Evaluate the Efficacy and Safety of Diclofenac Diethylamine 2.32% Gel Applied Twice or Three Times Daily in Patients With Acute Ankle Sprain: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluate the Efficacy and Safety of Diclofenac Diethylamine 2.32% Gel Applied Twice or Three Times Daily in Patients With Acute Ankle Sprain (NCT00955513), a randomized phase 3 study. The primary outcome is Measure: Pain on Movement on Day 5 (Change From Baseline)..

2. Clinical Question

The question concerns the average change reported for each schedule relative to placebo, rather than a direct comparison of the twice-daily and three-times-daily schedules. The posted results show mean changes of 49.1 mm for twice-daily diclofenac, 49.7 mm for three-times-daily diclofenac, and 25.4 mm for placebo. The corresponding unadjusted mean differences versus placebo are 23.7 mm and 24.3 mm. These estimates describe the registry’s reported outcome and should be read alongside their confidence intervals, which convey uncertainty around the estimated differences.

The registry record does not report the enrolled participants’ further characteristics, such as age or other clinical details. It also does not identify a separate primary analysis population. The interpretation is therefore limited to the stated condition, treatment schedules, placebo comparison, and outcome summary in the record.

3. Trial Design

The study is listed as a phase 3, randomized, triple-masked, parallel-group trial with three treatment arms and a placebo control. Its official title describes it as multi-center and double-blind; the registry fields separately list triple masking. The record does not identify which specific people or roles were masked, so the masking label cannot be made more specific from the posted information.

The arms were diclofenac diethylamine 2.32% gel applied twice daily, the same gel applied three times daily, and placebo applied three times daily. The registry lists enrollment as 242. For the primary outcome, the reported group sizes are 80 for the twice-daily regimen, 80 for the three-times-daily regimen, and 82 for placebo. Those are the group sizes associated with the outcome summaries; the record does not explain whether they represent all enrolled participants or an analysis population.

The trial status is completed. The start is recorded as 2009-07 and primary completion as 2009-12. Novartis is listed as sponsor. The brief summary states that the main purpose was to compare the efficacy and safety of the two diclofenac schedules with placebo in acute ankle sprains.

The design permits each diclofenac schedule to be assessed against the placebo group. It does not, in the posted primary comparisons, give a direct statistical comparison between the two diclofenac schedules. The registry record does not report the original sample-size justification, allocation ratio as a design specification, detailed treatment procedures, follow-up beyond the stated endpoint timeframe, or a full statistical analysis plan. Those omissions limit reconstruction of the trial’s planned analysis.

4. Participant Flow and Accounting

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

Overall Study

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Measure: Pain on Movement on Day 5 (Change From Baseline)., measured over baseline and day 5.

The primary endpoint is the mean change from baseline in pain on movement on day 5. Pain was assessed on a visual analog scale extending from 0 to 100 mm, and the listed unit for the endpoint is millimeters. A larger change from baseline is defined in the registry as a better outcome. The posted summaries report means and standard deviations for the treatment groups.

Pain on movement is a direct measure of the symptom named in the study question. Assessing change from baseline expresses the day-5 result in relation to each participant’s starting measurement, rather than relying only on a day-5 score. The registry specifies baseline and day 5 as the timeframe, but does not report the endpoint’s detailed measurement procedures, how missing measurements were handled, or how the group means were estimated.

The posted mean changes are 49.1 mm with twice-daily diclofenac, 49.7 mm with three-times-daily diclofenac, and 25.4 mm with placebo. These are group averages, not a description of every participant’s experience. A mean can conceal variation among individuals, and the reported standard deviations show that scores varied within each group. The registry record does not report a threshold for a change considered important to patients, so the clinical importance of a numerical difference cannot be determined from these summaries alone.

7. Results Posted in the Registry

• Diclofenac Diethylamine Gel 2.32% Gel. Applied 2 Times a Day: mean 49.10 versus 25.40 on control; difference 23.70 (95% CI 18.39 to 29.01), standardized effect d = 1.38; z-test p = <0.001.
• Diclofenac Diethylamine Gel 2.32% Gel. Applied 3 Times a Day: mean 49.70 versus 25.40 on control; difference 24.30 (95% CI 18.60 to 30.00), standardized effect d = 1.32; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The posted endpoint is a continuous outcome: pain-on-movement change from baseline, measured in millimeters. For a continuous measure, a group mean describes its average value, while a standard deviation describes how dispersed individual measurements are around that average. The reported means are 49.1 mm for twice-daily diclofenac, 49.7 mm for three-times-daily diclofenac, and 25.4 mm for placebo. The corresponding standard deviations are 19.3, 21.5, and 14.8 mm.

What does a mean difference represent?

A mean difference expresses how far apart the average outcome values are between two groups, in the outcome’s own units. Here, the posted comparisons use placebo as the reference group. The unadjusted mean difference is 23.7 mm for twice-daily diclofenac versus placebo and 24.3 mm for three-times-daily diclofenac versus placebo. Because the endpoint defines a greater change as better, positive differences in this direction indicate a larger average change in the diclofenac group. These are group-average contrasts; they do not state how much any particular participant changed.

The comparison values are based on the posted group summaries and are unadjusted. The registry record does not report a model-based adjusted estimate, covariates, or a detailed method for estimating the endpoint. The record also does not identify an analysis population. Readers should not assume an adjustment or analysis procedure that is not described.

What does a confidence interval communicate?

A confidence interval gives a range of values compatible with the data and the calculation method, expressing uncertainty around an estimated effect. The 95% confidence interval for the twice-daily comparison is 18.39 to 29.01 mm; for the three-times-daily comparison it is 18.6 to 30.0 mm. A narrower interval indicates greater precision than a wider interval on the same measurement scale, all else being equal. The interval does not show the range of individual participant outcomes, nor does it incorporate every possible source of uncertainty in trial conduct or reporting.

The intervals are for the mean differences versus placebo. They are not intervals for the separate group means, and they do not provide a direct interval for the difference between the active schedules. The registry record does not report a direct active-schedule comparison. The intervals and associated p-values are described as unadjusted, so no correction for testing multiple comparisons is reflected in those reported figures.

How should the p-values be read?

Each posted unadjusted p-value is <0.001. A p-value describes how compatible the observed data are with a specified null hypothesis under the assumptions of the test; it is not the probability that the null hypothesis is true. The record does not state the full test procedure or analysis model. The p-values should therefore be read as the registry’s unadjusted results, not as a complete account of the statistical plan or the chance that the findings arose randomly.

Statistical significance and clinical importance are different questions. The confidence intervals describe uncertainty in the estimated mean differences, while the clinical meaning of a difference depends on context, including a meaningful-change threshold. Such a threshold is not reported in the registry record. A small p-value does not supply that missing clinical interpretation.

Why do standard deviations matter?

Standard deviations indicate variability among measurements within a group. Greater variability can make a group mean less precisely estimated for a given group size. The posted standard deviations differ across the three groups, so the observed means should be considered with both the within-group spread and the confidence intervals for between-group differences.

In general, over-dispersion means that observed variability is greater than a statistical model expects. A model that fails to account for over-dispersion may understate uncertainty and produce confidence intervals that are too narrow. The registry record does not identify an over-dispersion assessment or model, and there is no basis for asserting that over-dispersion was present in this trial. This is a general statistical consideration, not a reported trial finding.

The trial is randomized and parallel-group, but the registry record does not report allocation procedures in detail, missing-data methods, sensitivity analyses, or the statistical model. Those details matter because they clarify which participants contributed to each estimate and whether conclusions depend on analytic choices. Their absence from the record prevents a full replication or independent assessment of those aspects.

10. Confidence Intervals and Precision

The confidence intervals for the mean differences quantify the precision of the two reported comparisons with placebo. For twice-daily diclofenac, the estimated difference is 23.7 mm, with a 95% confidence interval from 18.39 to 29.01 mm. For three-times-daily diclofenac, the estimated difference is 24.3 mm, with a 95% confidence interval from 18.6 to 30.0 mm. Each interval gives a range around its estimate rather than a single exact value.

Both intervals lie above zero, the value corresponding to no mean difference, and both posted unadjusted p-values are <0.001. This alignment indicates that the reported unadjusted comparisons are statistically distinguishable from zero under their calculation. It does not answer whether the differences meet a patient-important threshold; the registry record does not report such a threshold.

Confidence intervals describe uncertainty in the estimated group contrast, not the spread of individual responses. The group standard deviations—19.3 mm, 21.5 mm, and 14.8 mm—describe within-group variation instead. These measures answer different questions. The record does not provide confidence intervals for the group means or for a direct comparison between the two diclofenac schedules.

Precision depends on the sample information and the variability, as well as the analysis method. The record gives outcome group sizes and standard deviations but does not report all analysis details, missing-data handling, or the population used for the comparisons. The intervals should consequently be interpreted as precision for the posted unadjusted estimates, not as a complete representation of uncertainty from every design or analysis decision.

11. Planning a Similar Trial: Sample Size

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

The sample-size figures are planning illustrations derived from the observed effect, not the trial’s original design calculations. The assumptions stated for these illustrations are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect. The listed figures are participants per arm, not total participants or total events.

For each comparison, the planning rows show the number of participants per arm for 80% power and for 90% power at the stated effect fraction. In plain terms, power is the probability that a study would detect an effect of the specified size under the planning assumptions if that effect were present. The 90% power column represents a higher target probability of detecting that effect than the 80% column. These values are not observed power for the completed trial.

The rows for 100% of the observed effect use the full observed comparison as the planning target. The 75% and 50% rows use smaller target effects. Smaller effects are harder to distinguish from random variation, so planning to detect a smaller effect generally requires more participants per arm. The listed figures illustrate how the planning requirement changes with the chosen effect size and power target; they are not a recommendation for a future study.

These calculations do not reconstruct the actual sample-size justification. The original design assumptions and sample-size rationale are not reported in the registry record. The observed effects may also differ from effects anticipated before the trial. The illustration should therefore be read as a conditional planning exercise based on the posted estimates, not as evidence about whether the completed trial had adequate or inadequate power.

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 = 23.700; pooled standard deviation σ = 17.170.
2. n = 2 × (1.96 + 0.842)² × 17.170² / 23.700² = 8.2, rounded up to 9 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 <- 23.7                      # observed difference in means
sigma <- 17.1699137301269                     # 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(955513)
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 = 9 (80% power), 12 (90% power)
 75% of observed effect: n per arm = 15 (80% power), 20 (90% power)
 50% of observed effect: n per arm = 33 (80% power), 45 (90% power)
power.t.test: 9.3 
Simulated power at n = 9 per arm: 0.788 (20000 replicates)

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

13. Multiplicity, Missing Data and Analysis Populations

The registry record reports one primary outcome measure and no posted secondary outcomes. It provides two unadjusted treatment-versus-placebo comparisons for that outcome: one for each diclofenac schedule. The record does not report a multiplicity-adjustment method or a statistical plan stating how multiple comparisons were to be handled.

In general, making multiple statistical comparisons can increase the chance that at least one result appears statistically significant by chance. A prespecified approach to multiplicity can address that issue, for example by controlling the overall error rate across a defined family of tests. This is a general statistical consideration; the registry record does not say whether such an approach was planned or used. The posted p-values are explicitly unadjusted and should be read as such.

The record lists no analyses in addition to the posted outcome summaries. It does not report whether the primary comparisons were prespecified in a protocol or statistical analysis plan, whether interim analyses occurred, or whether any additional analyses were conducted but not posted. Those details are not reported in the registry record.

Missing-data methods are also not reported. The record does not explain whether outcome data were missing, how missing values were handled, or whether sensitivity analyses examined alternative assumptions. The reported outcome group sizes do not, by themselves, establish the amount of missing data or identify the analysis population. Likewise, the record does not specify whether the analysis followed an intention-to-treat, per-protocol, or other population definition.

These omissions do not show that a particular method was absent from the trial’s internal documentation. They mean only that the registry record does not describe it. Without those details, readers can assess the posted unadjusted summaries and their reported uncertainty, but cannot fully evaluate the prespecified analysis strategy, the handling of incomplete data, or the scope of the analyses performed.

14. Safety Results

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

Other (non-serious) adverse events

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

Most frequent non-serious adverse event terms

The registry reports serious adverse events affecting 0 participants in each of the three groups: twice-daily diclofenac, three-times-daily diclofenac, and placebo. The serious-event risk groups are listed as 80, 80, and 82, respectively. No serious adverse-event terms are listed.

For other adverse events, the record reports 0 affected participants with twice-daily diclofenac, 1 with three-times-daily diclofenac, and 1 with placebo. These are counts of participants recorded as affected, not descriptions of event severity or a comparison adjusted for follow-up or exposure.

Deaths are not reported in the registry record. The adverse-event figures are limited to the categories and counts posted. They do not establish that no other events occurred, and they do not provide event descriptions, timing, duration, or a detailed assessment of causality. The small counts should be read as registry reporting, not as a complete safety evaluation.

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

The posted results describe the mean change in pain on movement from baseline to day 5 in a randomized, placebo-controlled trial of diclofenac diethylamine 2.32% gel for acute ankle sprain. The registry defines a greater change as better. On that measure, the reported average changes were larger in both diclofenac groups than in the placebo group, and the unadjusted mean differences versus placebo were 23.7 mm and 24.3 mm.

The confidence intervals and p-values indicate that the posted unadjusted mean differences are estimated with a degree of precision and are inconsistent with a zero difference under the stated comparisons. They do not determine whether the differences are important to patients, because a meaningful-change threshold is not reported. The group averages also do not tell whether every participant improved or how individual responses were distributed.

The results do not establish a difference between the twice-daily and three-times-daily schedules. The posted comparisons use placebo as the reference, and a direct comparison between the active schedules is not reported. The registry record also does not report the statistical plan, missing-data handling, or analysis populations, so the summaries cannot resolve how those decisions may affect interpretation.

The findings are specific to the recorded population and endpoint: Grade I/II ankle sprain and pain on movement at day 5. The record does not establish results for other conditions, outcomes, or timeframes. Safety interpretation is similarly limited to the adverse-event counts posted, with deaths not reported in the registry record. These registry results should be understood as trial statistics, not as individual medical guidance or a complete account of all clinical evidence.

16. Why This Trial Matters Statistically

This trial illustrates why the comparison being estimated matters. The registry gives a separate placebo comparison for each diclofenac schedule, allowing readers to examine the estimated mean change for each regimen against the control group. Those comparisons do not answer whether the two active schedules differ from one another. A direct contrast would require its own estimate and uncertainty, which are not reported.

It also demonstrates the distinction between statistical evidence and clinical interpretation. The posted unadjusted p-values are <0.001, and the confidence intervals for the mean differences lie above zero. Those results describe evidence about the group-average contrast, while clinical importance requires context not included in the record, such as a threshold for a meaningful change.

Precision is not conveyed by a p-value alone. The confidence intervals express uncertainty around each estimate, and the standard deviations describe variation within the groups. Considering these quantities together gives a fuller statistical description than relying only on whether a p-value crosses a threshold.

The record also leaves key analysis details unreported: multiplicity handling, missing-data methods, and analysis populations. Such information is important for judging how the estimates were produced and how sensitive they may be to analytic decisions. The example underscores that a statistically clear posted comparison can coexist with limits in what the registry permits readers to conclude.

17. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record contains limited detail about participants beyond the condition Grade I/II ankle sprain. Other baseline characteristics and eligibility details are not reported in the registry record. This limits assessment of how closely the recorded participants resemble any particular clinical population.

The primary endpoint is described as change from baseline to day 5, but details of the measurement process, timing of assessments, and handling of missing observations are not reported. The record also does not define the analysis population or explain whether the outcome group sizes represent all randomized participants. Consequently, the posted group summaries cannot answer how incomplete data or exclusions were handled.

The reported comparisons are unadjusted and use placebo as the reference. A direct comparison between the diclofenac schedules is not reported, nor is multiplicity handling. The statistical model, covariates, and sensitivity analyses are also not described. The original sample-size rationale and design assumptions are not reported in the registry record; the separate planning illustration is based on the observed effect and does not supply that missing design history.

Only the stated primary outcome is posted, with no secondary outcomes or analyses listed. The endpoint timeframe is baseline and day 5, so these data do not describe later outcomes. Adverse-event reporting is limited to the posted counts; event details and deaths are not reported in the registry record. These limitations constrain interpretation of both efficacy-related outcome summaries and safety reporting without establishing that unreported procedures or events did not occur.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Evaluate the Efficacy and Safety of Diclofenac Diethylamine 2.32% Gel Applied Twice or Three Times Daily in Patients With Acute Ankle Sprain — NCT00955513.
• Registry record last updated 2012-04-20; status last verified 2011-01.
• Results first posted 2011-01-26.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

21. Record Summary

NCT00955513 is a completed phase 3 randomized, triple-masked, parallel-group study sponsored by Novartis. It enrolled people with Grade I/II ankle sprain and compared diclofenac diethylamine 2.32% gel applied twice daily or three times daily with placebo applied three times daily. The record lists start as 2009-07 and primary completion as 2009-12.

The primary measure was mean change from baseline in pain on movement on day 5, assessed on a 0 to 100 mm visual analog scale; greater change was defined as better. The posted mean changes were 49.1 mm, 49.7 mm, and 25.4 mm for twice-daily diclofenac, three-times-daily diclofenac, and placebo, respectively. The unadjusted mean differences versus placebo were 23.7 mm and 24.3 mm, with p-values <0.001.

The record reports no secondary outcomes and does not report analysis populations, missing-data methods, or multiplicity handling. Serious adverse events affected 0 participants in each group; deaths are not reported in the registry record.