An Equivalence Study of Generic Ingenol Mebutate Gel 0.015% and Picato Gel 0.015% in Subjects With Actinic Keratosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for An Equivalence Study of Generic Ingenol Mebutate Gel 0.015% and Picato Gel 0.015% in Subjects With Actinic Keratosis (NCT03200912), a randomized phase 3 study. The primary outcome is Complete Clearance of AK Lesions.

2. Clinical Question

3. Trial Design

This was a Phase 3, randomized, multicenter, quadruple-masked, parallel-group, vehicle-controlled study. The official title describes a comparison of generic ingenol mebutate gel and Picato gel in participants with actinic keratosis on the face or scalp. The registry lists enrollment of 507 and a completed study, with a start date of 2016-08-19 and primary completion date of 2017-03-07.

Participants were assigned to generic ingenol mebutate, Picato, or vehicle gel. The posted primary outcome counts are 45 of 137 for generic ingenol mebutate, 44 of 144 for Picato, and 7 of 139 for vehicle gel. The primary outcome analysis population is identified as the per-protocol population. The registry does not explain how participants entered or were excluded from that population, or how it relates to the overall enrollment.

The study’s stated objective combined two aims: evaluating therapeutic equivalence between the active products and establishing superiority of each active product over vehicle. The posted sponsor analysis is labeled as an equivalence analysis for the active-product comparison. The registry also posts unadjusted recalculations comparing each active group with vehicle. These analyses address related but different contrasts and should not be read as interchangeable.

The title and summary state a concentration of 0.015%, but the arm descriptions state 0.15%. This inconsistency is present in the registry record. The original sample-size rationale, allocation details beyond randomization, masking procedures, equivalence margin, and planned statistical analysis are 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.

Before assignment: The populations for this study included the Safety Population, the Per-Protocol Population, and the modified Intent-to-Treat (mITT) population.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: AK Complete Clearance Rate at Day 57 (PP population)

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.

Population: Subjects are from Safety Population

6. Primary Endpoint

The registry lists the primary outcome as Complete Clearance of AK Lesions, measured over 57 days.

The primary endpoint was complete clearance of actinic keratosis lesions at Day 57. A participant was counted as having treatment success if there were no clinically visible actinic keratosis lesions in the treatment area. The posted result is a participant count, so the outcome is binary at the individual level: each participant either met the complete-clearance definition or did not.

Complete clearance is a direct way to express whether the specified lesion state was present at the assessment time. It differs from measuring a change in lesion count: a participant with some remaining lesions does not meet the complete-clearance definition, even if the number of lesions has decreased. The registry does not post a separate lesion-count outcome or a further description of how the treatment area was assessed.

The endpoint is reported at Day 57 and for the per-protocol population. Its interpretation therefore concerns the recorded clearance status at that time in that analysis population, rather than a longer-term outcome or all enrolled participants. The registry record does not report details about assessment procedures, assessor training, or handling of participants without an evaluable Day 57 outcome.

7. Results Posted in the Registry

• Generic Ingenol Mebutate: 32.8% (45/137) versus 5.0% (7/139) on control; risk difference 27.8 percentage points (95% CI 19.1 to 36.5), risk ratio 6.52 (3.05–13.95); unadjusted two-proportion z-test p = <0.001.
• Picato (Ingenol Mebutate): 30.6% (44/144) versus 5.0% (7/139) on control; risk difference 25.5 percentage points (95% CI 17.2 to 33.9), risk ratio 6.07 (2.83–13.01); unadjusted two-proportion z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

What does the risk difference describe?

A risk difference subtracts the event proportion in one group from the event proportion in another. For this binary endpoint, the event is complete clearance. A positive risk difference in the posted comparisons means the observed clearance proportion was higher in the active-product group than in the vehicle group. The recalculated estimates are 0.278 for generic ingenol mebutate versus vehicle and 0.255 for Picato versus vehicle. They are simple, unadjusted comparisons based on the posted counts and denominators, not adjusted estimates from a model reported by the sponsor.

The risk difference is expressed on the proportion scale. It directly describes the absolute separation between the two observed group proportions. Other measures can describe relative separation, but they answer a different question and can make the size of an effect appear different because their scales differ.

What do the relative measures add?

The registry’s recalculations also give risk ratios and odds ratios. For generic ingenol mebutate versus vehicle, the risk ratio is 6.522, with a confidence interval from 3.049 to 13.95, and the odds ratio is 9.224, with a confidence interval from 3.983 to 21.36. For Picato versus vehicle, the risk ratio is 6.067, with a confidence interval from 2.83 to 13.01, and the odds ratio is 8.297, with a confidence interval from 3.586 to 19.2.

A risk ratio compares the event proportions as a ratio. An odds ratio compares the odds of the event. Because odds and probabilities are not the same quantity, an odds ratio should not be read as though it were a risk ratio. The risk difference remains useful for understanding the absolute separation in this trial, while the relative measures express comparisons on other scales. Each measure is derived from the same posted endpoint counts and does not provide independent evidence.

How should the p-values be read?

The recalculated p-values are p < 0.001 for each active-product comparison with vehicle. A p-value describes how incompatible the observed data are with a specified null model, under the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not measure the clinical importance of the observed difference. These values are explicitly unadjusted; the registry does not report whether the sponsor used a multiplicity procedure.

What is different about an equivalence analysis?

An equivalence analysis asks whether the difference between two treatments is sufficiently small to fall within prespecified acceptable bounds. A failure to find a statistically detectable difference is not, by itself, evidence of equivalence. The confidence interval must be evaluated against an equivalence margin set before interpreting results. The registry reports a sponsor analysis labeled equivalence, with a net mean difference of 2.29 and a 90% confidence interval from -7.55 to 12.14. It does not report the margin, the units of the estimate, or the analysis method. The posted binary risk-difference recalculations compare each active product with vehicle, not generic ingenol mebutate with Picato, and therefore do not recreate the sponsor’s equivalence analysis.

Why do the analysis population and outcome matter?

The endpoint is a participant-level count of complete clearance, and the primary population is identified as per protocol. A per-protocol analysis generally concerns participants meeting specified protocol conditions, but the registry does not state those conditions or identify the exclusions. Results in that population can differ from results based on all randomized participants. Missing-data handling and participant flow are also not reported, so the posted denominators cannot be fully reconciled with enrollment from the registry record alone.

The study includes vehicle comparisons and an active-product equivalence question. Those questions involve distinct contrasts and may require distinct inferential criteria. The record does not provide the original statistical analysis plan, the sponsor’s method for the binary outcome, or details of any interim analysis. No such methods should be inferred from the recalculated statistics.

10. Confidence Intervals and Precision

A confidence interval gives a range of values compatible with the data and the stated method, subject to the method’s assumptions. It communicates uncertainty around an estimate; it is not a guarantee that the true value lies in the interval, nor does it describe the range of individual participant outcomes.

For generic ingenol mebutate versus vehicle, the recalculated risk difference is 0.278, with a 95% confidence interval from 0.192 to 0.365. For Picato versus vehicle, the recalculated risk difference is 0.255, with a 95% confidence interval from 0.172 to 0.339. Both intervals lie above zero, consistent with the higher observed clearance proportions in the active-product groups under these unadjusted comparisons. The interval widths also show that the estimates are not exact values; a range of effect sizes remains compatible with the posted data and calculation.

The sponsor-reported equivalence analysis has a different form: a net mean difference of 2.29, with a 90% confidence interval from -7.55 to 12.14. The registry does not state the units, method, or equivalence bounds. As a result, that interval cannot be judged against the criterion required for an equivalence conclusion from the registry record alone.

Precision is influenced by the number of observed outcomes and the number of participants contributing data, as well as the variability and analysis method. The per-protocol denominators are the basis for the posted primary outcome results. The registry does not report missing-outcome details or the method used to construct the sponsor’s interval. The confidence intervals should therefore be interpreted alongside the limitations in the reported analysis information.

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 figures are participants per arm, not total events. They are illustrations based on the observed effect, not the trial’s original design assumptions. The illustration uses a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is the stated fraction of the observed effect. The original trial’s sample-size assumptions are not reported in the registry record.

For the generic ingenol mebutate versus vehicle comparison, planning for 100% of the observed effect gives 30 participants per arm for 80% power and 40 participants per arm for 90% power. Planning for 75% of the observed effect gives 46 participants per arm for 80% power and 62 participants per arm for 90% power. Planning for 50% of the observed effect gives 85 participants per arm for 80% power and 113 participants per arm for 90% power.

For the Picato versus vehicle comparison, planning for 100% of the observed effect gives 35 participants per arm for 80% power and 46 participants per arm for 90% power. Planning for 75% of the observed effect gives 53 participants per arm for 80% power and 70 participants per arm for 90% power. Planning for 50% of the observed effect gives 97 participants per arm for 80% power and 129 participants per arm for 90% power.

The 80% and 90% columns describe the planned probability of detecting the specified effect under the illustration’s assumptions if that effect were present. A smaller effect is harder to distinguish from random variation, so the planning figures require more participants per arm when the target is a smaller fraction of the observed effect. These calculations are not observed power and do not describe what power the completed trial achieved.

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 = 0.050; treatment proportion p₁ = 0.328; average p̄ = 0.189.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5541 = 1.0861.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5181 = 0.4360.
4. n = (1.0861 + 0.4360)² / (0.2781)² = 30.0, rounded up to 30 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 <- 0.0503597122302158                          # control proportion
p1 <- 0.328467153284672                          # 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(3200912)
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 = 30 (80% power), 40 (90% power)
 75% of observed effect: n per arm = 46 (80% power), 62 (90% power)
 50% of observed effect: n per arm = 85 (80% power), 113 (90% power)
power.prop.test: 30 
Simulated power at n = 30 per arm: 0.836 (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. Analyses Reported by the Sponsor

The registry reports the sponsor’s active-product comparison as an equivalence analysis. Its estimate is a net mean difference of 2.29, with a 90% confidence interval from -7.55 to 12.14. The method, units, and equivalence margin are not reported in the registry record. Equivalence depends on comparing an appropriate confidence interval with prespecified bounds; the interval alone, without those bounds and metric details, is not enough to assess the criterion.

The recalculated statistics address different comparisons. They use the posted binary clearance counts to compare generic ingenol mebutate with vehicle and Picato with vehicle. They are unadjusted calculations and do not reproduce the sponsor’s generic-versus-Picato analysis. The risk differences, risk ratios, odds ratios, and p-values therefore provide context for the active-versus-vehicle results, but they do not replace or verify the sponsor-reported equivalence analysis.

The registry does not report the sponsor’s analysis method for the equivalence statistic or a detailed statistical analysis plan. Consequently, the relation between the reported net mean difference and the binary complete-clearance endpoint is not explained. The sponsor’s label identifies the intended analysis type, but the missing margin and method limit independent interpretation.

14. Multiplicity, Missing Data and Analysis Populations

The registry identifies the primary outcome population as the per-protocol population. It does not report the full analysis-population definitions, the criteria for inclusion in the per-protocol analysis, or participant flow from enrollment to the posted denominators. Enrollment is listed as 507, while the primary outcome denominators are 137, 144, and 139. The registry record does not explain the difference between enrollment and these analysis counts.

Missing-data handling is not reported in the registry record. It is not stated how participants without an evaluable Day 57 assessment were treated, whether any outcomes were imputed, or whether sensitivity analyses were conducted. Without this information, the effect of missing assessments on the posted estimates cannot be assessed from the registry record.

The objective includes comparisons of each active product with vehicle and an equivalence comparison between the active products. The registry lists one outcome measure and one analysis, but that does not establish how the different comparisons were prespecified or whether multiplicity was addressed. The recalculated p-values are unadjusted. Adjustment procedures, if any, are not reported in the registry record.

The statistical analysis plan, interim-analysis procedures, and original sample-size justification are not reported in the registry record. The randomized, masked design is described, but details about allocation implementation, masking assessment, protocol deviations, and analysis handling are not posted in the registry record. These omissions limit evaluation of how closely the reported analyses followed the intended protocol and how robust the results are to alternative analysis choices.

15. 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.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (0.6%), breast cellulitis (0.6%), diverticulitis (0.6%), atrial fibrillation with hospitalization (0.6%).

The registry lists serious adverse events for 2 of 170 participants in the generic ingenol mebutate group, 0 of 169 in the Picato group, and 2 of 168 in the vehicle group. These are counts within the recorded at-risk populations. The registry also lists pneumonia, breast cellulitis, diverticulitis, and atrial fibrillation with hospitalization among the serious adverse event terms, each at 0.6%.

These safety counts are separate from the primary clearance outcome and should not be interpreted as evidence about the comparative risk of an event without considering the full safety definitions and follow-up. The registry record does not describe event attribution, timing, duration, or the criteria used to classify events as serious. It also lists deaths as 29 for generic ingenol mebutate, 29 for Picato, and 24 for vehicle gel, but does not explain the definition, timing, or relation of those entries to treatment or adverse events. The listed figures alone do not establish causation.

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

The posted Day 57 data show complete clearance in 45 of 137 participants in the generic ingenol mebutate group, 44 of 144 in the Picato group, and 7 of 139 in the vehicle group, within the per-protocol population. The unadjusted recalculations show higher observed clearance proportions for each active product than for vehicle, with confidence intervals for the risk differences above zero and p-values of p < 0.001. These statements describe the registry results and the specified recalculations.

The registry also reports an equivalence analysis comparing generic ingenol mebutate with Picato. That analysis gives a net mean difference of 2.29 and a 90% confidence interval from -7.55 to 12.14. Because the equivalence margin, units, and method are not reported, the posted information is insufficient to independently determine whether the sponsor’s equivalence criterion was met. The active-versus-vehicle recalculations do not answer that equivalence question.

These results do not establish how the findings apply beyond the analyzed participants, the treatment area, the Day 57 assessment, or the per-protocol population. They also do not resolve the inconsistency between the 0.015% concentration in the title and summary and the 0.15% concentration in the arm descriptions. Missing-data handling, participant flow, and details of the original analysis plan are not reported in the registry record.

The statistical evidence should therefore be read as a set of specific comparisons with stated populations and limitations, not as a complete account of all clinical outcomes or longer-term effects. The posted primary endpoint concerns complete lesion clearance at one stated assessment time; it does not report other dimensions of clinical response or safety in detail.

17. Why This Trial Matters Statistically

This trial illustrates why the statistical question must match the comparison being made. Comparing each active product with vehicle addresses differences in the observed clearance proportions. Comparing the generic product with Picato for equivalence requires a separate analysis and a prespecified equivalence margin. A result that distinguishes an active product from vehicle does not, by itself, establish equivalence between active products.

It also shows why the analysis population matters. The primary outcome is reported for a per-protocol population, while enrollment and outcome denominators differ. Without participant flow and missing-data details, readers cannot fully assess which participants contribute to the primary comparison or how exclusions may affect interpretation.

The confidence intervals provide information about precision beyond the p-values. They indicate a range of effect sizes compatible with the unadjusted comparisons, while the reported equivalence interval cannot be judged without its margin and analysis details. This distinction is central to interpreting a study with both superiority and equivalence objectives.

Finally, the registry record contains information gaps and a concentration inconsistency. Statistical interpretation depends not only on numerical results but also on clear definitions of the intervention, endpoint, analysis population, and decision criteria. When these details are absent or conflicting, conclusions should remain bounded by what the record actually documents.

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.

The primary outcome is reported for the per-protocol population, but the registry does not provide participant flow, criteria for inclusion in that population, or reasons participants may not have contributed to the result. Enrollment is listed as 507, whereas the outcome denominators are 137, 144, and 139. The registry does not reconcile these counts or report missing-outcome handling.

The concentration is inconsistent across the record: the title and brief summary state 0.015%, while the arm descriptions state 0.15%. This prevents the intervention concentration from being established consistently from the registry entry alone.

The sponsor’s equivalence analysis lacks the reported margin, method, and units needed for independent assessment. The relationship between its net mean difference and the binary complete-clearance endpoint is not explained. The recalculated active-versus-vehicle comparisons are unadjusted and do not substitute for the sponsor’s active-product equivalence analysis.

The original statistical analysis plan, sample-size justification, multiplicity approach, interim analyses, and details of missing-data procedures are not reported in the registry record. The primary outcome is assessed at Day 57; longer-term outcomes are not described in the posted primary result. Safety reporting also lacks event attribution and timing details, and the recorded death counts are not explained. These limitations restrict interpretation to the specific posted outcomes and comparisons.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: An Equivalence Study of Generic Ingenol Mebutate Gel 0.015% and Picato Gel 0.015% in Subjects With Actinic Keratosis — NCT03200912.
• Registry record last updated 2020-01-14; status last verified 2020-01.
• Results first posted 2020-01-14.
• 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

NCT03200912 is a completed Phase 3 randomized, quadruple-masked, parallel, vehicle-controlled study of generic ingenol mebutate, Picato, and vehicle gel for actinic keratosis on the face or scalp. The registry lists enrollment of 507 and a primary outcome of complete clearance at Day 57 in the per-protocol population.

Complete clearance was recorded for 45 of 137 participants assigned to generic ingenol mebutate, 44 of 144 assigned to Picato, and 7 of 139 assigned to vehicle. Unadjusted recalculations compare each active product with vehicle. The registry separately reports an equivalence analysis between the active products, but its method, units, and equivalence margin are not reported. The concentration also differs between the title and summary and the arm descriptions. Missing-data handling and the original statistical plan are not reported in the registry record.