Study of Safety, Tolerability and Effectiveness of A-101 in Subjects With Seborrheic Keratosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Safety, Tolerability and Effectiveness of A-101 in Subjects With Seborrheic Keratosis (NCT01986920), a randomized phase 1, phase 2 study. The primary outcome is Mean Change in Physician Lesion Assessment Scale.

2. Clinical Question

3. Trial Design

The study is identified as randomized and double-blind, with A-101 25%, A-101 32.5%, A-101 40%, and A-101 Vehicle as the treatment conditions. Its official title calls it a within-subject comparison, and the population description says each target lesion on a participant was randomly assigned one of the four medications. In contrast, the registry’s model classification is parallel. These descriptions refer to different elements of the record; the lesion-level assignment description is important for understanding the clinical comparison, while the registry classification should not be mistaken for evidence that each participant belonged to only one treatment group.

Participants and timing

The record reports 35 enrolled and 34 in the analysis population. The listed study start was 2013-10-22, primary completion was 2014-02-25, and status is completed. The primary outcome timeframe is Visit 2 to Visit 9 (78 days). Further details about the visit schedule or the number of lesions contributed by each participant are not reported in the registry record.

Outcome and analysis description

The primary outcome is mean change in Physician Lesion Assessment Scale score. The registry describes the intended primary effectiveness analysis as ANCOVA with the Visit 2 score as a covariate, comparing vehicle with each active treatment using least-squares means and a common error term. The posted outcomes include arm-level means and standard deviations, but the adjusted model estimates and its results are not reported in the registry record. The separate comparisons in the statistical display are recalculated, unadjusted comparisons based on the posted summary statistics; they should not be read as the registry-described ANCOVA results.

Other recorded outcomes

The registry lists Subject’s Self Assessment Scale as a secondary outcome. A secondary outcome name is recorded, but its results are not reported in the registry record. The record lists four interventions and a completed study, but does not report the original sample-size justification, allocation concealment details, or the trial’s own statistical planning assumptions.

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: In this study each patient is treated with all 4 treatments on 4 different lesions on their back. Therefore, each patient participates in each group so the total enrollment matches the number of lesions treated but not the total participants.

A- 101 25%

Reasons for not completing this period:

A-101 32.5%

Reasons for not completing this period:

A-101 40%

Reasons for not completing this period:

Placebo

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: A total of 35 subjects were enrolled with 34 subjects in the analysis population. Each target lesion on a subject was treated with one of the 4 study medications in a random fashion.

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 Mean Change in Physician Lesion Assessment Scale, measured over Visit 2 to visit 9 (78 days).

The primary endpoint is mean change in Physician Lesion Assessment Scale (PLA) score for each target lesion from Visit 2 to Visit 9 (78 days). The PLA is a four-point scale from 0 to 3: 0 means clear and 3 means the worst lesion. Change describes how the score at the later assessment differs from the starting assessment; a negative change is a decline in score. The endpoint therefore summarizes change in physician-rated lesion severity rather than a participant-level measure of overall health.

A change score gives a common way to compare the condition of lesions across the study interval. The registry’s planned analysis uses the Visit 2 PLA score as a covariate in ANCOVA, which is a way to account for baseline score when estimating treatment comparisons. The registry says comparisons with vehicle were to use least-squares means and a common error term. Those adjusted estimates are not reported in the registry record, so the posted arm means and recalculated unadjusted comparisons should be interpreted as summary-level evidence, not as the specified adjusted primary analysis.

The record lists Subject’s Self Assessment Scale as a secondary outcome, but does not report its results. Details about how physician ratings were obtained, including assessor training or reproducibility, are not reported in the registry record.

7. Results Posted in the Registry

• A-101 25%: mean -0.47 versus -0.15 on control; difference -0.32 (95% CI -0.57 to -0.07), standardized effect d = -0.60; z-test p = 0.013.
• A-101 32.5%: mean -0.88 versus -0.15 on control; difference -0.73 (95% CI -1.00 to -0.46), standardized effect d = -1.27; z-test p = <0.001.
• A-101 40%: mean -1.12 versus -0.15 on control; difference -0.97 (95% CI -1.27 to -0.67), standardized effect d = -1.55; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean change represent?

The endpoint is a continuous score-change measure. A mean is the arithmetic average of the recorded changes in a treatment condition. In this study, negative mean changes indicate that the average PLA score at Visit 9 was lower than at Visit 2. The reported means are -0.47 for A-101 25%, -0.88 for A-101 32.5%, -1.12 for A-101 40%, and -0.15 for vehicle. A mean condenses many observations into one value, so it does not show every lesion’s change or the shape of the distribution.

Standard deviation describes how dispersed the individual observations are around their mean. The reported standard deviations are 0.66, 0.73, 0.81, and 0.36, respectively. Standard deviation is not the same as a confidence interval: it characterizes variation among observations, whereas a confidence interval characterizes uncertainty around an estimated quantity. General statistical principle: when observations are more variable, estimates of group means and contrasts can be less precise, all else being equal.

What does an unadjusted mean difference compare?

The recalculated mean difference subtracts the vehicle mean from the active-treatment mean. The posted estimates are -0.32 for A-101 25%, -0.73 for A-101 32.5%, and -0.97 for A-101 40%. A negative difference means the active-treatment mean change was more negative than the vehicle mean change. These are simple unadjusted comparisons derived from the posted summary statistics. They do not adjust for Visit 2 scores or other factors.

General statistical principle: an unadjusted contrast describes the observed difference between two group summaries. An adjusted analysis can account for specified variables, which may change the estimate or its uncertainty. The registry describes ANCOVA with the baseline Visit 2 PLA score as a covariate, then comparisons using least-squares means and a common error term. Adjusted results for that analysis are not reported in the registry record. The unadjusted recalculations are therefore distinct from the described primary model.

How should confidence intervals be read?

A confidence interval gives a range of estimates compatible with the data and the calculation’s assumptions, and it conveys uncertainty around an estimate. In general, intervals that are narrower indicate greater precision, while wider intervals indicate greater uncertainty. The reported intervals for the recalculated mean differences are below zero. This is consistent with the unadjusted p-values reported for these contrasts. A confidence interval is not a range containing every individual outcome, and it does not measure clinical importance.

General statistical principle: a confidence interval’s coverage interpretation depends on the statistical procedure and assumptions being appropriate. In this study, the summary-based recalculations use the posted arm means and standard deviations. Because the design description assigns treatments to lesions within participants, dependence among lesions from the same participant may matter. The recalculation does not incorporate a participant-level correlation structure. The registry-described ANCOVA results would be needed to assess the primary analysis as specified.

What does a p-value say?

The unadjusted p-values are 0.013 for A-101 25% versus vehicle and <0.001 for each of the A-101 32.5% and A-101 40% comparisons versus vehicle. A p-value describes how unusual data at least as discrepant as the observed data would be under a specified null model and its assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of a difference.

These are unadjusted p-values for three comparisons against vehicle. The registry record does not report a multiplicity adjustment or a formal plan for handling multiple comparisons. Without that information, the values should be read as individual unadjusted results, not as evidence that family-wise error was controlled. The registry also does not report adjusted model p-values for its described ANCOVA.

Why can lesion-level dependence matter?

General statistical principle: observations from the same participant may be correlated. If several lesions from one person are analyzed as though they were entirely independent, uncertainty can be understated because the effective information is not equivalent to the same number of unrelated observations. A within-subject design can be efficient because each participant may contribute observations under multiple treatments, but analysis should reflect the assignment and correlation structure. The registry’s stated ANCOVA description does not provide enough detail to determine how within-participant clustering or lesion pairing was handled. Further model details are not reported in the registry record.

What does the registry analysis description imply?

ANCOVA is a general method for comparing outcome means while including a covariate. Here, the registry identifies Visit 2 PLA score as the covariate. Least-squares means are model-based adjusted means, and a common error term is a shared estimate of residual variation used for comparisons in the model. Those features describe the planned primary effectiveness analysis. They do not supply the numerical adjusted results. The posted arm-level mean changes and recalculated contrasts cannot establish what the ANCOVA estimates would be.

10. Confidence Intervals and Precision

The recalculated unadjusted mean differences are -0.32 for A-101 25%, -0.73 for A-101 32.5%, and -0.97 for A-101 40%, each compared with vehicle. The reported confidence intervals for all three contrasts lie below zero. These intervals indicate the range of values compatible with each unadjusted estimate under the calculation and assumptions used. They do not describe the range of changes among individual lesions, nor do they establish whether a difference is clinically important.

Precision differs across comparisons. It depends on the amount of observed variation and the information contributing to an estimate. The arm-level standard deviations range from 0.36 for vehicle to 0.81 for A-101 40%, and the posted summaries list 34 observations in each condition. However, the record describes lesion-level treatment assignment within participants. If observations are correlated within a participant, treating them as independent may not give an appropriate estimate of uncertainty. The unadjusted recalculations do not account for such dependence.

The registry describes an ANCOVA with the Visit 2 score as a covariate and least-squares mean comparisons, but the model’s adjusted estimates and confidence intervals are not reported in the registry record. Consequently, the available intervals speak to the recalculated summary-based contrasts, not to the precision of the registry-described primary analysis. The original sample-size assumptions and details of the analysis population beyond the reported count are also not reported in the registry record.

11. Planning a Similar Trial: Sample Size

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

The sample-size illustrations are planning calculations based on the observed contrast between each A-101 condition and vehicle. For each comparison, rows consider planning for 100%, 75%, or 50% of the observed effect. The columns give participants per arm for 80% power and participants per arm for 90% power. These are planning illustrations, not observed power.

The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect equal to the stated fraction of the observed effect. The figures are participants per arm, not total participants or total events. The note that time-to-event tables use total events does not apply to these continuous-outcome illustrations.

Power is the probability that a study would reject the null hypothesis under a specified assumed effect and the calculation’s assumptions. The 80% power column gives the illustrated per-arm sample size for an 80% chance of detecting that assumed effect; the 90% power column gives the per-arm size for a 90% chance. These are forward-looking planning quantities, not a retrospective measure of how likely the posted trial results were to be detected.

For a given comparison, the illustrated sample size increases when the planning target is a smaller fraction of the observed effect. That is expected in general: smaller effects are harder to distinguish from random variation and usually require more participants for the same power target. The trial’s own original design assumptions, sample-size justification, and any allowance for missing outcomes are not reported in the registry record. The illustrations should therefore not be interpreted as the study’s original enrollment target or as proof that its design had adequate power.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -0.320; pooled standard deviation σ = 0.532.
2. n = 2 × (1.96 + 0.842)² × 0.532² / -0.320² = 43.3, rounded up to 44 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 <- -0.32                      # observed difference in means
sigma <- 0.53160135440008                     # 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(1986920)
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 = 44 (80% power), 58 (90% power)
 75% of observed effect: n per arm = 78 (80% power), 104 (90% power)
 50% of observed effect: n per arm = 174 (80% power), 232 (90% power)
power.t.test: 44.3 
Simulated power at n = 44 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.

13. Multiplicity, Missing Data and Analysis Populations

The posted results include three unadjusted comparisons of A-101 concentrations with vehicle. The registry record does not report a multiplicity adjustment, a hierarchy for testing these comparisons, or a prespecified strategy for interpreting multiple primary comparisons. Each unadjusted p-value should therefore be understood as applying to its individual recalculated contrast. No claim about family-wise error control can be made from the record.

The registry describes ANCOVA with Visit 2 PLA as a covariate and comparisons using least-squares means and a common error term. Numerical adjusted results, test statistics, and model diagnostics are not reported in the registry record. The unadjusted calculations based on arm-level summary statistics are not a substitute for that model, particularly because the study description indicates that lesions within participants received randomized treatments. Details of how the intended analysis handled within-participant dependence are not reported.

The record reports 35 enrolled and 34 in the analysis population, and each treatment condition lists 34 observations for the primary outcome. It does not report participant flow by treatment condition, reasons for exclusion, the extent or handling of missing endpoint values, or whether all randomized lesions were included. The exact analysis-population definition is not reported in the registry record. It is therefore not possible to determine from these entries whether missing observations were absent, excluded, imputed, or handled through another approach.

The secondary outcome listed is Subject’s Self Assessment Scale, but its numerical results are not reported in the registry record. Further planned outcomes, subgroup analyses, interim analyses, and the trial’s original statistical analysis plan are also not reported. These gaps limit assessment of selective reporting and the full inferential plan.

14. 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: acute pyelonephritis (2.9%).

The safety summary lists 35 participants at risk for serious adverse events in each condition. It records 1 participant affected in each of the A-101 25%, A-101 32.5%, A-101 40%, and vehicle conditions. Deaths are recorded as 0 in each condition. The registry lists Acute Pyelonephritis as the top serious-event term, with 2.9% shown. The record does not provide further detail about the event’s timing, relationship to treatment, or participant-level overlap across conditions.

These figures are counts recorded in the safety summary, not estimates of comparative risk adjusted for the lesion-level design. Because the study description indicates that participants could contribute lesions to multiple conditions, the condition entries should not automatically be interpreted as independent participant groups. The summary also reports other adverse events: 21 affected in each of the A-101 25% and A-101 32.5% conditions, and 25 in each of the A-101 40% and vehicle conditions, with 35 at risk in each. The record does not provide event-level details or an analysis comparing these counts. Counts alone do not establish causation or comparative safety.

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

The posted endpoint summaries describe mean change in physician-rated lesion score from Visit 2 to Visit 9 (78 days). Mean changes were negative in the three A-101 conditions and in vehicle. The recalculated unadjusted comparisons show a more negative mean change in each active-concentration condition than in vehicle, and the confidence intervals for those contrasts lie below zero. Those findings describe the posted summaries and the unadjusted calculations.

What they cannot establish

The recalculated comparisons do not provide the numerical results of the registry-described ANCOVA. The registry does not report adjusted least-squares means, adjusted confidence intervals, or adjusted tests. The available calculations also do not account for potential dependence among lesions contributed by the same participant. These limitations matter when interpreting uncertainty and when comparing the unadjusted contrasts with the specified primary analysis.

The results do not quantify clinical importance because a threshold for an important change is not reported in the registry record. They do not establish durability beyond the Visit 2 to Visit 9 interval, nor do they describe the secondary self-assessment outcome because its results are not reported. The record also does not report enough information to assess whether missing observations, multiplicity, or other analysis decisions influenced the estimates.

Limits on broader interpretation

The study enrolled 35 participants, with 34 in the analysis population, and the described treatment assignment occurred at the lesion level. Results from this record should be understood in that study context. The registry does not report participant characteristics, additional eligibility details, or results for clinical subgroups, so generalization to groups not described in the record cannot be evaluated from these entries alone.

The safety summary records serious adverse events and other adverse events by condition, but does not provide detailed event narratives or a statistical comparison. These counts are descriptive and do not establish whether an event was caused by a treatment. Overall, the posted material supports a description of observed score changes, unadjusted comparisons, and recorded adverse-event counts; it does not settle questions that require the unreported adjusted analysis, longer follow-up, or additional clinical context.

16. Why This Trial Matters Statistically

This study illustrates why the treatment-assignment unit and the outcome-observation unit both matter. The registry describes randomized treatment of target lesions within participants, while reporting means and standard deviations for each treatment condition. When one participant contributes lesions under more than one condition, measurements may be related. Statistical comparisons need to reflect that structure to estimate uncertainty appropriately. Summary-based comparisons that do not incorporate within-participant dependence can be informative descriptively, but they are not equivalent to a model that accounts for the design.

It also demonstrates the distinction between a planned adjusted analysis and a recalculation from summary statistics. The registry describes ANCOVA with baseline PLA score as a covariate and comparisons based on least-squares means. The posted numerical results support unadjusted comparisons, but the adjusted results are not reported in the registry record. A reader should not silently treat one analysis as the other: adjustment can affect both the estimated contrast and its precision.

Finally, the three active-versus-vehicle comparisons raise a multiplicity question. Their reported p-values are unadjusted, and the record does not report a multiple-testing strategy. Statistical significance for individual comparisons does not itself show that a family of comparisons was controlled as a whole. The study is a useful example of how endpoint definition, analysis population, repeated or clustered observations, adjustment, multiplicity, and reporting completeness all shape interpretation—not just the direction of group means.

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 gaps constrain interpretation. Although the official title describes a within-subject study and the population description says target lesions were assigned treatments within participants, the registry classifies the model as parallel. The record does not explain this classification or report enough design detail to determine the number of lesions per participant, how lesion assignment was conducted, or how the analysis accounted for correlation among lesions from the same participant.

The primary analysis is described as ANCOVA with Visit 2 PLA as a covariate, using least-squares means and a common error term. Numerical results from that adjusted analysis are not reported in the registry record. The available recalculated contrasts use posted summary statistics and are unadjusted. They cannot establish the results of the described model or assess whether its assumptions were met.

The registry lists 35 enrolled and 34 in the analysis population, but does not report participant flow, exclusion reasons, missing endpoint handling, or the precise analysis-population definition. The original statistical plan, multiplicity procedure, sample-size justification, and any interim analyses are not reported in the registry record. Results for the listed secondary self-assessment outcome are also not reported.

Further limits include absent participant characteristics and details about lesion assessment procedures. The primary outcome covers Visit 2 to Visit 9 (78 days); longer-term outcomes are not reported. Safety entries give counts but not event-level timing, treatment relationship, or comparative analyses. These omissions prevent fuller assessment of representativeness, measurement reliability, missing-data effects, and the context of adverse events.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Study of Safety, Tolerability and Effectiveness of A-101 in Subjects With Seborrheic Keratosis — NCT01986920.
• Registry record last updated 2018-12-11; status last verified 2018-11.
• Results first posted 2018-12-11.
• 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

NCT01986920 is a completed randomized, double-blind study of A-101 topical solution for seborrheic keratosis. The registry lists A-101 25%, A-101 32.5%, A-101 40%, and A-101 Vehicle. Its official title and population description characterize treatment assignment at the target-lesion level within participants, while the registry model classification is parallel.

The primary outcome is mean change in Physician Lesion Assessment Scale score from Visit 2 to Visit 9 (78 days). The posted mean changes were -0.47, -0.88, and -1.12 for the three A-101 conditions, and -0.15 for vehicle. Recalculated unadjusted comparisons versus vehicle were -0.32, -0.73, and -0.97, respectively. Adjusted results for the ANCOVA described in the record are not reported in the registry record. The record reports 35 enrolled and 34 in the analysis population; it lists Subject’s Self Assessment Scale as a secondary outcome without numerical results.