Combination Therapy With Imiquimod Cream 5% and Tazarotene Cream 0.1% for the Treatment of Lentigo Maligna: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Combination Therapy With Imiquimod Cream 5% and Tazarotene Cream 0.1% for the Treatment of Lentigo Maligna (NCT00707174), a randomized na study. The primary outcome is The Absence of Lentigo Maligna (LM) at the Time of Staged Excisions in Participants.

2. Clinical Question

This is a treatment-strategy comparison within a surgical pathway, rather than a comparison of topical treatment without subsequent surgery. The study summary says participants in both groups were to undergo staged surgical excision, with rush permanent sections used to confirm negative histologic margins, followed by surgical repair. Long-term follow-up was planned to assess recurrences. These features describe the intended study pathway; the registry record does not establish that every planned treatment, procedure, or follow-up visit was completed.

The primary outcome is specifically framed around absence of lentigo maligna at staged excisions and is listed with a timeframe of 24 months. It is therefore distinct from the stated longer-term recurrence follow-up. The registry record does not report a separate posted recurrence result. The findings can address the posted comparison of outcome counts among evaluable participants, but they do not by themselves describe recurrence over the entire planned follow-up period.

3. Trial Design

The registry record describes a randomized, prospective, parallel-group study with no masking. It lists the study phase as not applicable and the enrollment as 90. The sponsor is the University of Utah. The recorded start is 2005-03, primary completion is 2013-03, and the status is completed. These registry descriptors identify the study structure and recorded milestones; they do not provide a complete account of recruitment, treatment delivery, or follow-up completion.

Participants were assigned to imiquimod alone or imiquimod combined with tazarotene. The imiquimod-only description specifies topical imiquimod 5% treatment at the lentigo maligna site, extending two centimeters beyond the perimeter margin, Monday through Friday for twelve weeks. It then mentions a one-month washout period after three months of topical treatment. The description ends mid-sentence, so further details of that arm are not reported in the registry record. The combination arm is described as using an identical protocol with tazarotene 0.1% cream added on Saturdays and Sundays.

The study summary states that both groups were to have polygonal staged excision using 2mm margins per stage. Rush permanent sections were intended to confirm negative histologic margins, with surgical repair and long-term follow-up of five years to assess recurrence. These statements describe the planned pathway in the registry summary and should not be read as evidence that all participants completed it.

The posted primary-outcome results include 41 participants in the imiquimod-only arm and 37 in the combination arm. The outcome description says all evaluable patients were compared. These arm counts do not account for all of the enrollment listed in the record, and the reason for that difference is not reported in the registry record. The adverse-event denominators are different from the primary-outcome arm counts, so safety and efficacy counts should be interpreted using their respective populations.

4. Participant Flow and Accounting

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

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All evaluable patients from both groups were compared

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 The Absence of Lentigo Maligna (LM) at the Time of Staged Excisions in Participants, measured over 24 months.

The primary endpoint counts participants who were without lentigo maligna at the time of staged excisions. Its title describes absence of lentigo maligna, and the outcome description frames the comparison as negative histologic margins for the combination group versus the imiquimod-only group. The reported timeframe is 24 months. In practical terms, this is a binary outcome: each participant contributes to the count according to whether the stated outcome was present or not.

Histologic margin status is used in this study because the protocol summary describes excision with tissue sections examined to confirm negative margins. The endpoint therefore connects the topical-treatment comparison with the subsequent surgical assessment. It is not a measure of long-term recurrence, symptoms, or every aspect of treatment experience. Although the summary describes planned five-year follow-up to rule out recurrences, the posted primary outcome is specifically about absence of lentigo maligna at staged excision, and no recurrence result is posted among the registry outcomes.

The registry record reports 27 participants with the outcome among 41 in the imiquimod-only group and 29 among 37 in the combination group. Those counts are the direct basis for describing the posted outcome. They do not alone establish why participants did or did not have the outcome, and the registry record does not provide individual participant data or a detailed account of endpoint adjudication.

7. Results Posted in the Registry

• Imiquimod and Tazarotene Combined: 78.4% (29/37) versus 65.9% (27/41) on control; risk difference 12.5 percentage points (95% CI -7.1 to 32.2), risk ratio 1.19 (0.90–1.57); unadjusted two-proportion z-test p = 0.220.

8. Statistical Interpretation

9. Statistical Methods Explained

How is a binary endpoint analyzed?

General statistical explanation: a binary endpoint classifies each participant into one of two outcome states, such as whether the recorded endpoint occurred. The basic data are the number of participants with the outcome and the number evaluated in each group. Here, the registry reports 27 of 41 participants in the imiquimod-only group and 29 of 37 in the combination group with the primary outcome. A comparison can summarize these group counts using an absolute measure, such as a risk difference, or relative measures, such as a risk ratio or odds ratio.

The risk difference expresses the difference between the groups’ outcome proportions on an absolute scale. Positive values in the registry’s stated comparison direction correspond to a greater outcome proportion in the combination group. The registry reports a risk difference estimate of 0.125. This can be interpreted as an estimated absolute contrast in the proportion with the endpoint, but precision and the study’s analysis details matter when judging how stable that estimate may be.

A risk ratio compares the outcome proportions by division, while an odds ratio compares the odds of the outcome. These measures answer related but different questions and can differ in magnitude. The posted estimates are 1.19 for the risk ratio and 1.88 for the odds ratio. The registry record does not report an adjusted analysis, so these should be treated as the posted group comparisons rather than as estimates adjusted for participant characteristics.

What does the p-value convey?

General statistical explanation: a p-value describes how unusual data at least as discrepant as those observed would be under a specified null hypothesis and analysis model. It is not the probability that the null hypothesis is true, and it does not measure the probability that the result will replicate. The registry gives an unadjusted p-value of 0.22. The exact test or model associated with that value is not reported in the registry record. The word unadjusted indicates that the posted value is not presented as adjusted for other factors, but the registry record does not explain the testing procedure.

A p-value should be interpreted together with the estimate and confidence interval. A threshold-based label can obscure the range of effect sizes that remain compatible with the data. Here, the interval for the risk difference crosses zero, and the intervals for the relative measures include their null values. This is consistent with uncertainty about the direction and magnitude of the group contrast, rather than a precise estimate.

What does a confidence interval add?

General statistical explanation: a confidence interval gives a range of values generated by a method that, under its assumptions and repeated use, would cover the target parameter at the stated confidence level. It reflects sampling uncertainty but does not incorporate every possible source of bias, such as incomplete follow-up, endpoint misclassification, or differences in how treatment was delivered. The confidence level used for the primary comparison is not reported in the registry record, and no confidence level should be inferred from the sample-size planning assumptions.

The risk-difference interval extends on both sides of zero. Zero is the no-difference value for this absolute measure. The relative-measure intervals include one, their no-relative-difference value. Those features explain why the registry’s estimates do not determine a single direction with precision. The exact interval endpoints are not repeated in this explanation because the central interpretation is the breadth and placement relative to the null value.

What is not specified about the analysis?

Many details needed to reproduce a trial analysis are not reported in the registry record. These include the statistical test or model used for the primary comparison, the confidence level for its intervals, any covariate adjustment, the approach to missing outcome data, and whether analysis followed the randomized assignment regardless of treatment received. The record states that all evaluable patients were compared, but does not define evaluability or explain how participants lacking endpoint information were handled.

The registry lists no posted secondary outcomes and no posted analyses. The record does not describe a prespecified analysis plan, interim analyses, or multiplicity handling. Those absences limit assessment of whether the primary analysis was selected in advance or how other possible analyses were treated. They do not demonstrate that such procedures were or were not used; the details are simply not reported in the registry record.

The outcome is a count of participants with an event, not a rate over person-time. General statistical explanation: count-based binary outcomes are typically compared by accounting for both the number with the outcome and the number assessed in each group. If observations are clustered or repeated, analyses may need to account for that structure, but no such modeling information is reported in the registry record. The parallel-group description identifies the broad structure, not the complete analysis method.

The trial summary describes random assignment, which is intended to support comparable groups on average. Random assignment does not guarantee balance in a particular trial, especially with limited group sizes, and the registry record does not post baseline characteristics. Without those characteristics and the analysis details, readers cannot assess balance or determine whether adjustment would affect the result. The registry comparison remains a useful description of the recorded outcome counts, interpreted with these reporting limits.

10. Confidence Intervals and Precision

Precision concerns how narrowly the data estimate the comparison, not whether a result is important. The risk-difference estimate is 0.125, and its reported confidence interval extends from a value below zero to a value above zero. Because zero represents no absolute difference, this interval includes both directions of the comparison. The range is broad, so the posted data leave substantial uncertainty about the size and direction of the underlying difference.

The relative estimates also have uncertainty. The registry reports a risk ratio of 1.19 and an odds ratio of 1.88; the confidence intervals for both include one, the null value for those measures. Thus the relative comparisons likewise do not isolate a single direction with precision. Absolute and relative scales communicate different aspects of the same data, so neither should be treated as a substitute for the other.

Group sizes for the primary endpoint were 41 and 37, and the recorded outcome counts were 27 and 29. The confidence intervals reflect sampling uncertainty under the methods used to calculate them. They do not automatically account for missing outcomes, departures from the protocol, measurement problems, or other possible biases. The method and confidence level for the primary intervals are not reported in the registry record, which also limits evaluation of their construction.

Precision is not the same as statistical significance or clinical importance. A broad interval can be compatible with effects that would be interpreted differently in practice, while a narrow interval can still describe an effect whose importance depends on context. The registry record does not state a threshold for an important difference. Its estimates therefore describe the observed comparison and its uncertainty without resolving the practical meaning of every value within the interval.

11. Planning a Similar Trial: Sample Size

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

The planning estimates are expressed as participants per arm, not as total events. They illustrate the group sizes that would be required under the stated planning assumptions if the effect to detect were the observed effect or a specified fraction of it. The assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The calculation uses the observed effect as its starting point; it is not observed power. The registry record does not report the trial’s original sample-size justification or design assumptions.

For planning at 100% of the observed effect, the illustration gives 201 participants per arm for 80% power and 268 participants per arm for 90% power. At 75% of the observed effect, it gives 369 participants per arm for 80% power and 493 participants per arm for 90% power. At 50% of the observed effect, it gives 856 participants per arm for 80% power and 1,145 participants per arm for 90% power.

In plain language, the 80% power column describes the illustrative group size associated with an 80% chance of detecting the specified effect under the planning assumptions, if that effect is truly present and the assumptions hold. The 90% column uses a higher target chance of detection and therefore requires more participants for each listed effect. These are planning scenarios, not findings about what the completed trial was capable of detecting.

The smaller the effect being targeted, the more participants the illustration requires. This is because a smaller group contrast is harder to distinguish from random variation. The observed effect may itself be an unstable estimate, particularly with the posted group sizes, so planning directly from it should be viewed as an illustration rather than a definitive design recommendation. The original design rationale is not reported in the registry record.

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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.659; treatment proportion p₁ = 0.784; average p̄ = 0.721.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6342 = 1.2430.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6280 = 0.5285.
4. n = (1.2430 + 0.5285)² / (0.1252)² = 200.0, rounded up to 201 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
p0 <- 0.658536585365854                          # control proportion
p1 <- 0.783783783783784                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(707174)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 201 (80% power), 268 (90% power)
 75% of observed effect: n per arm = 369 (80% power), 493 (90% power)
 50% of observed effect: n per arm = 856 (80% power), 1,145 (90% power)
power.prop.test: 200 
Simulated power at n = 201 per arm: 0.810 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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

Multiplicity arises when a study evaluates multiple outcomes, time points, subgroups, or statistical comparisons. Repeated testing can increase the chance that at least one result appears notable by chance. General statistical explanation: researchers may address this through a prespecified hierarchy, adjustment procedures, or a clearly defined primary analysis. Which approach is appropriate depends on the trial’s aims and analysis plan.

The registry record lists one primary outcome measure and no posted secondary outcomes. It also lists no posted analyses. This does not establish that no other outcomes or analyses were collected; it means that they are not available as posted results in the registry record. The record does not describe a multiplicity plan, a hierarchy of outcomes, adjustment for multiple comparisons, or interim analyses. Those details are not reported in the registry record.

The record identifies the primary outcome population as all evaluable patients from both groups. It does not explain how evaluability was defined, whether all randomized participants had outcome data, or how missing endpoint data were handled. The enrollment is listed as 90, while the posted primary-outcome arms contain 41 and 37 participants. The reasons for the different totals, including whether any participants were ineligible, excluded, or missing outcome data, are not reported in the registry record. No missing-data method or sensitivity analysis is described.

The randomized allocation is relevant to the intended comparison, but the analysis population is not fully characterized. The registry record does not say whether participants were analyzed according to assigned group, according to treatment received, or under another rule. It also does not state whether the comparison was adjusted for baseline factors. These omissions limit assessment of how closely the posted estimate reflects the randomized comparison and how robust it may be to missingness or analysis choices. They should be treated as reporting gaps, not as evidence that a particular method was or was not used.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse events for 46 participants at risk in the imiquimod-only group and 44 in the combination group. It records zero participants affected by a serious adverse event in each group. This is a count of affected participants in the reported safety groups; it does not describe the kinds of non-serious effects or the duration and severity of every event.

For other adverse events, the registry reports one affected participant among 46 at risk in the imiquimod-only group and six among 44 in the combination group. The record does not list the specific terms for these other events. The safety denominators differ from the primary-outcome group counts, so these figures should not be combined with or substituted for the efficacy results.

Deaths are not reported in the registry record. The posted figures are descriptive counts and do not establish whether an event was caused by a study treatment. The registry record does not report a detailed safety-analysis method, event collection period, or attribution process. Zero recorded serious events should therefore be read as the reported count in these groups, not as proof that no serious events could occur.

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

The posted primary results describe a higher count of participants without lentigo maligna at staged excision in the combination arm than in the imiquimod-only arm: 29 of 37 compared with 27 of 41. The estimated risk difference is positive, but its confidence interval crosses zero, and the unadjusted p-value is 0.22. The risk-ratio and odds-ratio intervals also include their respective null values. Together, these results show an uncertain comparison rather than a precise estimate of a group difference.

The figures do not establish that adding tazarotene caused the difference in the observed counts. Randomization supports a comparative design, but the registry record does not report enough analysis detail to assess all aspects of the comparison, including handling of missing outcomes and the exact statistical procedure. The posted primary-outcome population is described as evaluable patients, and the definition of that population is not given.

The endpoint is absence of lentigo maligna at staged excision, not long-term freedom from recurrence. Although the study summary describes planned follow-up of five years, no recurrence results are posted among the registry outcomes. The primary outcome’s stated timeframe is 24 months. The posted results therefore should not be extended to claims about recurrence over the full planned follow-up or about outcomes that were not measured in the reported endpoint.

The adverse-event counts provide a separate descriptive view: no serious adverse events were recorded among the safety participants at risk, and other adverse events affected one participant in the imiquimod-only group and six in the combination group. Specific event types and deaths are not reported in the registry record. These counts do not establish causation and should not be interpreted as a complete account of treatment safety.

Overall, the registry results allow readers to describe the recorded outcome counts and the uncertainty around their comparison. They do not answer every question about treatment delivery, recurrence, safety attribution, or clinical importance. The registry record does not state what magnitude of difference would be important, so the statistical estimates should not be converted into a treatment recommendation.

16. Why This Trial Matters Statistically

This trial raises a useful statistical question about how to compare treatment strategies when the measured endpoint is tied to a later surgical assessment. The registry summary describes topical treatment followed by staged excision and histologic margin assessment. That means the primary result is not simply a symptom score or a direct measure of topical response; it is a binary outcome recorded in the context of staged surgery. Clearly identifying what counts as the endpoint is essential for understanding what the comparison does and does not address.

The randomized parallel-group design provides a framework for comparing imiquimod alone with imiquimod plus tazarotene. The posted counts give the reader a direct view of the number of participants recorded with the outcome in each group. The accompanying absolute and relative effect estimates add different perspectives, while their confidence intervals emphasize that the data remain uncertain. This illustrates why an estimate should be interpreted with its precision rather than by its direction alone.

The record also highlights the importance of reporting the analyzed population and missing-data handling. Enrollment is listed as 90, while the primary outcome counts use 41 participants in one arm and 37 in the other. The record describes these as evaluable patients but does not explain the difference in populations. Without those details, readers cannot determine how exclusions or unavailable outcomes might affect interpretation.

Finally, the study summary describes longer-term recurrence follow-up, but the posted primary outcome is at staged excision and no recurrence outcome is posted. This distinction matters: a trial’s planned clinical pathway and follow-up can be broader than the results currently available in a registry. Separating the endpoint actually reported from outcomes that were planned or not posted is a basic part of responsible statistical interpretation.

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.

Several trial-specific reporting gaps constrain interpretation. The registry lists enrollment of 90, but primary-outcome results include 41 participants in the imiquimod-only group and 37 in the combination group. The outcome population is described as evaluable patients, yet the meaning of evaluable and the reasons that the posted group counts differ from enrollment are not reported in the registry record. The record also does not explain whether missing outcome data occurred or how any such data were handled.

The treatment description for the imiquimod-only arm ends mid-sentence after describing a washout period. The combination arm is described as adding weekend tazarotene to the imiquimod protocol, but the registry record does not provide a complete account of treatment adherence, deviations, or treatment completion. The planned surgical procedure and long-term follow-up are described, but completion of each component is not reported as a result.

The primary outcome is framed as absence of lentigo maligna at staged excision, with a 24-month timeframe. The registry record does not provide a posted recurrence result, despite describing planned follow-up to assess recurrence. It also does not report baseline characteristics, endpoint adjudication details, the primary analysis method, adjustment variables, confidence level, or a prespecified analysis plan. These omissions prevent a full assessment of comparability, reproducibility, and robustness.

Safety reporting is also limited: specific terms for the other adverse events are not listed, and deaths are not reported in the registry record. The record does not describe event attribution or the period over which events were collected. These are limits on what can be concluded from the registry results, rather than evidence that particular events, methods, or procedures were absent.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Combination Therapy With Imiquimod Cream 5% and Tazarotene Cream 0.1% for the Treatment of Lentigo Maligna — NCT00707174.
• Registry record last updated 2013-07-31; status last verified 2013-07.
• Results first posted 2012-08-20.
• 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

The registry record identifies a completed randomized, prospective, parallel-group study with no masking and enrollment of 90. It compares imiquimod 5% cream alone with imiquimod 5% cream plus tazarotene 0.1% for lentigo maligna. The study summary describes staged excision and histologic margin assessment for both groups, with longer-term follow-up planned.

The posted primary outcome counts participants without lentigo maligna at staged excision. Results include 27 of 41 participants in the imiquimod-only group and 29 of 37 in the combination group. The risk-difference estimate is positive, but the reported confidence interval crosses zero and the unadjusted p-value is 0.22. The registry also reports descriptive adverse-event counts, with zero serious events recorded in either safety group.

The registry record does not post secondary outcomes or analyses and does not report key details about missing data, analysis populations, multiplicity, or the original sample-size justification. Long-term recurrence results are not posted. The findings therefore describe the recorded endpoint and its uncertainty, with important limits on further interpretation.