjusted 95% intervals are 37.1 to 95.7 for the 50 mg comparison and 57.6 to 120.8 for the 75 mg comparison. They are based on a different calculation from the sponsor's ANCOVA intervals and should not be treated as interchangeable. The registry does not report a clinical-importance threshold for SPID48, so the intervals cannot be used from this record alone to determine whether the estimated differences meet such a threshold.

Confidence intervals also do not resolve uncertainty about generalizability, missing-data assumptions, or outcomes not reported in the registry. They describe precision for the analyzed endpoint and comparison, conditional on the analysis used.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm for 80% power and participants per arm for 90% power. The endpoint comparisons are between a tapentadol group and placebo, and these are per-arm planning illustrations, not total event counts. For each comparison, the rows use 100%, 75%, or 50% of the observed effect as the effect assumed for planning. The corresponding entries indicate the number of participants per arm under each effect assumption and target power.

The 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 the stated fraction of the observed effect. These calculations use the observed effect as their starting point and are not the trial's original sample-size justification; the trial's own design assumptions are not reported in the registry record.

General statistical context: power is the probability that a specified analysis will detect an effect of a specified size if that effect is present, under the assumptions used for planning. The 80% and 90% columns describe different target probabilities of detecting the assumed effect; the higher target generally requires more participants. The rows also illustrate that smaller assumed effects need more participants than larger assumed effects. These values are planning illustrations, not observed power, and they do not establish whether the completed trial had a particular probability of detecting its actual effect.

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 = 66.400; pooled standard deviation σ = 114.117.
2. n = 2 × (1.96 + 0.842)² × 114.117² / 66.400² = 46.4, rounded up to 47 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 <- 66.4                      # observed difference in means
sigma <- 114.117072496595                     # 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(1516008)
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 = 47 (80% power), 63 (90% power)
 75% of observed effect: n per arm = 83 (80% power), 111 (90% power)
 50% of observed effect: n per arm = 186 (80% power), 249 (90% power)
power.t.test: 47.3 
Simulated power at n = 47 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. Analyses Reported by the Sponsor

The registry reports the sponsor's primary comparisons using ANCOVA. The adjusted mean difference is 76.35 for tapentadol immediate-release 50 mg versus placebo, with a 95% confidence interval of 51.0 to 101.7 and p < 0.001. For 75 mg versus placebo, the adjusted mean difference is 90.60, with a 95% confidence interval of 65.1 to 116.1 and p < 0.001.

The recalculated comparisons are simple, unadjusted analyses from the posted group summaries. They give mean differences of 66.4 and 89.2, respectively, with their own confidence intervals and p-values. These are not alternative versions of the ANCOVA results: they answer the comparison using a different calculation. The registry does not flag a discrepancy between the posted analysis and recalculations. The sponsor's ANCOVA results remain the reported primary analysis; the unadjusted calculations serve as supplementary checks and should not replace the registry's analysis.

The registry does not report enough detail about the ANCOVA covariates to reproduce its adjusted estimates from the summary data. Interpretation should therefore retain the distinction between the adjusted sponsor analysis and the unadjusted recalculation.

14. Multiplicity, Missing Data and Analysis Populations

The primary outcome is SPID over 48 hours, and the registry reports a comparison of each tapentadol dose with placebo. It also lists secondary outcomes covering rescue medication use, pain-intensity changes and response rates at several assessment times, SPID and pain-relief summaries over other intervals, and a patient global impression score. Although the record lists these outcomes, it does not report their result estimates in the outcome results.

Multiplicity arises when many statistical comparisons or outcomes are examined. General statistical context: with more tests, the chance of at least one apparently unusual result can increase if no adjustment is made. The registry record does not report whether the primary comparisons or secondary analyses were adjusted for multiplicity, how the primary endpoint was protected within a testing hierarchy, or which secondary results were considered confirmatory. The reported p-values should therefore be interpreted as the values for the stated comparisons, without assuming an unreported multiplicity procedure.

The primary analysis set included randomized participants who received at least 1 dose. The record specifies last-observation-carried-forward imputation for missing values. It does not report the amount or pattern of missing primary outcome data, reasons for missingness, or sensitivity analyses using alternative assumptions. General statistical context: carrying the last observed value forward can make an analysis dependent on how plausible that carried value is for the later time point. If outcomes change after the last measurement, this assumption may not reflect the unobserved course.

The record does not report whether analyses were conducted in other populations, such as all randomized participants regardless of receiving a dose, or whether results were robust across alternative analysis choices. Details of the statistical analysis plan, including any planned interim analyses, are not reported in the registry record. These omissions limit assessment of the full analysis strategy, but they do not alter what the posted primary estimates state.

15. 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: procedural site reaction (0.8%), essential tremor (0.8%).

The registry reports serious adverse events for 0 participants in the placebo group, 2 in the tapentadol immediate-release 50 mg group, and 0 in the 75 mg group. The corresponding numbers at risk were 114, 121, and 117. The record lists procedural site reaction and essential tremor among the top serious adverse event terms, each reported as 0.8%. It does not identify which group or groups contributed to those terms in the information.

Other adverse events affected 22 participants in the placebo group, 58 in the 50 mg group, and 74 in the 75 mg group; the reported numbers at risk were 114, 121, and 117, respectively. The registry record does not provide further detail in these figures about event severity, duration, or individual event attribution. Death counts are not reported in the registry record.

General statistical context: adverse-event counts describe reported events within the recorded groups and should be read with their group sizes and the definitions used for collection. These counts alone do not establish that a treatment caused an event, nor do they provide a complete comparison of safety. The figures are descriptive; the registry's posted safety information should not be interpreted as medical advice.

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

The posted primary results show higher mean SPID48 values in both tapentadol groups than in the placebo group. The registry's ANCOVA estimates also report positive adjusted mean differences for each dose-versus-placebo comparison, with 95% confidence intervals above zero and p-values of <0.001. On the stated scale, higher SPID represents greater pain relief. These findings describe the trial's primary endpoint in its specified analysis population and under its stated missing-data method.

The results do not establish the size of benefit that an individual participant would experience. Group means and mean differences describe averages, while individual outcomes can vary. The registry does not report a clinically important difference threshold for SPID48, so statistical evidence of a difference cannot on its own establish its clinical importance.

The primary analyses compare each dose with placebo; they do not provide a direct statistical test comparing the two doses. Nor do these results answer every question about pain over time, rescue medication, patient-rated change, or safety. Although the registry lists secondary outcomes, their result estimates are not reported in the posted results addressed.

Interpretation is also bounded by the analysis population and missing-data approach. The primary set included randomized participants who received at least 1 dose, and missing values were imputed using last observation carried forward. The record does not report sensitivity analyses that might show how alternative assumptions affect the estimates. The findings should be understood as results from this completed study of Korean patients with acute pain after bunionectomy, not as a guarantee of an outcome in other settings or populations.

17. Why This Trial Matters Statistically

This trial illustrates how a repeated pain rating can be summarized into a continuous, time-weighted endpoint and compared across randomized groups. SPID48 combines pain-intensity differences over a defined interval, and the registry explains the direction of interpretation: higher scores indicate greater pain relief. The result is therefore interpretable as a difference in average endpoint score, rather than a difference in the proportion crossing a response threshold.

It also demonstrates why the analysis method matters. The registry's ANCOVA estimates are adjusted mean differences, while the recalculated values use unadjusted group summaries. Both approaches report positive differences, but they are not the same estimand or calculation. Keeping that distinction visible helps readers avoid treating a simple summary-data check as a reproduction of the sponsor's analysis.

The confidence intervals add information beyond the p-values by showing the range of estimates compatible with each analysis. The sample-size illustrations connect the observed effects with planning assumptions and show how planning for smaller effects requires more participants. They are not evidence of the trial's original design rationale or of its observed power.

Finally, the registry record includes important boundaries on interpretation: an intent-to-treat definition requiring at least 1 dose, last-observation-carried-forward imputation, limited reporting of the analysis plan, and no posted estimates for the listed secondary outcomes. Reading the numerical findings alongside these details is essential for understanding what the primary comparison addresses and what remains unresolved.

18. 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 covariates used in the ANCOVA model, so the adjusted estimates cannot be independently reconstructed from the posted summary statistics. It also does not provide the trial's original sample-size justification or design assumptions, or details of any interim analyses. The planning illustrations based on observed effects should not be mistaken for the original trial plan.

For missing data, the record specifies last-observation-carried-forward imputation but does not report the amount or pattern of missingness, reasons for missing measurements, or sensitivity analyses. The result may depend on the assumptions underlying this approach. The composition of the intent-to-treat set is defined, but analyses using other populations are not reported in the registry record.

The registry lists multiple secondary outcomes but does not report their outcome estimates in the results addressed. It also does not report the multiplicity strategy, a clinically important difference threshold for SPID48, or a direct statistical comparison between the two tapentadol doses. These omissions limit conclusions about secondary outcomes, clinical importance, and differences between doses.

Further participant characteristics, detailed dosing and assessment procedures, and additional safety context are not reported in the registry record. The posted safety counts do not provide the full event-level information needed to assess severity, timing, or attribution. The trial's Korean bridging context and bunionectomy population should also be kept in view when considering whether the results apply to other populations or pain settings.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Study of Tapentadol Immediate-Release in the Treatment of Patients With Acute Pain From Bunionectomy — NCT01516008.
• Registry record last updated 2014-04-28; status last verified 2014-03.
• Results first posted 2014-04-28.
• 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.

22. Record Summary

This completed phase 3 randomized, double-blind, placebo-controlled, parallel-group study evaluated tapentadol immediate-release 50 mg and 75 mg for acute pain after bunionectomy in Korean patients. The primary endpoint was SPID over 48 hours, analyzed in an intent-to-treat set of randomized participants who received at least 1 dose, with last-observation-carried-forward imputation for missing values.

The registry reports positive ANCOVA mean differences versus placebo for both doses, each with a 95% confidence interval above zero and p < 0.001. The record also lists secondary outcomes and reports serious and other adverse-event counts, but does not provide results for the listed secondary endpoints in the posted outcomes addressed. Important analysis-plan details, including the original sample-size rationale and multiplicity approach, are not reported in the registry record.