Oral Treatment for Orthopaedic Post-operative Pain With Dexketoprofen Trometamol and Tramadol Hydrochloride: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Oral Treatment for Orthopaedic Post-operative Pain With Dexketoprofen Trometamol and Tramadol Hydrochloride (NCT01902134), a randomized phase 3 study. The primary outcome is SPID8 (Sum of Pain Intensity Differences Over 8 Hours).

2. Clinical Question

3. Trial Design

This was a phase 3, randomized, triple-masked, parallel-group study, listed as completed. Its title describes a placebo- and active-controlled evaluation of the analgesic efficacy and safety of oral dexketoprofen and tramadol as a fixed combination after elective unilateral total hip arthroplasty. The registry reports enrollment of 641. The study started in 2013-04, and primary completion was in 2014-02.

The interventions included placebo, single-dose tramadol, single-dose dexketoprofen, and a single dose of the fixed combination, as well as multiple-dose versions of the active treatments. Arm descriptions also specify sequences in which a single dose was followed by multiple doses. Some sequences began with placebo and then continued with an active treatment. The primary-endpoint description says the randomization arms, including placebo, were combined into four analysis groups: DKP/TRAM, dexketoprofen, tramadol, and placebo.

The primary outcome was SPID8 over 8 hours after the first dose. The registry also posts SPID48 and two responder outcomes for later or different assessment periods. These measures do not all address the same time window or outcome scale, so their comparisons should be read in their own context.

The registry record does not report details of the randomization procedure, allocation concealment, the exact masking arrangements, the original sample-size justification, or the protocol’s planned statistical analysis. Although triple masking is recorded, the registry does not specify which roles were masked. It also does not report a participant flow account or the analysis population definitions. Those omissions limit how fully the conduct and analysis can be evaluated from the registry entry alone.

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:

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: Intention-to-treat (ITT) population (which includes all patients randomized).

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as SPID8 (Sum of Pain Intensity Differences Over 8 Hours), measured over over 8 hours after the first dose.

The primary endpoint, SPID8, is a continuous summary of changes in pain intensity during the 8 hours after the first dose. Pain intensity was assessed using a 0-100 visual analogue scale, where 0 means no pain and 100 means the worst pain imaginable. Measurements were taken at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, and 8h after dosing. The differences from the initial pain-intensity assessment were weighted and summed across the period.

A higher SPID indicates greater pain relief. The endpoint therefore condenses repeated assessments over the first post-dose period into one continuous measure for each analysis group. This can make a treatment comparison more informative about the pattern of relief across the period than a single assessment at one time point. It also means the result depends on the specified measurement schedule and weighting method. The registry describes the calculation in general terms but does not report the precise weighting formula or how missing assessments were handled.

For the posted primary comparison, the combination group’s mean SPID8 was 246.9, compared with 151.1 for placebo. The unadjusted mean difference was 95.8, with a 95% confidence interval from 61.29 to 130.3. These summaries describe the average difference in the endpoint between the groups; they do not show how every participant’s pain changed, nor do they establish the clinical importance of a particular difference. The registry does not report a threshold defining a clinically important SPID8 difference.

7. Results Posted in the Registry

• DKP/TRAM: mean 246.90 versus 151.10 on control; difference 95.80 (95% CI 61.29 to 130.31), standardized effect d = 0.61; z-test p = <0.001.
• DEXKETOPROFEN: mean 208.80 versus 151.10 on control; difference 57.70 (95% CI 23.49 to 91.91), standardized effect d = 0.37; z-test p = <0.001.
• TRAMADOL: mean 204.60 versus 151.10 on control; difference 53.50 (95% CI 20.19 to 86.81), standardized effect d = 0.35; z-test p = 0.002.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

SPID48 (Sum of Pain Intensity Differences Over First 48 Hours of the Multiple-dose Phase)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • DEXKETOPROFEN: mean 1,678 versus 1,944 on control; difference -266.20 (95% CI -462.77 to -69.63), standardized effect d = -0.26; z-test p = 0.008.
  • TRAMADOL: mean 1,766 versus 1,944 on control; difference -178.10 (95% CI -364.43 to 8.23), standardized effect d = -0.18; z-test p = 0.061.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for DEXKETOPROFEN than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between TRAMADOL and the control. The interval gives the range of effects that remain compatible with the data.

Percentage of Responders According to PI-VAS (Pain Intensity - Visual Analogue Scale)

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • DEXKETOPROFEN: 76.6% (164/214) versus 90.1% (192/213) on control; risk difference -13.5 percentage points (95% CI -20.4 to -6.6), risk ratio 0.85 (0.78–0.93); unadjusted two-proportion z-test p = <0.001.
  • TRAMADOL: 82.2% (176/214) versus 90.1% (192/213) on control; risk difference -7.9 percentage points (95% CI -14.4 to -1.4), risk ratio 0.91 (0.85–0.98); unadjusted two-proportion z-test p = 0.018.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for DEXKETOPROFEN than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for TRAMADOL than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Percentage of Responders According to 50% Max TOTPAR (Total Pain Relief)

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • DKP/TRAM: 57.9% (92/159) versus 37.9% (61/161) on control; risk difference 20.0 percentage points (95% CI 9.2 to 30.7), risk ratio 1.53 (1.20–1.94); unadjusted two-proportion z-test p = <0.001.
  • DEXKETOPROFEN: 56.5% (91/161) versus 37.9% (61/161) on control; risk difference 18.6 percentage points (95% CI 7.9 to 29.3), risk ratio 1.49 (1.17–1.90); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for DKP/TRAM than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for DEXKETOPROFEN than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Across the posted secondary outcomes, the general pattern is that the fixed combination has higher observed values than the single agents on the multiple-dose responder endpoint and SPID48 summaries, while the corresponding uncertainty differs by endpoint and comparison. These outcomes provide additional context for the primary SPID8 result, but they address different periods or definitions of pain relief. They should not be treated as interchangeable replications of the primary endpoint.

The secondary results have limitations as evidence about the overall study question. The registry lists three secondary outcomes, but the analysis details field reports no analyses. The displayed pairwise comparisons are unadjusted, and the record does not state how many hypotheses were prespecified, whether a testing hierarchy was used, or whether any multiplicity adjustment was applied outside the posted information. When multiple outcomes and contrasts are examined, the chance of at least one apparently unusual result can increase. This is a general statistical concern, not proof that any particular result is spurious.

Consequently, the secondary estimates are best read as descriptive and exploratory evidence unless additional analysis details are available. Their confidence intervals communicate uncertainty for individual contrasts, but unadjusted intervals do not necessarily provide simultaneous coverage across all outcomes and comparisons. The pattern can be considered alongside the primary outcome, while keeping the primary endpoint’s 8-hour period distinct from the multiple-dose phase outcomes.

The secondary findings cannot establish that the combination is superior to either single agent without an appropriate direct comparison and an analysis plan that supports that claim. The registry posts comparisons of dexketoprofen and tramadol against the combination for SPID48 and the PI-VAS responder outcome, but these are unadjusted. Interpretation should therefore focus on the stated contrasts, their scales, and their uncertainty rather than extrapolating to an overall ranking of treatments.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• SPID48 (Sum of Pain Intensity Differences Over First 48 Hours of the Multiple-dose Phase)
• Percentage of Responders According to PI-VAS (Pain Intensity - Visual Analogue Scale)
• Percentage of Responders According to 50% Max TOTPAR (Total Pain Relief)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous: SPID8 is reported as a mean with a standard deviation for each group. A mean describes the group’s average endpoint value, while a standard deviation describes how much individual values vary around that average. A standard deviation is not the uncertainty interval for the mean. The mean difference compares the active group’s mean with the placebo group’s mean, with positive values indicating higher SPID8 in the active group. Since higher SPID indicates greater pain relief, a positive difference points toward greater average relief on this endpoint.

A confidence interval gives a range of values compatible with the observed data under the calculation’s assumptions. The 95% intervals reported for the primary mean differences are 61.29 to 130.3 for the combination, 23.49 to 91.91 for dexketoprofen, and 20.19 to 86.81 for tramadol. For each, the full interval is on the positive side of zero. This is one way to understand the direction and statistical precision of the posted comparisons. An interval is not a guarantee that the true value lies within its endpoints, and its width does not describe participant-to-participant variability; the standard deviations address that latter feature.

The p-values are reported as unadjusted. In general, a p-value measures how compatible the observed data are with a specified null hypothesis, given a statistical model. It does not measure the probability that the null hypothesis is true, the size of an effect, or whether an effect is clinically important. Here, the primary comparisons have unadjusted p-values of <0.001, <0.001, and 0.002. The registry record does not report a multiplicity procedure or the sponsor’s full statistical model, so these p-values should not be treated as evidence that accounts for every endpoint or comparison in the study.

The posted comparisons use placebo as the reference for the primary endpoint. The primary description states that the analysis combined randomization arms, including placebo, into four groups. The record does not report whether covariates were included, how deviations from the analysis population were handled, or whether the displayed comparisons match a prespecified primary analysis. The registry record does not report those details, so the displayed contrasts are most safely interpreted as the endpoint-specific group summaries and unadjusted comparisons available in the registry.

General statistical explanation: repeated measures can produce a useful summary endpoint, but the calculation depends on the timing and weighting of measurements. A summary such as SPID8 captures information from across the assessment period, but it can obscure whether differences were concentrated at particular times. The registry gives the assessment times and says the differences were weighted and summed. It does not report the detailed weighting formula or the approach to missing values within the repeated assessments.

General statistical explanation: unequal or unusually large variability can affect the precision of a comparison. When a continuous endpoint has substantial spread relative to the difference between group means, the estimated group contrast is less precise than it would be with less spread, all else equal. The posted standard deviations indicate appreciable variation in each group, while the confidence intervals show uncertainty in the estimated mean differences. The registry record does not report diagnostics for distributional assumptions, whether a transformation was considered, or whether any robust methods were used.

There are also binary secondary outcomes, reported as percentages of participants meeting responder definitions. For these, a risk difference expresses the difference between two proportions on the probability scale. A positive difference means a higher observed responder percentage in the group named in the comparison than in its reference group; a negative difference means a lower percentage. Confidence intervals communicate the uncertainty around that difference. The posted secondary comparisons are unadjusted, and no formal analyses are listed in the registry for those outcomes. General statistical explanation: binary-outcome summaries and continuous-outcome summaries use different scales, so the magnitudes should not be compared directly across endpoints.

The registry also reports planning illustrations based on observed effects. They use a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and effects set at stated fractions of the observed effect. For outcomes other than time-to-event outcomes, the figures represent participants per arm. These are planning scenarios rather than a report of the trial’s original design calculation. The registry record does not report the original sample-size assumptions or justification.

11. Confidence Intervals and Precision

Precision concerns how narrowly the data locate an estimated group difference. The primary mean-difference intervals provide one direct indication. For DKP/TRAM versus placebo, the estimate is 95.8 and the 95% confidence interval is 61.29 to 130.3. For dexketoprofen versus placebo, the estimate is 57.7 and the interval is 23.49 to 91.91. For tramadol versus placebo, the estimate is 53.5 and the interval is 20.19 to 86.81. Each interval is entirely above zero, but each still covers a range of possible mean differences rather than a single known value.

The interval for the combination is wider in absolute units than the intervals for the single agents, and the estimated difference is also larger. Width alone is not a measure of whether an effect is important. It reflects uncertainty in the estimated contrast, and it should be considered alongside the endpoint scale, group variability, and the range of values compatible with the data. The registry does not report a clinically important difference threshold for SPID8, so the confidence intervals cannot be classified against such a threshold from the record.

The group standard deviations, from 145.8 to 158.5, describe spread among observed SPID8 values. They are not confidence intervals. A confidence interval for a mean difference addresses uncertainty about the average contrast, whereas a standard deviation describes variation among individual endpoint values. Both are useful, but they answer distinct questions.

The secondary confidence intervals also show varying precision. For SPID48, the dexketoprofen-versus-combination mean difference is -266.2, with a 95% interval from -462.8 to -69.63; the tramadol-versus-combination difference is -178.1, with an interval from -364.4 to 8.226. For the responder outcomes, the posted risk-difference intervals likewise give a range of compatible contrasts. Because these are secondary, unadjusted comparisons, their intervals should be read as endpoint-specific rather than as a complete family-wise account of uncertainty.

Confidence intervals do not account automatically for every source of uncertainty in trial conduct or analysis. The registry record does not report detailed missing-data methods, the prespecified analysis populations, or multiplicity handling. Those omissions matter when judging how precisely the posted results answer the broader set of study questions.

12. 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, not a record of the study’s original design calculation. For these outcomes, the displayed quantities are participants per arm, not total participants across the study. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set at the stated fraction of the observed effect. The registry record does not report the trial’s original sample-size assumptions or justification.

The 80% power column gives the illustrated participants per arm for a design intended to have an 80% chance of detecting the specified effect under the listed assumptions, if that effect and the assumptions are correct. The 90% column gives the corresponding illustration for a design intended to have a 90% chance. These are planning concepts: power is calculated before observing the results and depends on the assumptions used. The figures are not observed power.

Each row changes the assumed effect size relative to the effect observed in the trial. Planning for 75% of the observed effect or 50% of the observed effect represents a smaller target difference than planning for 100% of the observed effect. Smaller effects generally require more participants to detect, if other assumptions remain the same. The values therefore increase as the assumed fraction of the observed effect decreases. A curve can be read as another way to trace how the planning requirement changes as the target effect changes; it does not add evidence about the treatment effect itself.

The illustrations are useful for understanding how assumptions about effect size and desired power influence study size. They should not be interpreted as validating the trial’s original enrollment, because the registry does not state the original design assumptions. They also do not establish that a future study will reproduce the observed effect.

13. 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 = 95.800; pooled standard deviation σ = 157.515.
2. n = 2 × (1.96 + 0.842)² × 157.515² / 95.800² = 42.4, rounded up to 43 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 <- 95.8                      # observed difference in means
sigma <- 157.514526793383                     # 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(1902134)
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 = 43 (80% power), 57 (90% power)
 75% of observed effect: n per arm = 76 (80% power), 101 (90% power)
 50% of observed effect: n per arm = 170 (80% power), 228 (90% power)
power.t.test: 43.4 
Simulated power at n = 43 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.

14. Multiplicity, Missing Data and Analysis Populations

The registry reports one primary endpoint and three secondary outcomes. Several groups and contrasts appear in the posted results. When a study evaluates multiple endpoints or makes multiple comparisons, interpreting each unadjusted p-value as if it were the only test can overstate the strength of the combined evidence. A multiplicity strategy may control the overall chance of false-positive findings, prioritize a testing sequence, or define which comparisons are confirmatory. The registry record does not report whether such a strategy was prespecified or used.

The primary comparisons are posted with unadjusted p-values. The secondary comparisons are also unadjusted, and the reported analyses field is empty for those outcomes. The record does not identify a hierarchical testing plan, family of hypotheses, or adjusted p-values. This absence does not establish that the study had no such plan; it means the approach is not reported in the registry record. Therefore, the nominal p-values and confidence intervals should be understood as results for individual comparisons, not as evidence adjusted for the full set of possible analyses.

Missing-data handling is also not reported. The registry gives group sizes for each posted endpoint, but it does not explain whether all randomized participants contributed to every analysis, why any observations were unavailable, or how missing pain assessments were handled when calculating SPID. For repeated measurements, missing assessments may affect a summed endpoint, and different assumptions about unavailable values can produce different estimates. The record does not report imputation procedures, sensitivity analyses, or the extent of missing outcome data.

Analysis populations are not defined in the registry entry. It does not specify whether the primary analysis followed an intention-to-treat principle, used a modified intention-to-treat population, or followed another definition. The record also does not report a participant flow account or details of exclusions from each analysis. These omissions prevent a full assessment of whether the displayed group summaries preserve the benefits of randomization and how robust they are to missingness or exclusions. They should be treated as limits of the registry information, not as evidence that any specific analysis choice was made.

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: soft tissue infection (1.9%), heart valve replacement (0.6%), vascular graft (0.6%), face oedema (0.6%), laryngeal oedema (0.6%).

The registry reports serious adverse events and other adverse events by treatment sequence. Serious adverse events were reported for 2 of 159 at risk in DKP/TRAM followed by DKP/TRAM, 3 of 161 in DKP followed by DKP, and 1 of 160 in TRAM followed by TRAM. Among the placebo-first sequences, serious adverse events were reported for 1 of 54 in placebo followed by DKP/TRAM, 0 of 53 in placebo followed by DKP, and 0 of 54 in placebo followed by TRAM. The registry record does not report deaths.

Other adverse events were reported for 15 of 159, 18 of 161, and 24 of 160 in the three active-from-the-start sequences, respectively. In the placebo-first sequences, the corresponding counts were 9 of 54, 2 of 53, and 5 of 54. The registry also lists serious-event terms and percentages, including soft tissue infection at 1.9% and several terms at 0.6%.

These counts describe reported events in the registry’s groups; they do not by themselves establish causation, comparative risk, or the clinical seriousness of every event term. The record does not provide event narratives, timing, attribution, or a detailed safety analysis plan. Comparisons should also take account of the different treatment sequences and group sizes.

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

The posted primary results show higher average SPID8 values in the active-treatment groups than in placebo over 8 hours after the first dose. The mean differences and their confidence intervals describe the size and precision of those observed group contrasts. Because the primary endpoint is a summary of repeated pain-intensity assessments, the result concerns average change over the specified assessment period, not an individual response at every time point.

These findings do not establish that every participant experienced greater relief, or that a particular difference was clinically important. The registry does not report a threshold for clinical importance on SPID8. It also does not provide the sponsor’s complete statistical analysis plan, multiplicity procedures, missing-data methods, or analysis population definitions. Those details are relevant to judging how the posted comparisons relate to all planned analyses.

The primary comparisons are each against placebo. They do not, by themselves, establish a definitive difference between the combination and either individual agent. Similar care is needed with the secondary outcomes: they address other periods and response definitions, and the posted results are unadjusted. The pattern can inform the statistical reading of the study, but it does not supply a single overall ranking of treatments.

The population and context are specific: acute pain after elective primary unilateral total hip arthroplasty, with the registry summary describing eligibility based on moderate to severe pain on the day after surgery. The findings should not be extended automatically to different procedures, pain conditions, dosing circumstances, or patient groups. The registry record does not provide enough detail to characterize those broader settings.

Safety counts are descriptive. They show the serious and other adverse events reported by treatment sequence, but the registry information does not establish whether events were caused by a study treatment or permit a complete comparative safety assessment. Overall, the results are evidence about defined outcomes in this trial record, with uncertainty and reporting limits that should remain part of their interpretation.

17. Why This Trial Matters Statistically

This trial is statistically useful because it illustrates the distinction between a continuous summary outcome and responder outcomes. SPID8 combines pain-intensity differences across repeated assessments, whereas responder measures classify participants according to specified criteria. The resulting estimates have different interpretations and scales. Reading them together requires attention to their time windows and definitions rather than treating them as equivalent measures.

The primary results also show why effect estimates and uncertainty intervals are more informative than a p-value alone. The mean differences describe the scale and direction of the observed contrasts, and the confidence intervals show a range of values compatible with each comparison under its assumptions. The standard deviations separately describe variation in the group outcomes. These statistics answer different questions and are not substitutes for one another.

The registry’s secondary outcomes demonstrate the importance of multiplicity. Multiple outcomes and comparisons can provide a broader picture, but unadjusted results do not automatically preserve an overall error rate across all tests. Without a reported testing strategy, secondary findings should be interpreted with more caution than a prespecified, multiplicity-controlled confirmatory analysis.

Finally, the planning illustrations show how sample-size needs depend on the effect a future study aims to detect. Planning for smaller effects requires more participants under the stated assumptions. The illustrations are distinct from the trial’s original design calculation, which is not reported. Together, these features make the record a useful example of how endpoint definition, uncertainty, multiple comparisons, and planning assumptions shape statistical interpretation.

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 entry leaves important design and analysis details unreported. It records randomization, triple masking, and a parallel-group model, but does not describe the randomization method, allocation concealment, or which study roles were masked. The primary analysis description says randomized arms were combined into four groups, but the record does not explain how that grouping relates to the planned analysis or report the sponsor’s full model.

The primary outcome combines repeated pain assessments, yet the exact weighting formula and handling of missing measurements are not reported. The registry also does not define analysis populations, give a participant flow account, or report the extent and reasons for missing outcome data. These gaps constrain assessment of the analysis set and robustness of the estimates.

The primary results include three comparisons with placebo, while the registry does not report a multiplicity plan. Secondary results are also posted as unadjusted comparisons, with no reported analyses listed. The available estimates therefore do not show whether the full family of planned comparisons was controlled or whether other analyses were conducted.

The record does not report a clinically important difference threshold for SPID8, so the clinical relevance of the numerical mean differences cannot be judged against a study-specific threshold. Nor does it report the original sample-size justification. The planning illustrations use observed effects and stated assumptions, and should not be mistaken for the rationale behind the enrollment target.

Safety information is limited to event counts, at-risk counts, and selected serious-event terms. The record does not provide event timing, attribution, narratives, or detailed comparative safety analyses. These limitations describe what cannot be established from the registry record; they do not imply that the omitted analyses or procedures were absent.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Oral Treatment for Orthopaedic Post-operative Pain With Dexketoprofen Trometamol and Tramadol Hydrochloride — NCT01902134.
• Registry record last updated 2016-03-07; status last verified 2016-02.
• Results first posted 2015-04-01.
• 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

The registry describes a completed phase 3 randomized, triple-masked, parallel-group study of oral dexketoprofen, tramadol, their fixed combination, and placebo for moderate to severe acute pain after elective unilateral total hip arthroplasty. Enrollment was 641. The primary endpoint was SPID8 over 8 hours after the first dose; the posted mean differences versus placebo were positive for all three active groups, with unadjusted confidence intervals entirely above zero.

Three secondary outcomes were also posted, including SPID48 and responder measures. Their comparisons are unadjusted and address different outcome periods or definitions. The registry reports adverse-event counts by treatment sequence but does not report deaths. Detailed multiplicity, missing-data, analysis-population, and original sample-size planning methods are not reported in the registry record. Interpretation should therefore remain tied to the posted outcomes, comparisons, and their stated uncertainty.