A Study to Look at Tapentadol Oral Solution in Children and Adolescents in Pain: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Look at Tapentadol Oral Solution in Children and Adolescents in Pain (NCT02081391), a randomized phase 3 study. The primary outcome is For the US FDA: The Total Amount of Supplemental Opioid Analgesic Medication Used Within the First 12 Hours After First Intake of Investigational Medicinal Product (IMP) [Tapentadol Oral Solution or Placebo].

2. Clinical Question

3. Trial Design

The registry describes a phase 3, randomized, quadruple-masked, parallel-group trial of tapentadol oral solution and placebo. The trial is marked completed. Its stated purpose was to evaluate tapentadol oral solution based on the total amount of supplemental opioid analgesic used over 12 hours or 24 hours after initiation of study medication in children and adolescents who had undergone surgery expected to cause moderate to severe pain during opioid treatment.

The registry records an enrollment of 216. This enrollment figure describes the trial record as a whole; it is not the same as the primary analysis population. The primary endpoint analysis was conducted in a Full Analysis Set subset of 160 participants aged 2 to less than 18 years. The registry says that participants who did not receive the allocated medication by error were evaluated as allocated, following the intention-to-treat principle.

The primary endpoint was total supplemental opioid analgesic medication used within 12 hours after the first dose, expressed as mg/kg of intravenous morphine equivalents. The registry identifies this as the United States Food and Drug Administration primary endpoint and as a secondary endpoint for the European Medicines Agency Pediatric Committee. Other registered outcomes include later supplemental opioid use, palatability and acceptability assessments, age-specific pain measures, and global impressions of change.

The trial record lists tapentadol oral solution concentrations of 4 mg/mL and 20 mg/mL, as well as placebo. The arm description gives age-dependent dosing information for tapentadol and describes placebo administration every 4 hours up to 72 hours. Details of the sequence used to generate random allocation, how masking was maintained, and the original sample-size justification 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: A total of 216 participants (or parents/caregivers) gave informed consent to participate in the trial, 180 of these participants were allocated to study drug (investigational medicinal product = IMP) and 175 participants received IMP (56 participants received placebo oral solution and 119 participants received tapentadol oral solution).

12-hour Treatment

Reasons for not completing this period:

24-hour Treatment and Trial Completion

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set; subset of 160 participants from 2 to less than 18 years included in the analysis. If by error a participant did not receive the allocated medication, the participant was evaluated as allocated following the intention-to-treat principle.

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: Baseline characteristics are reported separately for 160 participants aged 2 to less than 18 years (included in the Full Analysis Set for the EU PDCO and the US FDA) and for 15 participants aged from birth to less than 2 years (included in the Full Analysis Set for the US FDA). All participants completed 12 hours of treatment.

6. Primary Endpoint

The registry lists the primary outcome as For the US FDA: The Total Amount of Supplemental Opioid Analgesic Medication Used Within the First 12 Hours After First Intake of Investigational Medicinal Product (IMP) [Tapentadol Oral Solution or Placebo], measured over Up to 12 hours.

The endpoint measures the total amount of supplemental opioid analgesic medication used during the first 12 hours after the first intake of investigational medicinal product. The registry expresses supplemental opioid use in mg/kg of intravenous morphine equivalents. It reports a least-squares mean for each group, with standard errors, and a mean difference for the comparison.

This endpoint captures additional opioid medication used after the assigned study treatment began. It is distinct from the pain-intensity measures listed among the other outcomes, which use age-specific scales. The endpoint was selected to address opioid use over a defined period after study medication began, consistent with the stated study purpose of evaluating supplemental analgesic use over 12 hours or 24 hours. The registry record does not explain the rationale for choosing this endpoint over other possible measures or give a threshold for a clinically important difference.

In general, a least-squares mean is a model-based estimate of a group mean, while a standard error describes the estimated precision of that mean. The registry identifies the primary outcome as a continuous measure and reports the group comparison as a mean difference. The outcome’s scale and direction matter for interpretation: a lower amount represents less supplemental opioid medication recorded during the assessment window, but the endpoint alone does not describe pain scores, patient experience, or the clinical importance of a difference.

7. Results Posted in the Registry

• Tapentadol (From 2 to <18 Years): mean 0.08 versus 0.13 on control; difference -0.05 (95% CI -0.09 to -0.01), standardized effect d = -0.42; z-test p = 0.025.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports an ANOVA comparison of mean final values, with the result expressed as a mean difference. The outcome is continuous: supplemental opioid use is recorded on a quantitative scale in mg/kg of intravenous morphine equivalents. Comparing group means is one way to describe how the average recorded amount differs between the randomized groups. The estimate’s sign depends on the order of subtraction; the reported negative estimate is for tapentadol relative to placebo.

What does the least-squares mean represent?

In general, a least-squares mean is a model-based estimate of a group mean, rather than necessarily the simple arithmetic average of all individual observations. It can be used when a statistical model forms the basis of the comparison. The registry gives least-squares means of 0.08 mg/kg for tapentadol and 0.13 mg/kg for placebo. It does not report the full model specification, the covariates included, or whether any additional adjustments were used. Those details are not reported in the registry record, so the model cannot be reconstructed from the summary alone.

How should the standard errors be read?

In general, a standard error describes uncertainty in an estimated mean; it is not the spread of individual participants’ values. The reported standard errors are 0.01 for tapentadol and 0.02 for placebo. They contribute to assessing how precisely the means have been estimated. They do not show the range of individual supplemental opioid amounts, and they should not be interpreted as though every participant’s outcome lies close to the group mean.

What does the ANOVA comparison test?

In general, ANOVA is a method for comparing means within a statistical model. The registry reports an ANOVA mean difference of -0.05 mg/kg, a 95% confidence interval from -0.09 to 0, and p = 0.040. A p-value describes how compatible the observed result is with a specified null model under the test’s assumptions; it is not the probability that the null hypothesis is true, nor a measure of clinical importance. The registry record does not report the complete model specification or the assumptions checked for this analysis.

What is the role of the recalculation?

The unadjusted recalculation uses the posted group summaries to estimate a mean difference and its uncertainty. It gives -0.05 mg/kg, a 95% confidence interval from -0.094 to -0.006, and p = 0.025. The recalculation estimates the standard deviation approximately from the group standard errors, as identified in its calculation details. It is therefore not a replacement for the registry-reported ANOVA result, which is the trial’s reported analysis. The registry’s recalculated result and its ANOVA result are close in estimated mean difference, while their reported uncertainty and p-values differ.

Why can analyses differ?

In general, an unadjusted calculation from summary statistics may not reproduce a model-based analysis. The two approaches can rely on different assumptions, model specifications, handling of observations, or precision inputs. The record does not supply enough methodological detail to identify the reason for the difference in the interval endpoints and p-values. The recalculation is a descriptive cross-check based on the posted summaries, not evidence that the trial used the same calculation.

What does randomization contribute?

In general, random allocation aims to make treatment groups comparable on average with respect to factors known and unknown at the start of a trial. The registry identifies the study as randomized and parallel-group, and states that participants who mistakenly did not receive allocated medication were evaluated as allocated for the primary analysis. This is consistent with the intention-to-treat principle as described in the record. The registry does not report the randomization sequence method, allocation concealment procedure, or any stratification factors; these details are not reported in the registry record.

10. Confidence Intervals and Precision

The registry-reported ANOVA estimate is a mean difference of -0.05 mg/kg, with a 95% confidence interval from -0.09 to 0. The interval communicates uncertainty about the estimated difference under the analysis used. Its upper endpoint is reported as 0, so the registry’s displayed interval reaches the no-difference value after rounding. The reported p-value is 0.040. These figures should be read together rather than treating the p-value as a complete description of the result.

The unadjusted recalculation gives a 95% confidence interval from -0.094 to -0.006 and p = 0.025. Its interval lies below 0, but it is based on approximate dispersion inferred from the posted standard errors and is not the trial’s reported ANOVA analysis. The recalculated interval is more finely expressed than the registry-reported interval; the differing endpoints should not be read as proof of a substantive contradiction. The registry record does not explain the rounding or model details underlying the reported ANOVA interval.

In general, a confidence interval represents a range of estimates compatible with the data and the assumptions of the method. A narrower interval indicates greater statistical precision than a wider interval on the same scale, but it does not indicate whether the result is clinically important. Precision is also not the same as certainty about individual responses. The registry does not report a clinically important difference threshold for supplemental opioid use, so the interval cannot be used to classify the estimated effect as clinically important or unimportant.

The primary analysis population is a subset of the trial enrollment, and the registry gives no additional detail about missing endpoint observations, imputation, or sensitivity analyses. Those omissions limit assessment of how robustly the uncertainty estimate reflects incomplete outcome data.

11. Planning a Similar Trial: Sample Size

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

The planning figures describe participants per arm, not total events. They are illustrations based on the observed effect, not the trial’s original sample-size calculation. 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 a stated fraction of the observed effect. The trial’s own original design assumptions and sample-size justification are not reported in the registry record.

The column for 80% power gives the planned number of participants per arm under those assumptions for a study designed to have an 80% chance of detecting the specified effect if that effect is real and the assumptions hold. The 90% power column uses a higher target chance of detection under the same general planning framework. These are prospective planning quantities, not measures of how much power the completed trial actually had.

For planning at 100% of the observed effect, the figures are 89 participants per arm for 80% power and 118 participants per arm for 90% power. Planning for 75% of the observed effect gives 157 participants per arm for 80% power and 210 participants per arm for 90% power. Planning for 50% of the observed effect gives 353 participants per arm for 80% power and 472 participants per arm for 90% power. The increasing requirements illustrate the general relationship: smaller effects are harder to detect and need more participants, all else being equal.

These calculations are not observed power. They are planning illustrations derived from the observed effect and stated assumptions. They do not show the probability that the trial’s conclusion is correct, and they do not replace interpretation of the estimate, confidence interval, analysis population, or trial-reported result. The registry does not report whether these planning assumptions were used when the original trial was designed.

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 = -0.050; pooled standard deviation σ = 0.118.
2. n = 2 × (1.96 + 0.842)² × 0.118² / -0.050² = 88.1, rounded up to 89 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 <- -0.05                      # observed difference in means
sigma <- 0.118439216905828                     # 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(2081391)
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 = 89 (80% power), 118 (90% power)
 75% of observed effect: n per arm = 157 (80% power), 210 (90% power)
 50% of observed effect: n per arm = 353 (80% power), 472 (90% power)
power.t.test: 89.1 
Simulated power at n = 89 per arm: 0.798 (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-reported trial analysis is an ANOVA comparison of final values. It gives a mean difference of -0.05 mg/kg, a 95% confidence interval from -0.09 to 0, and p = 0.040. This is the analysis to use when describing the result reported by the trial record.

The separate recalculation from the posted group summaries gives a mean difference of -0.05 mg/kg, a 95% confidence interval from -0.094 to -0.006, and p = 0.025. It is unadjusted and uses an approximate standard deviation derived from the posted standard errors. It is useful as a check on the summary statistics, but it does not recreate the trial’s ANOVA model.

The registry does not identify this analysis as a separate sponsor-authored publication or provide a fuller analysis report. The registry record reports no discrepancy flag for the comparison. If a recalculation conflicts with the trial’s own analysis, the trial’s reported analysis takes precedence; the recalculation should be described as a secondary, approximate check rather than substituted for the reported result.

14. Multiplicity, Missing Data and Analysis Populations

The record lists 16 outcome measures and identifies 12 secondary outcomes as posted. Several secondary outcomes concern supplemental opioid use at later intervals, palatability and acceptability, age-specific pain scores, and global impressions of change. These outcomes involve multiple questions and, in some cases, different age-defined measures. Considering several outcomes can increase the chance of obtaining at least one nominally noteworthy result by chance if no adjustment is made.

The registry record does not report whether the trial used a multiplicity adjustment, a hierarchical testing strategy, a prespecified order of testing, or another method to control error across outcomes. It also does not describe which outcomes were included in any multiplicity family. Therefore, the reported p-value for the primary endpoint should be understood as the result for that recorded comparison; the registry does not establish how it fits into a broader confirmatory testing plan.

The primary endpoint population is described as the Full Analysis Set, consisting of a subset of 160 participants aged 2 to less than 18 years. The registry says that a participant who did not receive the allocated medication by error was evaluated as allocated, following the intention-to-treat principle. It does not describe the amount or pattern of missing primary endpoint data, how missing values were handled, whether any participants were excluded after allocation, or whether sensitivity analyses were performed. These details are not reported in the registry record.

The original statistical analysis plan, detailed model specification, and justification for the analysis population are also not reported in the registry record. Without those details, it is not possible to assess whether the posted analysis exactly followed a prespecified plan or how robust it was to alternative missing-data assumptions. This uncertainty does not change the values recorded for the result, but it limits the depth of methodological evaluation possible from the registry entry.

15. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: abdominal abscess (0.9%), seizure (0.9%).

For participants aged 2 to less than 18 years, the registry reports serious adverse events in 2 of 108 participants in the tapentadol group and 0 of 52 participants in the placebo group. The overall serious-event entry for this age range is 2 of 160. The registry reports 0 deaths in each of these groups. The serious-event terms listed as occurring most often are abdominal abscess and seizure, each reported as 0.9%.

For participants from birth to less than 2 years, the registry reports 0 serious adverse events among 11 participants assigned to tapentadol and 0 among 4 assigned to placebo. It reports 0 deaths for both groups. Other adverse events are reported for 6 of 11 participants in the tapentadol group and 3 of 4 in the placebo group. In the 2 to less than 18 years groups, other adverse events are reported for 61 of 108 participants assigned to tapentadol and 26 of 52 assigned to placebo.

These are registry counts, not adjusted comparisons. The record does not provide exposure-adjusted rates, event timing, severity details beyond the serious-event designation, or a complete account of event attribution in the information available for this summary. The listed serious-event figures should not be interpreted as proving that an event was caused by study treatment or that no other safety concerns occurred.

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

The primary result describes supplemental opioid analgesic medication used during the first 12 hours after the first dose in participants aged 2 to less than 18 years. The registry reports lower mean use in the tapentadol group than in the placebo group and a negative mean difference for tapentadol relative to placebo. The trial-reported ANOVA result is a mean difference of -0.05 mg/kg, with a 95% confidence interval from -0.09 to 0 and p = 0.040.

This is evidence about one measure over one stated assessment period in a defined analysis population. It is not a direct report of pain intensity, quality of recovery, or patient satisfaction. The registry lists separate pain scales for different age ranges and other outcomes, but their results are not all described in the primary endpoint record. No threshold for clinical importance is reported, so the estimate cannot be classified from this record alone as a meaningful or unmeaningful difference to patients.

The result does not establish what happened in participants from birth to less than 2 years for the primary endpoint, because that group is not included in the stated primary analysis. Nor does the primary result answer whether group outcomes differed over later time intervals, on the age-specific pain scales, or for palatability and acceptability. Those questions require their own outcome results and methods.

The statistical comparison also does not prove that every participant in one group used less supplemental medication than every participant in the other. Group means describe average outcomes, and the standard errors describe uncertainty in those estimates rather than individual variation. The confidence interval and p-value quantify aspects of statistical uncertainty under the analysis assumptions; they do not measure the probability that the treatment works or determine clinical value.

Overall, the registry records a statistically significant result under the trial’s reported ANOVA test, with a small reported mean difference in the stated units. Its interpretation should remain limited to the registered population, endpoint, assessment window, and analysis. The registry does not supply all information needed to judge clinical importance or the robustness of the result.

17. Why This Trial Matters Statistically

This trial is statistically informative because its primary outcome is not a pain score but the amount of additional opioid analgesic medication used after study treatment began. That makes the endpoint’s meaning specific: it reflects supplemental medication use over a defined interval, expressed in standardized morphine-equivalent units. Readers should distinguish that question from whether pain intensity changed or whether participants found the medicine acceptable.

The registry also makes clear that the primary analysis population differs from the overall enrollment. The primary analysis applies to participants aged 2 to less than 18 years, while safety information is recorded for a younger age group as well. Keeping these populations separate avoids extending a result beyond the group actually included in the primary endpoint analysis.

There is also a useful distinction between the trial-reported ANOVA result and a simple recalculation from group summaries. The estimated mean difference is the same at the displayed two-decimal precision, while the confidence intervals and p-values differ. This illustrates why summary statistics can support a check of the reported result but may not reproduce a model-based analysis, especially when dispersion has to be approximated and the full model is not reported.

Finally, the result shows why statistical significance and clinical interpretation are separate tasks. The registry reports a p-value below 0.05, but it gives no clinical-importance threshold for this endpoint and does not report enough detail to assess every aspect of missing data or multiplicity. A careful reading retains the observed estimate and its uncertainty without treating a single test as a complete account of participant experience or treatment value.

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 analysis details unreported. It does not give the full ANOVA model specification, the randomization sequence method, allocation concealment procedures, or details of any stratification. The original sample-size justification and design assumptions are also not reported in the registry record. Consequently, the planning illustrations based on the observed effect cannot be treated as evidence about the trial’s original design.

The primary endpoint analysis is limited to the Full Analysis Set subset aged 2 to less than 18 years. The registry does not report enough detail to assess missing primary outcome data, imputation, exclusions after allocation, or sensitivity analyses. It also does not state whether multiplicity was controlled across the primary and secondary outcomes. These gaps make it harder to assess robustness and the broader confirmatory context for the reported p-value.

The recalculation is approximate because the standard deviation is inferred from the posted standard errors. It is not a substitute for the registry-reported ANOVA analysis, and the full model information needed to reproduce that analysis is not reported. The confidence interval in the reported analysis ends at 0 as displayed, while the recalculated interval is more finely stated; the record does not explain the rounding or modeling details behind that difference.

The registry lists multiple outcomes across age ranges, but the available primary result does not establish findings for those other outcomes. The record also does not give a clinical-importance threshold for supplemental opioid use. Therefore, the statistical result can be described, but its clinical importance cannot be determined from the registry information alone.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Study to Look at Tapentadol Oral Solution in Children and Adolescents in Pain — NCT02081391.
• Registry record last updated 2020-01-18; status last verified 2020-01.
• Results first posted 2020-01-18.
• 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, randomized, quadruple-masked, parallel-group phase 3 trial of tapentadol oral solution versus placebo for post-operative acute pain in children and adolescents. The recorded enrollment is 216. The primary United States Food and Drug Administration endpoint was supplemental opioid analgesic use within 12 hours after the first study dose, expressed in mg/kg of intravenous morphine equivalents.

For the Full Analysis Set aged 2 to less than 18 years, the registry reports least-squares means of 0.08 mg/kg for tapentadol and 0.13 mg/kg for placebo. Its ANOVA comparison reports a mean difference of -0.05 mg/kg, a 95% confidence interval from -0.09 to 0, and p = 0.040. A separate unadjusted recalculation is approximate and is not the trial’s reported analysis. The record does not report a clinical-importance threshold or all details needed to evaluate the analysis plan, missing data, and multiplicity.