Eflornithine and/or Diclofenac in Treating Patients With Sun-Damaged Skin: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Eflornithine and/or Diclofenac in Treating Patients With Sun-Damaged Skin (NCT00601640), a randomized phase 2 study. The primary outcome is Changes in Putrescine Over 3 Months.

2. Clinical Question

3. Trial Design

This was a randomized, parallel-group phase II trial of topical treatments for sun-damaged skin on the forearm. The registry lists the sponsor as the University of Arizona, enrollment as 184, and the study status as completed. The study began in 2007-01, with primary completion in 2010-02. It is identified as a phase IIB study in the official title.

The three treatment groups were eflornithine hydrochloride, diclofenac sodium, and eflornithine hydrochloride with diclofenac sodium. According to the arm descriptions, participants applied treatment to the left forearm on days 1-90. Eflornithine ointment was applied twice daily; diclofenac gel was applied once daily; and the combination followed those respective schedules. The registry records no masking. It describes random allocation and a parallel model, so participants were assigned to a treatment group and the groups were followed in parallel.

The primary outcome was the change in putrescine over three months, measured in nmol/g skin. The posted arm-level results include 47 participants for eflornithine, 47 for diclofenac, and 42 for the combination. The registry also posts one secondary outcome, change in histologic score diagnosis and treatment group. Its arm-level counts differ from those for the primary endpoint. Reasons for the differing outcome counts, the analysis population definitions, and handling of missing outcome measurements are not reported in the registry record.

The trial description states that the study assessed side effects and how well eflornithine worked compared with diclofenac, alone or together. The registry does not report the original sample-size justification, detailed statistical analysis plan, allocation-concealment procedures, or whether any interim analyses were planned or conducted. Those details should not be inferred from the posted results.

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: 166 participants were accrued after the change in formulation. 10 participants were not randomized for various reasons. 156 participants were randomized to one of the 3 treatment groups.

Overall Study

Reasons for not completing this period:

5. Baseline Characteristics

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

6. Primary Endpoint

The registry lists the primary outcome as Changes in Putrescine Over 3 Months, measured over 3 months.

The primary endpoint is the change in putrescine measured in skin biopsy samples over three months. The reported unit is nmol/g skin. The registry says one baseline biopsy and one end-of-study biopsy were measured for each participant, and defines the change as the end-of-study level minus the baseline level. A positive mean change therefore represents higher measured putrescine at the end of the study than at baseline; a negative change would represent a lower level. The posted group means are mean changes, with standard errors reported as the measure of dispersion.

This outcome turns the two biopsy measurements into a single summary of within-participant change during the study period. Comparing mean changes between treatment groups addresses whether their average changes differed, rather than simply comparing end-of-study values without accounting for baseline measurements. Putrescine is the biochemical measure selected as the primary endpoint in this registry record. The record does not explain why it was selected, how a change should be interpreted clinically, or what size of change would be important to patients or clinicians.

The endpoint is not itself a clinical event or a direct account of symptoms. The registry’s stated purpose concerns treatment of sun-damaged skin, while the primary posted outcome is a laboratory measurement from biopsy tissue. Interpretation should therefore stay with the measured outcome and its uncertainty. The record does not establish how the putrescine measure relates to later clinical outcomes.

7. Results Posted in the Registry

• Diclofenac Sodium: mean 1.45 versus 0.03 on control; difference 1.42 (95% CI -1.84 to 4.68), standardized effect d = 0.18; z-test p = 0.393.
• Eflornithine Hydrochloride/Diclofenac Sodium: mean 0.20 versus 0.03 on control; difference 0.17 (95% CI -2.72 to 3.06), standardized effect d = 0.02; z-test p = 0.908.

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.

Change in Histologic Score Diagnosis and Treatment Group

• 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 errors.
• Result:
  • Diclofenac Sodium: mean 0.26 versus 0.33 on control; difference -0.07 (95% CI -0.46 to 0.32), standardized effect d = -0.07; z-test p = 0.724.
  • Eflornithine Hydrochloride/Diclofenac Sodium: mean 0.64 versus 0.33 on control; difference 0.31 (95% CI -0.15 to 0.77), standardized effect d = 0.28; z-test p = 0.186.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Diclofenac Sodium and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Eflornithine Hydrochloride/Diclofenac Sodium and the control. The interval gives the range of effects that remain compatible with the data.

The registry posts one secondary outcome: change in histologic score diagnosis and treatment group over three months. Its group summaries and comparisons provide a different view of change in the treated skin than the primary biochemical measure. Across those comparisons, the point estimates do not all point in the same direction relative to eflornithine, and the confidence intervals include zero. This gives no clear, precise pattern of between-group differences in the posted summaries.

The secondary outcome is related to the primary result in that both concern changes assessed over the study period in participants with sun-damaged forearm skin. They are not interchangeable measures: the primary endpoint is putrescine measured from biopsies, while the secondary endpoint is a histologic score. A pattern in one should not be treated as confirmation of a pattern in the other. The registry does not report a prespecified relationship between the two measures or an analysis linking them.

The registry lists the secondary outcome but does not post reported analyses for it. The displayed comparisons should therefore be understood as unadjusted summaries rather than as a documented confirmatory analysis. The record does not say whether the secondary outcome was prioritized, whether multiple testing was considered in the analysis plan, or whether any results were selected for posting. Those details are not reported in the registry record.

Unadjusted secondary results carry less weight because multiple outcomes and comparisons create more opportunities for apparently notable results to arise by chance. This general concern is separate from whether any particular estimate is large or small. Without a reported multiplicity strategy and analysis plan, secondary findings are best treated as exploratory context. They can complement the primary result, but do not independently establish a treatment difference or resolve the uncertainty in the primary outcome.

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

• Change in Histologic Score Diagnosis and Treatment Group

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: each participant has a numerical change in putrescine, measured in nmol/g skin. The registry reports the mean change for each group and a standard error. A mean summarizes the group’s average observed change. It does not show the full distribution of participant-level changes, whether values were skewed, or how many participants changed in each direction.

What does the mean difference compare?

A mean difference is one group’s mean minus the reference group’s mean. In the posted primary comparisons, eflornithine is the reference. The diclofenac estimate compares its mean change with the eflornithine mean change; the combination estimate does the same for the combination group. The sign indicates the direction of the estimated difference according to that subtraction. A value above zero means the comparison group’s mean change is higher than the reference mean change; a value below zero means it is lower. The estimate is a group-level contrast, not the change experienced by every participant.

The posted arm means and comparison estimates are internally presented as the registry’s results. The comparison estimates are accompanied by confidence intervals and unadjusted p-values. No discrepancy between the posted summaries and the recalculated comparisons is flagged in this record. The registry does not describe an adjusted model, covariates, transformations, or another analysis that might alter the comparisons, so none should be assumed.

What does a standard error describe?

The standard error describes the estimated precision of a mean, under the assumptions of the calculation. It is not the same as the standard deviation, which describes variation among participant measurements. The registry reports standard errors for the arm means; these indicate uncertainty in the estimated group averages, not the range of individual changes. The comparison calculations use pooled standard deviations listed in the posted statistical summaries. Those pooled values are used in standardized effect-size and planning calculations; they should not be confused with the standard errors shown for the arm means.

For a continuous endpoint, comparing means is a familiar way to summarize group differences. It can be useful when an average change is meaningful for the research question, as it is specified. However, a mean alone can conceal variation in individual responses. The registry does not post distributions, medians, or participant-level data, so it is not possible to assess the shape or spread of the observed changes beyond the summarized standard errors.

How should the confidence intervals and p-values be read?

A confidence interval expresses uncertainty around an estimated difference. It gives a range of values compatible with the data and the interval’s calculation assumptions. For these comparisons, zero represents no difference in average change. An interval that includes zero is compatible with no difference as well as with differences in either direction. It does not prove that the true difference is zero. The interval’s width is also important: a wider interval leaves more uncertainty about the magnitude of the group difference.

The p-values posted for the primary comparisons are unadjusted. In general, a p-value assesses how unusual data at least as discrepant as those observed would be under a specified null hypothesis and model. It is not the probability that the null hypothesis is true, and it does not measure the clinical importance of an effect. Because the registry does not report a multiplicity adjustment, the p-values should not be described as adjusted for the number of comparisons or outcomes.

What cannot be inferred from the registry?

The record does not report the trial’s original statistical analysis plan, the sample-size justification, the handling of missing measurements, or the analysis population definitions. It also does not state whether the primary analysis adjusted for baseline characteristics or other variables. These are not details that can be reconstructed from the arm summaries. The posted comparisons can be interpreted as reported, while those absent design and analysis details remain unknown.

The sample-size illustrations on the page are separate from the trial’s original planning. They are based on the observed effect and stated assumptions, and are not evidence about the trial’s power or design intent. General power calculations ask how many participants would be needed to detect a specified effect under chosen assumptions. They cannot show whether a study was adequately planned without the original assumptions and target effect, which are not reported in the registry record.

The randomized allocation is relevant because randomization is intended to make groups comparable on average, but the record’s summary alone cannot establish that all procedures were implemented as intended or that the analysis preserves the benefits of randomization. No masking was recorded. That may matter for outcomes susceptible to measurement or assessment influence, although the record does not describe how biopsy processing or histologic assessment was conducted. The design information supports a description of the trial structure, not a claim about procedures that are unreported.

11. Confidence Intervals and Precision

The primary comparisons have confidence intervals that span zero. For diclofenac compared with eflornithine, the mean difference is 1.42 nmol/g skin, with a 95% confidence interval from -1.84 to 4.68. For the combination compared with eflornithine, the mean difference is 0.17 nmol/g skin, with a 95% confidence interval from -2.721 to 3.061. Both estimates are therefore uncertain in direction as well as magnitude: the ranges include no difference and values on either side of it.

A confidence interval is not a list of outcomes that were individually observed, and it does not guarantee that the true difference lies within the range. In general, it summarizes uncertainty under the statistical method and assumptions used to calculate it. Here, the interval width is a useful caution against treating either point estimate as an exact or definitive measure of the group difference. The estimates are compatible with a range of possible differences, rather than only the central value.

The arm means also have standard errors: 1.12 for eflornithine, 1.23 for diclofenac, and 0.96 for the combination. These are measures of precision for the group means, not standard deviations of individual participant changes. The registry does not post confidence intervals for the arm means themselves. The comparison intervals are more directly relevant to the between-group questions.

Precision should be considered alongside the endpoint’s meaning. The registry does not report a threshold for a clinically important change in putrescine, so it is not possible to judge whether values within the intervals would be clinically consequential. The intervals and p-values also do not address the unreported analysis-population and missing-data details. The posted results support a cautious description of uncertain group differences, not a claim of equivalence or a precise estimate of clinical effect.

12. Planning a Similar Trial: Sample Size

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

The sample-size table and curve are planning illustrations based on the observed effect, not the trial’s original design calculations. The assumptions listed for the illustrations are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each row considers an effect set at the stated fraction of the observed effect. The primary outcome comparisons are continuous, so the figures are participants per arm, not a total number across both arms or a number of events.

The 80% power column gives the estimated participants per arm for a hypothetical study to have an 80% chance of detecting the specified effect under those planning assumptions, if that effect and the assumptions were correct. The 90% power column gives the corresponding per-arm planning figure for a 90% chance. These are design illustrations; they do not describe the probability that the completed trial found a result, nor do they establish that the original trial had a particular power.

Rows that plan for a smaller fraction of the observed effect require more participants per arm. A smaller difference is harder to distinguish from random variation under otherwise similar assumptions. The table makes this relationship visible for each posted comparison. Very large estimates in the table reflect the small observed standardized effects used in those particular illustrations; they are not estimates of the trial’s enrollment or recommendations for a future study without additional design work.

This is not observed power. The original trial’s sample-size justification and assumptions are not reported in the registry record. The illustrations therefore should be read only as conditional planning information, not as a retrospective verdict on the study design.

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 = 1.420; pooled standard deviation σ = 8.064.
2. n = 2 × (1.96 + 0.842)² × 8.064² / 1.420² = 506.3, rounded up to 507 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 <- 1.42                      # observed difference in means
sigma <- 8.0642141588626                     # 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(601640)
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 = 507 (80% power), 678 (90% power)
 75% of observed effect: n per arm = 901 (80% power), 1,205 (90% power)
 50% of observed effect: n per arm = 2,026 (80% power), 2,712 (90% power)
power.t.test: 507.2 
Simulated power at n = 507 per arm: 0.800 (20000 replicates)

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

14. Multiplicity, Missing Data and Analysis Populations

The registry posts one primary outcome and one secondary outcome, with comparisons of diclofenac and the combination against eflornithine for each. The primary comparison p-values are unadjusted, and the record does not report a multiplicity adjustment for the comparisons or outcomes. It also does not describe a hierarchy for testing outcomes, a prespecified strategy for controlling false-positive findings, or a plan for interpreting secondary analyses alongside the primary endpoint. The absence of these details means the posted p-values should not be treated as if they account for all statistical testing in the trial.

Multiplicity is a general statistical concern when several hypotheses are examined: each additional test can create another opportunity for a result to appear unusual by chance. Adjustments or a prespecified testing hierarchy can address that issue, but the registry record does not say whether such methods were used beyond the posted unadjusted results. It would be inappropriate to infer an adjustment, or to claim that none was done outside the information recorded.

The posted group sizes also vary by outcome. The primary endpoint includes 47 participants in the eflornithine group, 47 in the diclofenac group, and 42 in the combination group; the secondary endpoint has different counts. The record does not explain why participants are absent from particular outcome summaries. It does not describe missing-data methods, imputation, exclusions, or whether these results use an intention-to-treat population, a per-protocol population, or another analysis set.

These omissions matter because missingness and analysis-population decisions can affect the estimated group differences. Randomization alone does not show how outcome availability was handled. The registry also does not report whether any interim analyses were performed, or provide a fuller statistical analysis plan. These details should be regarded as not reported in the registry record, rather than guessed from the posted summaries.

15. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists serious adverse events as affecting zero participants in each of the three safety groups. Each group has 52 participants at risk for serious adverse events. No serious adverse event terms are listed. The record’s death entries are null, so deaths are not reported in the registry record; a null entry should not be read as a confirmed zero.

For other adverse events, the registry lists 20 affected participants in Arm I, 45 in Arm II, and 28 in Arm III, with 52 at risk in each group. The adverse-event groups are identified by these arm labels in the safety section; the record does not map those labels there to the treatment names, so treatment-specific attribution should not be inferred from these figures alone. The registry does not provide event types, severity details, duration, or whether events were considered related to study treatment.

These figures describe the safety entries posted in the registry and should not be taken as a complete clinical safety assessment. In particular, the absence of listed serious events is a statement about the posted counts, not a guarantee that no harms occurred.

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

The results show the group mean changes in putrescine observed among participants included in the posted primary summaries, along with estimated differences between treatment groups. The confidence intervals for the comparisons include zero and extend in both directions. The data therefore leave uncertainty about whether average putrescine change differed between eflornithine and either diclofenac or the combination, and about the magnitude of any such difference.

This is not the same as demonstrating that the groups are equivalent. Equivalence requires a suitable design, a prespecified margin for what difference would count as unimportant, and analysis against that margin. The registry does not report such a margin or an equivalence analysis. Nor do the p-values establish that any treatment effect is absent; they are unadjusted results from the posted comparisons and do not quantify the probability that a conclusion is true.

The primary outcome is a biopsy-based biochemical measure. The registry does not explain what change in putrescine would be clinically meaningful or establish how the result predicts symptoms, future skin outcomes, or other clinical endpoints. The findings should not be translated into a claim about clinical benefit. The trial description gives a chemoprevention rationale, but the posted primary outcome is change in putrescine over three months, not cancer occurrence or another long-term clinical event.

The record also does not provide an untreated or placebo comparison in the posted primary results. Consequently, the comparisons do not identify how the measured outcome would have changed without the listed treatments. Findings should be interpreted as differences, or lack of precision in differences, among the trial’s active groups.

Finally, incomplete reporting of analysis populations, missing measurements, multiplicity, and original design assumptions limits broader conclusions. The posted results are useful for describing the study’s measured outcomes and their statistical uncertainty. They are not sufficient to establish equivalence, clinical effectiveness, or a complete account of safety.

17. Why This Trial Matters Statistically

This trial illustrates the distinction between a numerical point estimate and the precision of an estimate. The primary comparisons have point estimates, but their confidence intervals include zero and allow differences in either direction. Reading the estimate without its interval could make the results seem more definite than the data support. The intervals show why uncertainty is central to interpretation, especially when group sizes in the posted outcome summaries are limited.

It also illustrates that a biomarker or tissue-based endpoint is not automatically a clinical outcome. The trial’s primary measure is putrescine change in biopsy samples. It can be described and compared statistically, but the registry does not establish a threshold for clinical importance or a link to later health outcomes. Separating the measured endpoint from claims about clinical benefit is essential to accurate reporting.

The registry further shows how reporting completeness shapes statistical interpretation. Randomization, parallel allocation, masking status, arm-level means, and comparisons are available, while details such as missing-data handling, analysis populations, multiplicity procedures, and original sample-size rationale are not reported. Those gaps prevent readers from assuming how the analysis was planned or implemented.

Lastly, the sample-size illustrations demonstrate the dependence of planning requirements on the effect size one wants to detect. They are based on observed effects and explicit assumptions, not on the original trial design. Keeping planning calculations separate from observed results avoids confusing hypothetical design needs with the study’s actual enrollment or its probability of detecting an effect.

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.

Several limitations are specific to the available record. The study is described as having no masking, so participants and study personnel were not masked according to the registry. The record does not explain whether laboratory or histologic outcome assessors were masked, or how biopsy measurements were processed. This leaves an important procedural detail unknown for outcomes involving tissue assessment.

The primary endpoint is based on one baseline biopsy and one end-of-study biopsy per participant. That provides the change measure described in the registry, but the record does not report repeated measurements or another way to assess within-participant measurement variability. The clinical meaning of a putrescine change is also not specified. The registry provides no threshold for an important change and no stated relationship to longer-term clinical outcomes.

The participant counts differ across the posted outcomes and do not match the enrollment figure. Reasons for those differences, the analysis populations, and missing-data handling are not reported in the registry record. The available summaries therefore do not allow assessment of whether outcome availability differed by group or how missing measurements may have influenced the estimates.

The primary comparisons use eflornithine as the reference and do not include an untreated or placebo group in the posted results. This restricts interpretation to comparisons among the listed active treatment groups. In addition, the registry does not post a detailed statistical analysis plan, multiplicity strategy, sample-size justification, or interim-analysis information. These limitations concern what can be concluded from the record; they should not be filled in by assumption.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Eflornithine and/or Diclofenac in Treating Patients With Sun-Damaged Skin — NCT00601640.
• Registry record last updated 2017-03-23; status last verified 2017-02.
• Results first posted 2017-03-23.
• 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

NCT00601640 is a completed randomized, parallel-group phase II trial sponsored by the University of Arizona. It evaluated topical eflornithine, topical diclofenac, and their combination for sun-damaged skin on the forearm, with treatment applied to the left forearm on days 1-90 according to the posted arm descriptions. The registry records no masking and enrollment of 184.

The primary outcome was change in putrescine in skin biopsy samples over three months. The posted comparisons use eflornithine as the reference and have confidence intervals that include zero. One secondary outcome, change in histologic score, is also listed. The record posts serious and other adverse-event counts, but provides limited event detail. Important information on original design assumptions, missing data, analysis populations, multiplicity, and some safety details is not reported in the registry record.