A Safety and Efficacy Study for Tapentadol (CG5503) Extended Release for Patients With Painful Diabetic Peripheral Neuropathy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Safety and Efficacy Study for Tapentadol (CG5503) Extended Release for Patients With Painful Diabetic Peripheral Neuropathy (NCT00455520), a randomized phase 3 study. The primary outcome is Change From Baseline (at Randomization) in Average Pain Intensity on an 11-point Numerical Rating Scale (NRS) Over the Last Week of the Double-blind Maintenance Period at Week 12.

2. Clinical Question

The registry record describes a randomized-withdrawal study intended to evaluate both effectiveness and safety. The primary outcome is a continuous pain score, so the main contrast is between group mean changes rather than the proportion crossing a threshold. The posted group summaries and sponsor analysis both indicate a difference favoring a smaller pain score in the tapentadol ER group. That comparison is a description of the trial results, not by itself a conclusion about how an individual patient would respond or whether the result applies to other populations.

3. Trial Design

This was a phase 3, randomized, parallel-group study with quadruple masking. The registry record lists enrollment as 395 and status as completed. The study started in 2007-04, with primary completion in 2008-08. Johnson & Johnson Pharmaceutical Research & Development, L.L.C. is listed as the sponsor.

The trial is described as a randomized-withdrawal study. The intervention arm received CG5503 extended release twice daily at dose levels of 100, 150, 200, or 250mg for up to 15 weeks. The placebo arm received matching placebo twice daily for 12 weeks. The primary endpoint was measured during the double-blind maintenance period at Week 12. The registry record does not describe the sequence of study periods or the rules used to enter the maintenance period in enough detail to reconstruct the full participant pathway.

The primary analysis population was the Intent to Treat analysis set as defined in the record: randomized subjects who took at least one dose during the double-blind maintenance period, with the exception of 3 subjects enrolled twice. This definition is narrower than simply saying everyone enrolled, and it is the population specified for the primary endpoint. The record does not report the trial's original sample-size assumptions, the planned statistical analysis details beyond the reported ANCOVA, or the method used for handling missing endpoint values.

The study evaluated pain intensity alongside secondary measures relating to pain improvement, patient global impression, health status, sleep latency, and pain impact. The registry record identifies 6 outcome measures, with 5 secondary outcomes posted. These outcomes provide broader context, but the primary interpretation centers on the prespecified change in average pain intensity.

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: The study consisted of a 2-week screening period followed by a 3-week open-label phase where all subjects received tapentadol extended release (ER) and were titrated to an optimal dose, and a 12-week double-blind phase where subjects were randomly assigned to receive tapentadol ER or placebo.

Open Label Tapentadol Extended Release

Reasons for not completing this period:

Double Blind Tapentadol ER vs Placebo

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent to Treat (ITT) analysis set included all randomized subjects who took at least one dose of study medication during the double blind maintenance period with the exception of 3 subjects who were enrolled in the study twice.

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 Change From Baseline (at Randomization) in Average Pain Intensity on an 11-point Numerical Rating Scale (NRS) Over the Last Week of the Double-blind Maintenance Period at Week 12, measured over Baseline and 12 weeks.

The primary endpoint was change from baseline at randomization in average pain intensity over the last week of the double-blind maintenance period at Week 12. Pain was assessed twice daily. Participants were asked to rate pain experienced over the previous 12 hours on an 11-point Numerical Rating Scale: 0 indicated no pain, and 10 indicated pain as bad as you can imagine. The endpoint is reported as a mean and standard deviation for each group.

Change from baseline is used to describe how scores at the maintenance endpoint compare with scores at the start of the relevant period. A between-group comparison of these changes helps distinguish the observed course in the intervention group from the course in the placebo group. The difference in group means does not describe every participant's experience, and the group average can conceal variation in individual responses.

A continuous pain score retains information across the scale rather than reducing the outcome to whether a participant did or did not reach a chosen threshold. That makes it useful for comparing average changes, while also making the interpretation dependent on the scale and the way the endpoint period is defined. The registry record identifies the measurement window and scale, but does not report a threshold for what would count as a clinically important difference. The statistical estimate therefore describes the size and uncertainty of the group contrast; it does not alone establish the importance of that contrast to patients.

7. Results Posted in the Registry

• Tapentadol ER: mean -0.10 versus 1.30 on control; difference -1.40 (95% CI -1.81 to -0.99), standardized effect d = -0.67; z-test p = <0.001.

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.

The Number of Patients Achieving at Least 30% Improvement in Pain Score at Week 12 of the Double-blind Maintenance Period From the Start of the Open Label Period.

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Tapentadol ER: 53.6% (105/196) versus 42.2% (81/192) on control; risk difference 11.4 percentage points (95% CI 1.5 to 21.3), risk ratio 1.27 (1.03–1.57); unadjusted two-proportion z-test p = 0.025.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Tapentadol ER than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change Over the Last Week of the Maintenance Period at Week 12

• 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:
  • Tapentadol ER: 63.8% (113/177) versus 37.8% (68/180) on control; risk difference 26.1 percentage points (95% CI 16.1 to 36.1), risk ratio 1.69 (1.36–2.10); 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 Tapentadol ER than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Change From Baseline in EuroQol-5 (EQ-5D) Health Status Index to Week 12

• 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:
  • Tapentadol ER: mean 0.70 versus 0.60 on control; difference 0.10 (95% CI 0.05 to 0.15), standardized effect d = 0.42; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Tapentadol ER than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Across the posted secondary outcomes, the overall descriptive pattern generally favors tapentadol ER: the reported response-based measures and the health-status measure have estimates in the direction of more favorable outcomes in that group. This broad pattern is consistent with the direction of the primary mean pain result, but the secondary measures capture different aspects of participants' experience and do not all answer the same question.

Secondary endpoints can help assess whether the primary result sits alongside changes in patient-perceived improvement, health status, sleep, and pain impact. They provide complementary context, not independent confirmation in a strict statistical sense. The registry record identifies 5 secondary outcomes, while only a subset have posted results in the record used for this analysis. The absence of a posted result for an outcome should not be interpreted as a null result; it means that result is not reported in the registry record.

Unadjusted secondary comparisons carry less weight because testing multiple outcomes increases the chance of obtaining apparently favorable findings by chance. A multiplicity plan can control or otherwise account for this issue, but such a plan is not reported in the registry record. The posted unadjusted p-values and intervals are useful descriptions of each comparison, yet they should be interpreted cautiously as exploratory unless a prespecified hierarchy or adjustment method is documented.

The secondary results also have their own populations and denominators, which differ across outcomes. Missing observations or outcome-specific eligibility can affect those summaries. The record does not provide enough information to determine how missing data were handled for each secondary measure. Accordingly, the strongest statistical focus remains the defined primary endpoint and its reported sponsor analysis, with the secondary pattern serving as supporting context rather than a replacement for the primary comparison.

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

• The Number of Patients Achieving at Least 30% Improvement in Pain Score at Week 12 of the Double-blind Maintenance Period From the Start of the Open Label Period.
• Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change Over the Last Week of the Maintenance Period at Week 12
• Change From Baseline in EuroQol-5 (EQ-5D) Health Status Index to Week 12
• Change From Baseline in Sleep Latency Time in Hours Over the Last Week of the Maintenance Period at Week 12.
• Change From Baseline in Brief Pain Inventory (BPI) Total Pain Score Over the Last Week of the Maintenance Period at Week 12.

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: each participant's pain rating is expressed on a numerical scale, and the registry reports group means and standard deviations. A mean summarizes the center of a distribution. A standard deviation describes how dispersed individual scores are around that mean. Neither statistic reveals the full shape of the data, but together they support a straightforward unadjusted comparison of group averages.

What does the mean difference represent?

The recalculated mean difference compares the tapentadol ER group mean change with the placebo group mean change. Its sign depends on the order of subtraction used for the contrast. In this analysis, the estimate is -1.4, reflecting the lower mean change in the tapentadol ER group relative to placebo. The units remain points on the pain scale. This estimate is unadjusted: it is calculated from the posted group summary values rather than from a participant-level model controlling for other variables.

A difference in group means is not the same as a difference in the experience of every participant. Participants can have changes above or below their group average, and the standard deviations show that outcomes vary within both groups. The mean contrast is a compact summary of the average separation; it does not indicate how many people had a particular response unless a separate threshold outcome is analyzed.

How should the confidence interval be read?

A confidence interval expresses the precision of an estimate under a specified statistical procedure. A narrower interval indicates greater precision than a wider interval, all else being comparable. The interval for the unadjusted mean difference runs from -1.815 to -0.985. Because the interval does not include zero, the data are inconsistent with a zero difference at the corresponding confidence level under the method's assumptions. It does not mean that there is a stated probability that the true value lies in this particular interval, nor does it guarantee that future results will fall within it.

The registry also reports the sponsor's ANCOVA estimate and interval. ANCOVA is a regression-based method that can compare groups while accounting for specified covariates or baseline values. The posted description identifies the method and labels the parameter as a mean difference in final values, but the registry record does not report which covariates were included or the detailed model specification. The sponsor's estimate therefore represents the reported analysis, while the summary-statistic recalculation is a separate, unadjusted comparison.

What does the p-value contribute?

A p-value measures how unusual the observed data, or data more extreme, would be under a statistical model that assumes no group difference. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of a difference. The primary recalculation and sponsor analysis both report p < 0.001. The estimate and confidence interval provide information about direction and magnitude that the p-value alone cannot provide.

General statistical interpretation also depends on the analysis assumptions. For a continuous endpoint, these can include the suitability of the model for the data, independence of observations, and how variability is represented. The registry record does not report diagnostics or a detailed assessment of these assumptions. The reported standard deviations and group means describe the posted summaries but cannot establish that every model assumption was met.

Why do the binary outcomes use different summaries?

Some secondary outcomes count participants meeting a response definition. For those outcomes, the comparison can be expressed as a difference in proportions, unlike the mean difference used for the continuous primary endpoint. The posted recalculations include risk differences and confidence intervals. These summarize the observed separation in response proportions and its uncertainty. The registry record also lists risk ratios and odds ratios for some secondary comparisons, but these are distinct scales and should not be interchanged with the absolute difference.

Binary outcomes discard some information compared with a continuous score because participants are classified according to whether they cross a threshold. They can nevertheless be easier to interpret when the threshold itself is meaningful and clearly defined. The secondary response definitions are stated in the outcome titles, but the registry record does not report a multiplicity adjustment for these analyses.

Why can extra variation matter?

General statistical explanation: over-dispersion occurs when observed variability in count or binary data is greater than a model assumes. If it is ignored, standard errors can be too small and confidence intervals too narrow. The primary endpoint is a continuous mean, and the registry record does not report an over-dispersion analysis. The broader point is that uncertainty estimates depend on whether a model represents the data's variability adequately.

Finally, the posted summaries are not a complete substitute for participant-level data. They do not show individual trajectories, the distribution of changes, the impact of missing observations, or the influence of any covariate adjustment. The sponsor-reported model and the unadjusted recalculation answer related but not identical statistical questions.

11. Confidence Intervals and Precision

The unadjusted primary estimate is a mean difference of -1.4 points, with a 95% confidence interval from -1.815 to -0.985. The interval is entirely on the negative side of zero, so the unadjusted comparison is compatible with a negative group difference across the range stated by the interval. Its width conveys the uncertainty in the estimated average contrast under the calculation used.

The sponsor's reported ANCOVA estimate is -1.3, with a 95% confidence interval from -1.7 to -0.92. This interval is also entirely below zero. The two estimates are similar in direction and magnitude, but the intervals belong to different analyses: one is an unadjusted recalculation from group summaries, and the other is the sponsor's reported ANCOVA result. They should not be treated as if they were generated by one identical model.

A confidence interval is not a range containing every participant's response. It describes uncertainty around a group-level parameter. Individual changes can vary substantially around a mean, as the posted standard deviations indicate. Nor does a confidence interval establish whether an observed difference is important to patients. The registry record does not report a clinical-importance threshold for this pain measure, so the interval informs statistical precision but cannot resolve that separate question.

The interval also depends on the analysis assumptions and the endpoint population. The registry record defines the primary analysis set but does not report the detailed handling of missing endpoint values or the full ANCOVA specification. Those omissions limit how completely the precision estimates can be evaluated from the registry record alone.

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 planning illustrations express required sample sizes as participants per arm, not as total events. They are hypothetical design calculations based on the observed effect, not observed power. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect equal to the stated fraction of the observed effect. The original trial's own sample-size assumptions are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm for a design that would have an 80% chance of detecting the assumed effect at the stated significance level, if that effect and the other assumptions were correct. The 90% power column applies the same idea with a higher chance of detection, which generally requires more participants. These figures are planning aids; they do not describe the probability that the completed study detected its true effect.

The rows consider planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. A smaller target effect is harder to distinguish from random variation, so the planning illustrations require more participants per arm. The required sample sizes also depend on the assumptions used, including the variability and allocation reflected in the calculation. They should not be read as a reconstruction of the trial's design or as evidence that the original study was planned using these values.

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 = -1.400; pooled standard deviation σ = 2.078.
2. n = 2 × (1.96 + 0.842)² × 2.078² / -1.400² = 34.6, rounded up to 35 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 <- -1.4                      # observed difference in means
sigma <- 2.07769214832526                     # 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(455520)
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 = 35 (80% power), 47 (90% power)
 75% of observed effect: n per arm = 62 (80% power), 83 (90% power)
 50% of observed effect: n per arm = 139 (80% power), 186 (90% power)
power.t.test: 35.6 
Simulated power at n = 35 per arm: 0.791 (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. Analyses Reported by the Sponsor

The sponsor's reported primary analysis used ANCOVA and gave a mean difference in final values of -1.3, with a 95% confidence interval from -1.7 to -0.92 and p < 0.001. The recalculation from the posted group means and standard deviations is unadjusted and gives a mean difference of -1.4, with a 95% confidence interval from -1.815 to -0.985 and p < 0.001. Both analyses point toward a lower pain score in the tapentadol ER group, and their estimates are close.

The small difference between the estimates is not flagged as a discrepancy in the registry record. It is expected that an adjusted model and an unadjusted comparison based on summary statistics may not match exactly: they can use different information and estimate different contrasts. The sponsor analysis is the trial's reported analysis; the recalculation is an additional, simple comparison and does not replace it. The registry record does not give enough detail to reproduce the ANCOVA model fully, including the complete covariate specification.

The reported and recalculated p-values are both below 0.001, but neither p-value measures clinical importance or guarantees the result would be identical in another study. The estimate and confidence interval are more informative about direction, magnitude, and statistical precision than the p-value alone.

15. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study makes several statistical comparisons. Even if each comparison is evaluated using a conventional threshold, the chance of at least one apparently favorable result can increase across a collection of tests. Trials may address this by identifying a primary endpoint, setting an ordered testing strategy, adjusting significance thresholds, or using another prespecified approach. The registry record identifies a primary outcome and lists secondary outcomes, but does not report a multiplicity adjustment or testing hierarchy for the secondary comparisons. The secondary p-values therefore should not be read as if each were the sole planned test.

The primary analysis population is described as randomized subjects who took at least one dose during the double-blind maintenance period, except for 3 subjects enrolled twice. This is the registry's stated Intent to Treat analysis set for the primary outcome. Because entry into the stated population requires taking a dose during the maintenance period, it is not simply every person initially randomized under the broadest possible meaning of intention to treat. The registry record does not explain further how this analysis set was chosen or how the repeated enrollment cases were handled beyond the stated exception.

The registry record does not report the method used to handle missing pain scores, the extent of missing primary endpoint data, or sensitivity analyses assessing the effect of missingness. These details matter because an analysis may rely on assumptions about outcomes that were not observed. The posted group summaries alone cannot show whether missingness was related to participants' pain, treatment assignment, or other factors.

The record reports an ANCOVA for the sponsor's primary analysis, but does not report its complete model specification, covariates, or diagnostic checks. It also does not report interim analyses or the original sample-size justification. These items should be treated as unavailable information, not inferred from the result or from the planning illustrations.

16. 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: diabetes mellitus inadequate control (0.5%), chest pain (0.5%), chronic lymphocytic leukaemia (0.5%), costochondritis (0.5%), helicobacter gastritis (0.5%).

The registry record reports serious adverse events for 10 participants in the tapentadol ER group, with 196 at risk, and for 3 participants in the placebo group, with 193 at risk. It also reports other adverse events for 87 participants in the tapentadol ER group, with 196 at risk, and for 48 participants in the placebo group, with 193 at risk. These are posted counts and denominators; they describe events recorded during the study and are not, on their own, a causal comparison.

The listed serious adverse event terms include diabetes mellitus inadequate control, chest pain, chronic lymphocytic leukaemia, costochondritis, Helicobacter gastritis, and pneumonia, each reported as 0.5%. These terms and percentages describe the record's listed serious-event information; they do not establish whether an event was caused by study medication. The registry record does not report deaths in the safety summary.

Safety summaries require attention to the population at risk, event definitions, observation period, and whether participants could experience more than one event. The record gives group counts but does not provide enough detail to establish event timing, severity beyond the serious classification, or individual-level overlap. The counts therefore should be read as descriptive safety reporting, not as a complete assessment of comparative risk.

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

The primary results show that the mean change in pain intensity differed between the randomized groups during the double-blind maintenance period. The tapentadol ER group had a mean change of -0.1, compared with 1.3 in the placebo group. The unadjusted mean difference was -1.4, and the sponsor-reported ANCOVA estimate was -1.3. Both confidence intervals are below zero, and both analyses report p < 0.001. These findings describe the average contrast observed in the specified analysis population and time period.

They do not establish that every participant benefited, that an individual response can be predicted from the group average, or that the numerical difference meets a clinical-importance threshold. The registry record does not report such a threshold. A statistically precise group difference and a clinically meaningful difference are related but separate questions; the latter requires context not given by the p-value alone.

The results also do not establish how the comparison would look with other populations, treatment durations, doses, or outcome definitions. The trial studied a particular regimen and a randomized-withdrawal design, and its primary endpoint was limited to the stated maintenance period. Applying the estimate elsewhere would require evidence about those settings.

Finally, the primary result should be considered alongside uncertainty about unreported analysis details, including missing-data handling and the complete ANCOVA specification. The secondary outcome pattern is broadly consistent with the primary direction, but those outcomes are subject to multiplicity concerns because an adjustment plan is not reported. The findings are evidence about the group comparison recorded in this trial, not a general guarantee of effect or safety for every person with diabetic peripheral neuropathy.

18. Why This Trial Matters Statistically

This trial illustrates why statistical interpretation should distinguish an estimated effect from its uncertainty and from its clinical importance. The mean difference gives a direct measure of the average separation between groups on the pain scale, while the confidence interval describes the precision of that estimate. The p-value adds evidence against a zero-difference model but does not convey the size of the contrast or its practical significance.

It also illustrates why adjusted and unadjusted analyses should be identified clearly. The sponsor's ANCOVA result and the summary-statistic recalculation are similar, but they arise from different methods and should not be collapsed into one estimate. A transparent reading preserves the sponsor's reported analysis while using the unadjusted calculation as a separate reference point.

The study's secondary outcomes show another important issue: a coherent direction across measures can be informative, but multiple unadjusted tests do not carry the same evidential weight as a primary result with a clearly reported analysis plan. The absence of a reported multiplicity strategy limits how strongly secondary p-values can be interpreted.

For clinical researchers, the record is also a reminder that endpoint populations, missing-data methods, and model specifications are part of the evidence. Group means and intervals can be interpreted, but not every design and analysis decision can be reconstructed from registry summaries. A careful statistical account states both what the results show and which details are not reported.

19. 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 a clinical-importance threshold for the pain scale, so the primary estimate cannot be classified from the record alone as meeting a prespecified patient-relevant difference. The endpoint is an average over a defined maintenance-period window; it does not show the trajectory of pain ratings across the study or how responses varied for individual participants.

The primary analysis population excludes 3 subjects who were enrolled twice and is defined by taking at least one dose during the double-blind maintenance period. The record does not provide a fuller account of the participant flow through the randomized-withdrawal design, the reasons for exclusions, or how many observations were missing for the endpoint. This limits assessment of selection and missing-data effects.

The sponsor's ANCOVA result is reported, but the complete model specification and covariates are not. The unadjusted recalculation uses group summaries and cannot reproduce participant-level adjustment. Neither the model diagnostics nor sensitivity analyses are reported in the registry record.

The registry record also does not report the original sample-size justification, interim analyses, or the trial's multiplicity strategy. Secondary comparisons should therefore be interpreted cautiously. Safety counts are descriptive, and the record does not provide enough detail to assess event timing, participant-level overlap, or causal attribution. These limitations do not negate the posted estimates, but they restrict how fully the analysis can be independently assessed.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Safety and Efficacy Study for Tapentadol (CG5503) Extended Release for Patients With Painful Diabetic Peripheral Neuropathy — NCT00455520.
• Registry record last updated 2013-07-19; status last verified 2013-07.
• Results first posted 2010-01-13.
• 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.

23. Record Summary

The registry record describes a completed, randomized, quadruple-masked, parallel phase 3 randomized-withdrawal study of tapentadol ER versus placebo for painful diabetic peripheral neuropathy. The primary endpoint was change from baseline at randomization in average pain intensity over the last week of the double-blind maintenance period at Week 12, measured on an 11-point Numerical Rating Scale.

The posted primary group means were -0.1 for tapentadol ER and 1.3 for placebo. The unadjusted recalculated mean difference was -1.4, with a 95% confidence interval from -1.815 to -0.985 and p < 0.001. The sponsor-reported ANCOVA estimate was -1.3, with a 95% confidence interval from -1.7 to -0.92 and p < 0.001.

The registry record does not report the original sample-size assumptions, detailed missing-data methods, complete ANCOVA specification, or a multiplicity strategy for secondary outcomes. Safety information is reported as event counts, with deaths not reported in the registry record.