Safety and Efficacy of Ingenol Mebutate 0.05% Gel When Used After Cryotherapy in the Hypertrophic Actinic Keratoses: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Ingenol Mebutate 0.05% Gel When Used After Cryotherapy in the Hypertrophic Actinic Keratoses (NCT02251652), a randomized phase 4 study. The primary outcome is Safety of Combination Therapy vs Cryotherapy Alone.

2. Clinical Question

3. Trial Design

This is a Phase 4, randomized, parallel-group study with single masking. The registry lists two arms: Combination Therapy, described as cryotherapy followed by ingenol mebutate gel, and Cryotherapy Alone. The official title identifies the treatment setting as hypertrophic actinic keratoses on dorsal hands. The condition listed in the record is actinic keratoses.

The registry lists enrollment as 16. The posted arm results give n=16 for Combination Therapy and n=16 for Cryotherapy Alone. Those entries do not reconcile with the enrollment field, and the registry record does not explain the difference. They should therefore be read as separate registry entries rather than as a reconciled account of enrollment or allocation.

The study start is recorded as 2013-04, primary completion as 2014-12, and status as COMPLETED. The sponsor is Icahn School of Medicine at Mount Sinai. The masking field says SINGLE, but whom it applied to and how masking was maintained are not reported in the registry record. Further information about randomization procedures, allocation concealment, sites, participant characteristics, treatment administration, adherence, and follow-up beyond the stated outcome timeframes is not reported in the registry record.

The registry also describes an interest in whether sequential treatment could address non-hypertrophic and subclinical lesions. The listed secondary outcomes concern change in the number of all actinic keratoses and change by anatomic site. A separately defined subclinical-lesion outcome is not reported in the registry record.

4. Participant Flow and Accounting

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

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 Safety of Combination Therapy vs Cryotherapy Alone, measured over Day 57.

The primary outcome is titled “Safety of Combination Therapy vs Cryotherapy Alone.” It is a count of participants, with the outcome timeframe listed as Day 57. The description says safety is evaluated by looking at adverse events after cryotherapy plus ingenol mebutate on dorsal hands and comparing that with cryotherapy alone. In this posted outcome, the relevant measure is whether a participant is counted as having an event, rather than a measure of event severity or a rate over person-time.

Adverse-event outcomes are used to describe unwanted events observed during a study and to compare their occurrence between groups. General statistical interpretation: a participant count can make the comparison straightforward, but its meaning depends on how events were defined, collected, and attributed, and on the observation period. Those operational details are not reported in the registry record. The registry separately lists serious and other adverse-event summaries, including deaths; those figures provide additional safety context but do not replace the stated primary outcome.

The posted primary results report zero participants with an event in each arm. That is a statement about the recorded outcome in this study and its stated timeframe. It does not establish that events cannot occur, and it does not by itself describe safety outside the study conditions or beyond Day 57.

7. Results Posted in the Registry

• Cryotherapy Alone: 0.0% (0/16) versus 0.0% (0/16) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.

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 Number of All Actinic Keratoses

• 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:
  • Cryotherapy Alone: mean -2.50 versus -4.60 on control; difference 2.10 (95% CI 0.63 to 3.57), standardized effect d = 0.99; z-test p = 0.005.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Cryotherapy Alone than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The listed secondary outcomes cover change in the number of all actinic keratoses and change by anatomic site. The posted numerical comparison is for change in the number of all actinic keratoses from Baseline to Day 57. The record does not include a reported analysis for that outcome, and it does not provide numerical results for the change-by-site outcome in the posted results. The registry record therefore offers a limited view of the secondary outcome pattern.

These outcomes address lesion counts rather than adverse events. They provide a different kind of information from the primary safety endpoint and should be interpreted on their own terms. A count change does not establish whether adverse events occurred, and a zero count for the primary event outcome does not determine how lesion counts changed. The secondary data can add context about measured changes in actinic keratoses, but they do not resolve the limited information in the zero-event safety comparison.

The posted secondary comparison has an unadjusted p-value. Unadjusted results do not account for the possibility that several outcomes or comparisons were examined. If multiple tests are considered, the chance of at least one apparently notable result can increase; methods for handling this issue depend on the analysis plan. The registry does not report a multiplicity strategy, so the secondary p-value should not be treated as if it were adjusted or as definitive on its own.

The registry record gives no detailed analysis populations, missing-data methods, or explanation of how each secondary outcome was measured and analyzed. It also does not provide the numerical results for the listed anatomic-site outcome in the posted results. Accordingly, the secondary evidence is incomplete as a set: the available comparison can be described, but the overall pattern across all listed secondary outcomes cannot be fully assessed from the registry record.

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

• Change in Number of All Actinic Keratoses
• Change in Actinic Keratoses by Anatomic Site

9. Statistical Interpretation

10. Statistical Methods Explained

The posted results include a binary primary safety measure and a continuous secondary measure. These data types call for different summaries. A binary outcome indicates whether a participant had the event or did not. A continuous outcome, such as percent change in the number of actinic keratoses, is summarized by a mean and a standard deviation. The registry reports the outcome values and comparisons, but does not give a complete statistical analysis plan.

How should the primary comparison be read?

The primary measure is a participant count. The registry reports zero participants with an event in each group, and the comparison is expressed as a risk difference. A risk difference describes the absolute contrast in the observed event proportions between groups. General statistical explanation: a risk difference of zero means the observed proportions match; it does not establish that the underlying risks are exactly equal. When both observed counts are zero, there is no observed event contrast to estimate beyond zero, and the result cannot show how the groups would compare if events were observed.

The posted risk-difference interval also runs from 0.0 to 0.0. An interval is intended to convey uncertainty around an estimate under the assumptions of the method used. The registry does not identify the method used to produce the primary interval, and the zero-event pattern makes a conventional interval difficult to interpret as a measure of all uncertainty. The record does not report a primary p-value or an inferential analysis for this outcome. The result should therefore be described as a posted count and contrast, without assigning it a stronger statistical conclusion.

What do the secondary means describe?

For the change in all actinic keratoses, the posted group means are -4.6 for Combination Therapy and -2.5 for Cryotherapy Alone, measured as percent change from Baseline to Day 57. A negative percent change indicates a decline relative to the baseline measurement. The standard deviations are 2.66 and 1.37, respectively. A standard deviation describes the spread of observations around a group mean; it is not the uncertainty in the mean itself and is not a confidence interval.

The registry posts a mean difference of 2.1, with an interval from 0.634 to 3.566. It also posts an unadjusted p-value of 0.005. A mean difference expresses a contrast between group means, while a confidence interval indicates a range of estimates compatible with the data and the method’s assumptions. The sign and group ordering matter when interpreting the contrast; the registry’s comparison identifies Cryotherapy Alone as the compared arm and Combination Therapy as the control. The reported means should be retained alongside the contrast so the direction is not inferred from the difference alone.

The comparison is labeled as recalculated from posted summary statistics. Such a recalculation is an unadjusted comparison derived from the reported group summaries; it is not a substitute for a prespecified model or analysis conducted on participant-level data. No sponsor-reported analysis is listed for the secondary outcome. The registry does not report whether the means were adjusted, whether the analysis accounted for baseline values, or whether the comparison used a particular model. No particular model should be assumed.

Why does over-dispersion matter in general?

General statistical explanation: for count outcomes, over-dispersion means the variation in the counts is greater than a model’s assumed variation. If a model assumes less variability than is present, its standard errors can be too small and its intervals too narrow. Methods designed for over-dispersed counts can account for that extra variation. The posted secondary endpoint is expressed as percent change and summarized with means and standard deviations; the registry does not report a count-model analysis or describe an over-dispersion assessment. It would therefore be inappropriate to claim that such a model was used or needed for the posted comparison.

What can planning illustrations tell readers?

The planning illustrations are explicitly based on the observed effect and are not the trial’s own design justification. They use a two-sided significance level of 0.05, equal allocation, and a normal approximation. For planning for 100% of the observed effect, the illustration gives 16 participants per arm for 80% power and 22 participants per arm for 90% power. For planning for 75% of the observed effect, it gives 29 participants per arm for 80% power and 38 participants per arm for 90% power. For planning for 50% of the observed effect, it gives 64 participants per arm for 80% power and 86 participants per arm for 90% power.

These are planning illustrations, not observed power and not evidence about the probability that the trial detected an effect. They are conditional on assumptions and on effect sizes taken from this study’s observed comparison. A future study planning around a smaller effect would require more participants per arm under these assumptions. The trial’s own sample-size justification and design assumptions beyond the listed illustration are not reported in the registry record.

11. Confidence Intervals and Precision

Precision concerns how much uncertainty surrounds an estimate, not whether a result is clinically important. For the primary safety comparison, the posted risk difference is 0.0 and the confidence interval runs from 0.0 to 0.0. This reflects the recorded zero-event counts in both arms, but it should not be read as a precise demonstration that the underlying event risks are equal. With no observed events, the posted comparison has no event-based variation to distinguish the groups; it cannot rule out event risks that were not observed in this study.

For the secondary mean difference in percent change, the posted estimate is 2.1 and the interval runs from 0.634 to 3.566. The interval is on the positive side of zero, and the registry reports an unadjusted p-value of 0.005. These are summaries of the recalculated comparison based on the posted group statistics. The registry does not report a sponsor analysis or explain the method used to form this interval. Its interpretation therefore depends on assumptions that cannot be checked from the record alone.

A confidence interval is not a range that guarantees the true value lies within its limits. General statistical explanation: it summarizes the uncertainty expected from a specified method when its assumptions hold. It does not account automatically for missing data, selective reporting, measurement error, or multiple comparisons. The registry record does not give enough detail to assess these issues fully.

The planning illustrations use the observed effect and stated planning assumptions. They can help illustrate how sample size changes when the target effect changes, but they do not make the estimates from this completed study more precise. The discrepancy indicator is false, so no flagged conflict is identified; nonetheless, the mismatch between listed enrollment and per-arm sample sizes remains unexplained. That reporting uncertainty is separate from the numerical confidence intervals.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary safety outcome and secondary outcomes concerning changes in actinic keratosis counts. It does not report a statistical plan specifying which comparisons were confirmatory, how many hypotheses were intended to be tested, or whether any multiplicity adjustment was planned. Multiplicity refers to the increased chance of a false-positive finding when several statistical tests are considered. General statistical explanation: adjustments or a prespecified hierarchy can help control that risk, but their choice depends on the questions and design.

The secondary comparison has an unadjusted p-value of 0.005. Because the record does not describe multiplicity handling, that value should be interpreted as unadjusted. The record also gives no sponsor-reported analysis for the secondary outcome. The reported comparison is a recalculation from summary statistics, and its p-value should not be treated as evidence that a broader testing strategy was satisfied.

Missing-data methods and analysis populations are not reported in the registry record. It does not state whether participants were analyzed according to random assignment, whether all randomized participants contributed to each outcome, how missing endpoint observations were handled, or whether any imputation was used. The discrepancy between enrollment listed as 16 and the n=16 entries for each arm is also not explained. Without participant flow and population definitions, the scope of the posted estimates cannot be established more precisely.

The record does not report interim analyses, a sample-size justification, or a prespecified statistical analysis plan. These omissions do not prove that such planning or methods were absent; they mean that they are not documented in the registry record. The planning illustrations are explicitly not the trial’s own design calculation. They should not be used to fill in missing information about design intent or analysis procedures.

13. Safety Results

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

Deaths

Other (non-serious) adverse events

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

The registry reports zero serious adverse events in Combination Therapy and zero in Cryotherapy Alone. Each group is listed with 16 participants at risk, and the posted serious adverse-event counts are zero. The record also lists zero other adverse events and zero deaths in each group. These are event summaries in the registry, not a demonstration that no event could occur outside the observed study circumstances.

The primary safety outcome also reports zero participants with an event in each arm at Day 57. The registry does not define the terms used to classify serious and other events, describe how events were elicited, or report event attribution and severity details. No serious adverse-event terms are listed. These absences limit assessment of the breadth and consistency of safety reporting.

With zero recorded events, there is no observed difference in these counts between groups. The data do not establish equivalence, exclude uncommon events, or support conclusions beyond the recorded follow-up and definitions. The registry record does not provide further safety analyses or details needed to interpret event ascertainment.

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

The posted results describe a randomized comparison of cryotherapy followed by ingenol mebutate gel with cryotherapy alone. They show zero participants with a primary safety event in either arm at Day 57 and report zero serious adverse events, other adverse events, and deaths in each group. The secondary comparison reports changes in all actinic keratoses and an unadjusted statistical result. These are observations in the registry record, not general guarantees about outcomes.

The zero-event primary result does not demonstrate that the treatments have identical safety profiles. It means that the recorded primary event count did not differ in this study. Rare or unobserved events remain possible, and the record does not provide enough methodological detail to assess event collection or the precision of underlying risks. The result also cannot support conclusions about safety beyond the stated timeframe.

The secondary measure is not the primary safety endpoint. Its mean comparison concerns percent change in actinic keratosis counts, and its unadjusted p-value does not establish a causal or broadly generalizable conclusion by itself. The registry does not report multiplicity handling, analysis populations, missing-data procedures, or a sponsor analysis for that comparison. The listed outcome concerning change by anatomic site has no numerical result in the posted results.

The record identifies the intended treatment setting as hypertrophic actinic keratoses on dorsal hands, but it does not report participant characteristics or detailed eligibility criteria. Generalizability to people or settings not described in the record cannot be evaluated. The enrollment entry and per-arm sample-size entries also remain unreconciled. The findings should therefore be read as descriptive results with important reporting limits, not as medical advice or a definitive judgment about treatment.

15. Why This Trial Matters Statistically

This study is statistically informative in part because it illustrates how different endpoints can tell different kinds of stories. The primary endpoint is a safety count, while the secondary measure concerns change in lesion counts. A result on one does not automatically answer the other. Keeping outcome type and purpose clear prevents a secondary efficacy-related measure from being mistaken for evidence about the primary safety question.

The zero-event pattern also shows why a point estimate alone can be misleading. Equal observed counts produce a zero risk difference, but that does not mean the data establish equal underlying risks. Statistical interpretation must distinguish the observed result from what remains uncertain, especially when no events are recorded. The posted interval does not remove that limitation.

The secondary comparison illustrates the separate role of unadjusted analyses. A p-value can summarize compatibility with a null comparison under particular assumptions, but it does not address multiplicity, missingness, or how the analysis was prespecified. Since those details are not reported, the numerical result should be considered alongside the reporting limits rather than on its own.

The registry also presents a practical data-quality issue: its enrollment field differs from the sample sizes listed for each arm, without an explanation. This is not resolved by statistical recalculation. Clear participant flow, analysis populations, endpoint definitions, and analysis methods are important for evaluating how estimates were produced and whom they represent. Those details are not reported in the registry record, so the statistical conclusions remain bounded by the information recorded.

16. 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 posted record. The enrollment field lists 16, while the results list n=16 for each arm. The record does not explain this discrepancy or provide participant flow, so the relationship between enrollment and the analyzed groups is unclear. It also does not identify the analysis population underlying the primary or secondary results.

The primary safety outcome is reported at Day 57, and the adverse-event summaries report zero serious events, other events, and deaths in each group. The registry record does not define event collection or classification, give details about severity or attribution, or describe follow-up outside the stated timeframe. The absence of recorded events should not be extended beyond those reported conditions.

The secondary outcome by anatomic site is listed, but numerical results are not reported in the results. No separate subclinical-lesion outcome is reported, despite the brief summary describing interest in potential treatment of subclinical lesions. The available secondary analysis is unadjusted, and no multiplicity strategy, missing-data approach, or sponsor-reported analysis is given.

Randomization methods, allocation concealment, the identity of those masked, participant characteristics, eligibility criteria, treatment adherence, and detailed measurement procedures are not reported in the registry record. The record also does not provide a sample-size justification or a full analysis plan. These omissions restrict assessment of bias, applicability, and the assumptions behind the posted estimates. They should be treated as reporting limitations, not as evidence that a particular procedure was or was not used.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Safety and Efficacy of Ingenol Mebutate 0.05% Gel When Used After Cryotherapy in the Hypertrophic Actinic Keratoses — NCT02251652.
• Registry record last updated 2017-04-26; status last verified 2017-03.
• Results first posted 2017-04-26.
• 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.

20. Record Summary

NCT02251652 is a completed Phase 4 randomized, single-masked, parallel-group study sponsored by Icahn School of Medicine at Mount Sinai. It compares cryotherapy followed by ingenol mebutate 0.05% gel with cryotherapy alone for actinic keratoses, with the official title specifying hypertrophic lesions on dorsal hands. The registry lists enrollment as 16 and records the study start as 2013-04 and primary completion as 2014-12.

The primary safety outcome is a participant count at Day 57. The posted results report zero participants with an event in each arm, with a risk difference of 0.0 and an interval from 0.0 to 0.0. Serious adverse events, other adverse events, and deaths are also reported as zero in each group. For change in all actinic keratoses from Baseline to Day 57, the registry posts means of -4.6 and -2.5, a mean difference of 2.1, and an unadjusted p-value of 0.005.

The record does not reconcile enrollment with the arm sample sizes or report a full analysis plan, analysis populations, missing-data methods, or multiplicity handling. These gaps limit interpretation of the posted results.