Evaluation of Efficacy and Safety of BF-200 ALA Used With Photodynamic Therapy in Patients With Actinic Keratosis.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of Efficacy and Safety of BF-200 ALA Used With Photodynamic Therapy in Patients With Actinic Keratosis. (NCT02799082), a randomized phase 3 study. The primary outcome is Total Patient Clearance Rate 12 Weeks After the Last Photodynamic Therapy (PDT).

2. Clinical Question

The question concerns complete clearance at the participant level, not the response of an individual lesion. A participant counted as clear only if all target-area lesions were in complete remission at the assessment. The registry record also lists lesion-level clearance, changes in lesion size and area, and other clearance and cosmetic outcomes as secondary measures. Those outcomes address related but distinct aspects of treatment response; they do not replace the primary question about complete patient clearance.

3. Trial Design

The registry describes a randomized, double-blind, Phase III, multicenter study with a parallel design. It compared topical BF-200 ALA with a matched Vehicle gel in participants with actinic keratosis, with photodynamic therapy used in both treatment descriptions. The study title and brief description identify evaluation of efficacy and safety as its purpose. The registry lists Biofrontera Bioscience GmbH as sponsor and reports a completed study.

Enrollment was 122. For the primary endpoint, the full analysis set included 40 participants in the Vehicle group and 80 in the BF-200 ALA group. The registry describes that endpoint as the percentage of participants with complete remission of all actinic keratosis lesions in the target area or areas. The assessment took place 12 weeks after the last photodynamic therapy, up to 24 weeks. The endpoint description allows assessment after the first photodynamic therapy or, if retreatment occurred, after the second.

The arm descriptions specify topical application of a 1 mm thick layer over each lesion and a 0.5 cm to 1.0 cm surrounding margin. The BF-200 ALA gel contained 78 mg/g 5-aminolevulinic acid, while the Vehicle gel contained no active ingredient. The registry record identifies randomization and double masking but does not report the method used to generate the allocation sequence, how allocation was concealed, or the practical procedures used to maintain masking.

The study start is reported as 2007-12 and primary completion as 2008-10. The registry record does not report the original sample-size justification or the detailed design assumptions behind the trial’s planned enrollment. Those details cannot be inferred from the results or from the planning illustrations based on the observed effects.

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: 128 patients were screened, of whom 122 patients were randomized (41 patients to the vehicle/placebo group, 81 patients to the BF-200 ALA group); 6 patients were screening failures (3 patients refused to participate, 3 patients meet exclusion criteria).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full analysis set (FAS), Overall

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: Baseline description is given for the FAS (Full Analysis Set). One patient each in the vehicle/placebo groupd and in the BF-200 ALA group dropped out without a post-treatment assessment of the target lesions and thus were not considered for the FAS.

6. Primary Endpoint

The registry lists the primary outcome as Total Patient Clearance Rate 12 Weeks After the Last Photodynamic Therapy (PDT), measured over 12 weeks after the last photodynamic therapy (PDT), up to 24 weeks.

The primary endpoint is the total patient clearance rate 12 weeks after the last photodynamic therapy. It measures the percentage of participants whose actinic keratosis lesions in the target area or areas were all in complete remission at the assessment. This is a participant-level binary outcome: each participant either met the complete-clearance definition or did not.

Complete patient clearance is useful because it captures an outcome across the full target area rather than describing the average response of individual lesions. It therefore asks whether a participant reached complete remission across all lesions included in the target area or areas. That is a stricter outcome than partial clearance or clearance of some lesions, which the registry lists separately among secondary outcomes.

The timing matters to interpretation. Assessment was 12 weeks after the last photodynamic therapy, with the registry timeframe extending up to 24 weeks. The description states that the assessment followed the first photodynamic therapy, or the second when retreatment occurred. The endpoint consequently reflects status at the specified post-treatment assessment, not a longer-term measure of persistence or recurrence. Such longer-term outcomes are not reported in the registry record.

The primary outcome is reported as a percentage with a 95% confidence interval for each arm. The interval conveys uncertainty around each estimated arm-specific percentage; the comparison between arms is a separate statistical question. Neither the percentage nor its interval alone establishes how the trial handled missing endpoint assessments or whether all randomized participants were included in the analysis. Those details are not reported in the registry record.

7. Results Posted in the Registry

• BF-200 ALA: 66.2% (53/80) versus 12.5% (5/40) on control; risk difference 53.8 percentage points (95% CI 39.2 to 68.3), risk ratio 5.30 (2.30–12.21); unadjusted two-proportion z-test p = <0.001.

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 Total Lesion Size 12 Weeks After the Last PDT

• 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:
  • BF-200 ALA: mean -360.20 versus -110.30 on control; difference -249.90 (95% CI -327.15 to -172.65), standardized effect d = -1.26; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for BF-200 ALA than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Change in Total Lesion Area 12 Weeks After the Last PDT (Treated Area Face)

• 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:
  • BF-200 ALA: mean -315.00 versus -94.10 on control; difference -220.90 (95% CI -313.80 to -128.00), standardized effect d = -1.08; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for BF-200 ALA than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Change in Total Lesion Area 12 Weeks After the Last PDT (Treated Area Scalp)

• 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:
  • BF-200 ALA: mean -340.20 versus -112.30 on control; difference -227.90 (95% CI -331.83 to -123.97), standardized effect d = -1.25; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for BF-200 ALA than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry lists a range of secondary outcomes, including lesion-level complete remission, remission with a narrow spectrum lamp, changes in lesion size and treated area, participant clearance outcomes, and overall cosmetic outcome. The posted continuous results concern change in total lesion size and changes in treated area for the face and scalp. The reported mean changes are negative in both groups for those measures, with larger decreases in the BF-200 ALA group than in the Vehicle group. Each posted unadjusted comparison has p < 0.001.

These secondary measures are directionally consistent with the primary result in that they describe greater observed lesion reduction in the BF-200 ALA group. They are related outcomes, not interchangeable definitions of success: changes in size or area quantify average change, whereas the primary endpoint requires complete remission of every target-area lesion for a participant. The secondary outcomes can therefore add context about response without replacing the primary endpoint.

Secondary analyses generally carry less confirmatory weight when many outcomes are examined, especially when no adjustment for multiple testing is reported. Testing multiple outcomes increases the chance that some comparisons appear statistically notable by chance alone. The registry record lists 15 outcome measures and 4 analyses, but does not report a multiplicity adjustment or identify a hierarchy for interpreting secondary endpoints. The posted secondary p-values should therefore be treated as unadjusted evidence rather than as a set of independent confirmations.

The registry record does not provide detailed results for every listed secondary outcome in the registry record for this analysis. The pattern should not be generalized to outcomes whose numerical estimates are not reported. Nor do the posted results establish persistence, recurrence, or effects beyond the stated assessment. Overall, the secondary findings offer supportive context for the primary clearance result, while the primary endpoint remains the main basis for the study’s efficacy comparison and the unadjusted secondary findings remain exploratory in interpretation.

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

• Percentage of AK Lesions Showing Complete Remission 12 Weeks After the Last PDT
• Percentage of AK Lesions Showing Complete Remission Treated With Narrow Spectrum Lamp 12 Weeks After the Last PDT
• Change in Total Lesion Size 12 Weeks After the Last PDT
• Change in Total Lesion Area 12 Weeks After the Last PDT (Treated Area Face)
• Change in Total Lesion Area 12 Weeks After the Last PDT (Treated Area Scalp)
• Subjects With Complete Clearance 12 Weeks After the First PDT
• Subjects With Partial Clearance 12 Weeks After the Last PDT
• Overall Cosmetic Outcome 12 Weeks After the Last PDT

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is binary at the participant level. A participant is classified according to whether all actinic keratosis lesions in the target area or areas were in complete remission at the assessment. The arm-specific clearance rate is the percentage of participants meeting that definition. For this kind of outcome, results are naturally expressed as proportions or percentages, and comparisons can be made using measures such as a risk difference, risk ratio, or odds ratio. The registry’s reported inferential method is Cochran-Mantel-Haenszel; the separately posted unadjusted recalculation gives a risk difference, risk ratio, odds ratio, and unadjusted p-value.

What the arm percentages mean

The percentage for an arm estimates the proportion of participants in that analysis group who met the endpoint definition. The estimate is not a guarantee that the same percentage would occur in every population. It is based on the observed participants and is subject to sampling uncertainty. The 95% confidence interval gives a range of values compatible with the observed data under the interval method’s assumptions. Wider intervals indicate less precision than narrower intervals, although the interval also needs to be interpreted in light of the design and analysis population.

The outcome is complete clearance, rather than a graded score. This distinction is important: a participant with substantial improvement but not complete remission of all target-area lesions does not meet the stated primary endpoint definition. The registry separately lists partial clearance and lesion-level remission outcomes, which can describe response patterns that the complete-clearance endpoint does not capture.

Comparing the arms

A risk difference is the absolute difference between the two estimated proportions. It is expressed on the proportion scale and directly describes how far apart the observed rates are. A risk ratio compares the two proportions as a relative measure, while an odds ratio compares the odds of the outcome. These measures answer different questions and can have different numerical scales. The recalculated measures are unadjusted summaries of the posted group counts; they are not substitutes for the trial’s own analysis.

The registry reports a Cochran-Mantel-Haenszel analysis. In general, this method compares categorical outcomes while accounting for strata, when strata are included in the analysis. The registry record does not identify the specific stratification variables or provide a detailed statistical analysis plan, so the precise implementation cannot be reconstructed. Its reported p-value is p < 0.001. The recalculated unadjusted comparison reports p < 0.001. Because the methods differ, the values should be described as results from their respective analyses rather than treated as an inconsistency.

What a p-value says

In general, a p-value describes how unusual data at least as inconsistent with a specified null hypothesis would be if that null hypothesis and the analysis assumptions held. A small p-value is evidence against that null hypothesis under those assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or practical importance of an effect. The estimated percentages and confidence intervals are needed to describe magnitude and precision alongside the p-value.

The registry’s p-value supports a statistical comparison under its reported method. It does not establish that every participant had the same response, that the result persists beyond the stated follow-up, or that the outcome applies unchanged to people outside the study population. Those are separate questions that the reported analysis does not answer.

Over-dispersion and binary outcomes

For a binary outcome, each participant contributes an event status rather than a continuous measurement. In general, simple binomial methods assume that participants contribute independent outcomes and that the event probability is adequately described by the model. Over-dispersion means the observed variability is greater than the model expects. It can arise when outcomes are more heterogeneous or correlated than the model accounts for; in that circumstance, standard errors may be too small if the extra variability is ignored. The registry record does not report an over-dispersion assessment or a model-based variance adjustment, so no such adjustment should be presumed for this trial.

Because the registry’s reported method is Cochran-Mantel-Haenszel, the result should be understood according to that named categorical-outcome approach, not as a continuous-outcome model. The available registry entry does not provide enough detail to determine all assumptions or implementation choices. The recalculated unadjusted comparison is simpler and uses only the posted summary counts, without adjustment for any strata.

Analysis population and endpoint timing

The primary population is called the full analysis set, overall. The registry record does not explain the full analysis set’s operational definition, the treatment of participants who did not complete follow-up, or the handling of missing endpoint data. It also does not report whether the analysis followed an intention-to-treat principle as defined in a protocol. The population label should therefore be quoted as reported without assigning additional meaning to it.

The assessment occurred 12 weeks after the last photodynamic therapy, up to 24 weeks, and could follow the first or second photodynamic therapy in the case of retreatment. This timing defines the estimand represented by the endpoint: clearance at that post-treatment assessment. It is not a measure of time to clearance, durability beyond the assessment, or recurrence after an initially clear result.

11. Confidence Intervals and Precision

For the primary endpoint, the BF-200 ALA clearance estimate is 66.3%, with a 95% confidence interval from 54.8% to 76.4%. The Vehicle estimate is 12.5%, with a 95% confidence interval from 4.2% to 26.8%. These intervals express uncertainty around the arm-specific percentages; they should not be read as containing 95% of individual participant outcomes.

The recalculated unadjusted risk difference is 0.537, with a 95% confidence interval from 0.392 to 0.683. This interval describes uncertainty around the absolute difference between the posted proportions under the unadjusted calculation. Its endpoints are both above zero, so the interval excludes a null difference for this calculation. The registry’s own inferential analysis remains the primary reported comparison and has p < 0.001.

Confidence intervals are useful because they show more than whether a test crossed a significance threshold. They indicate a range of effect values compatible with the data and method, while the width conveys precision. The arm-specific intervals and the interval for the difference are different quantities and should not be interchanged. Their interpretation also depends on the analysis method and assumptions, which are not fully documented in the registry record.

These estimates apply to the full analysis set at the endpoint’s stated assessment. The registry record does not report missing-data methods or a sensitivity analysis. Consequently, the intervals cannot resolve uncertainty about how missing observations may have affected the estimates. They also do not quantify uncertainty about generalizing to other settings or about outcomes beyond the follow-up assessment.

12. Planning a Similar Trial: Sample Size

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

The planning illustrations show participants per arm for 80% power and participants per arm for 90% power. These are planning quantities, not observed trial results. The registry record does not report the original sample-size justification or the trial’s own design assumptions; the figures in these illustrations use the observed effect as a starting point.

The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. For the binary primary outcome and the continuous secondary outcomes, the figures are participants per arm. The note about total events applies to time-to-event tables, and these results do not include a time-to-event outcome.

The 80% power column represents the planned number of participants per arm under which the calculation would have an 80% chance of detecting the specified effect if the assumptions held and the effect were real. The 90% power column uses a higher probability of detecting that specified effect under the same planning framework. Greater planned power generally requires a larger sample size for a given effect and assumptions.

Rows planning for a smaller fraction of the observed effect call for more participants per arm than rows planning for the full observed effect. This is because smaller differences are harder to distinguish from random variation. The observed effect is not guaranteed to recur in a future study, and the calculations depend on the assumptions stated for the illustration. This is not observed power.

These figures should not be read as evidence that the completed trial was designed around the posted effects, nor as a recommendation for a future trial’s sample size. A design decision would require a target effect and assumptions chosen before the study, along with considerations not documented in the registry record. The illustrations are best read as showing how required sample size changes as the target effect and desired power change under the listed assumptions.

13. How the Sample Size Is Derived

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

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.125; treatment proportion p₁ = 0.662; average p̄ = 0.394.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6910 = 1.3543.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5770 = 0.4856.
4. n = (1.3543 + 0.4856)² / (0.5375)² = 11.7, rounded up to 12 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 <- 0.125                          # control proportion
p1 <- 0.6625                          # 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(2799082)
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 = 12 (80% power), 16 (90% power)
 75% of observed effect: n per arm = 21 (80% power), 27 (90% power)
 50% of observed effect: n per arm = 41 (80% power), 54 (90% power)
power.prop.test: 11.7 
Simulated power at n = 12 per arm: 0.840 (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.

14. Analyses Reported by the Sponsor

The registry’s own analysis compares the Vehicle and BF-200 ALA groups using the Cochran-Mantel-Haenszel method and reports p < 0.001. This is the trial’s posted inferential result. The recalculated unadjusted comparison uses the posted group counts and reports a risk difference of 0.537 with a 95% confidence interval from 0.392 to 0.683, along with p < 0.001.

The two analyses are not identical procedures. The recalculation is an unadjusted summary based on the reported counts; the registry analysis is the named method reported by the study. A difference in the exact p-value threshold is therefore not, by itself, evidence of an error. The sponsor’s own analysis takes precedence when reporting the trial’s formal statistical result.

The registry record does not provide the strata or other implementation details for the Cochran-Mantel-Haenszel analysis, nor a complete statistical analysis plan. The recalculation can make the posted summaries easier to interpret, but it cannot recover those details or replace the reported method. The arm percentages and confidence intervals remain useful for describing the observed magnitude and uncertainty, while the sponsor analysis supplies the trial’s own reported inferential comparison.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists 15 outcome measures and 4 analyses. With several endpoints or comparisons, the chance of at least one apparently unusual result can increase if each is assessed separately without accounting for the number of tests. In general, multiplicity procedures can control this issue by adjusting the testing threshold or by defining an ordered testing strategy. The registry record does not report whether any multiplicity adjustment was used, whether outcomes were tested hierarchically, or which secondary outcomes were designated as key confirmatory endpoints. The secondary p-values should therefore be read as unadjusted where they are described that way, rather than as family-wise confirmatory evidence.

The primary endpoint and its reported analysis are identifiable in the registry record, but the complete statistical analysis plan is not. Details such as prespecified covariates, subgroup analyses, handling of protocol deviations, and sensitivity analyses are not reported in the registry record. It is not appropriate to infer these choices from the reported endpoint or from the test result.

The primary population is described as the full analysis set, overall. The registry record does not define eligibility for that set, clarify how participants were handled after randomization if they lacked a usable endpoint, or report the number of missing primary assessments. The methods used to address missing data, if any, are not reported in the registry record. Missing outcomes can affect both the estimated percentages and their uncertainty, so this absence limits independent assessment of robustness.

The participant counts differ across the registry’s outcome summaries: the primary result lists 40 participants for Vehicle and 80 for BF-200 ALA, while safety summaries list 41 and 81 at risk. These are outcome-specific analysis denominators as reported. The registry record does not explain the difference in denominators, so no reason should be assumed. The safety counts should not be substituted for the primary analysis counts.

The registry provides a Cochran-Mantel-Haenszel p-value for the primary comparison but not the stratification details. It does not report a protocol-based sample-size justification or the trial’s original design assumptions. These limitations do not negate the posted estimates; they constrain the ability to reconstruct the full analysis and to judge all possible sources of bias or uncertainty.

16. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: myocardial infarction (2.4%), myositis (2.4%).

The registry reports serious adverse events for 2 participants at risk in the Vehicle group and none in the BF-200 ALA group, with 41 and 81 participants at risk, respectively. The listed serious-event terms are myocardial infarction and myositis, each reported as 2.4%. The registry record does not establish from these summary figures whether the listed terms occurred in particular treatment groups, so they should not be attributed to an arm without further detail.

Other adverse events are reported for 20 of 41 participants at risk in the Vehicle group and 78 of 81 in the BF-200 ALA group. These are counts of participants affected as presented in the registry summary, not a complete description of event severity, duration, recurrence, or causal relationship to treatment. The registry record does not report deaths as a numerical result, so the absence of a death count should not be interpreted as evidence that no deaths occurred.

These safety figures are descriptive. They do not by themselves determine whether an event was caused by the study treatment, and the summary does not provide enough detail to compare event types, exposure duration, or clinical seriousness beyond the registry categories. The numbers also should not be combined with the primary efficacy denominators, which are reported for a different analysis population.

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

The posted primary result describes complete clearance in the full analysis set at 12 weeks after the last photodynamic therapy, up to 24 weeks. BF-200 ALA had a reported clearance rate of 66.3%, compared with 12.5% for Vehicle. The registry’s Cochran-Mantel-Haenszel analysis reported p < 0.001. These findings describe the participants and endpoint represented in the registry record.

The result does not mean that every participant receiving BF-200 ALA achieved complete clearance. The endpoint is a proportion, and the reported percentage is below 100%. It also does not mean that no Vehicle participant achieved clearance; the Vehicle percentage is above zero. The study’s average group results do not predict the outcome for any particular person.

The measure is limited to complete remission of all target-area lesions at a specified assessment. It does not tell readers how long clearance persisted after that assessment, whether lesions later recurred, or how every lesion responded. The registry record does not report longer-term follow-up for those questions. Nor does the primary efficacy estimate summarize all safety considerations; the adverse-event summaries require separate interpretation.

Statistical significance does not establish the practical importance of an effect or resolve all uncertainties about study conduct. The registry record does not report the original sample-size rationale, a detailed statistical analysis plan, multiplicity handling, or methods for missing primary outcomes. The confidence intervals describe sampling uncertainty under their methods, but they cannot address every limitation in the available record.

The most defensible interpretation is specific: the posted primary endpoint estimates and the sponsor’s reported comparison show a higher complete-clearance percentage in the BF-200 ALA group than in the Vehicle group at the stated follow-up. Broader conclusions about other populations, longer-term outcomes, individual treatment choices, or the full balance of benefits and harms are not established by these registry results alone.

18. Why This Trial Matters Statistically

This trial illustrates why a clinical outcome needs a precise statistical definition. Complete patient clearance is not the same as improvement in an average lesion measure: it requires all target-area lesions to be in complete remission. The primary endpoint therefore answers a clear participant-level question, while secondary lesion-size and lesion-area measures describe other dimensions of response.

It also shows why effect size and uncertainty should be considered together. The arm-specific percentages communicate the observed outcomes, while their confidence intervals indicate uncertainty in those estimates. The risk difference gives an absolute comparison that can be read directly on the proportion scale. The p-value addresses a different issue: how compatible the data are with a null comparison under the analysis assumptions. These statistics complement rather than replace one another.

The distinction between the registry’s reported analysis and an unadjusted recalculation is also important. A summary-data recalculation can help readers understand the magnitude of the observed contrast, but it does not reproduce unreported analysis details. The trial’s reported Cochran-Mantel-Haenszel result remains the formal sponsor analysis, and the registry record does not provide enough information to reconstruct every choice behind it.

Finally, the record emphasizes the role of endpoint timing, analysis population, multiplicity, and missing-data methods. The primary outcome was assessed at a specified time after the last photodynamic therapy, and the listed population is the full analysis set. The registry does not report all details needed to judge how missing observations were handled or how secondary comparisons were prioritized. Those are not minor editorial details: they affect how confidently results can be generalized and how much weight to place on a collection of outcomes.

19. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The registry record supports interpretation of the posted results but leaves several trial-specific details unavailable. It does not report the original sample-size justification, so the rationale for the planned enrollment cannot be evaluated from this entry. Planning illustrations based on observed effects are not evidence of the assumptions used when the trial was designed.

The registry identifies randomization and double masking but does not describe the allocation-generation procedure, allocation concealment, or how masking was maintained. It also does not provide the full protocol or statistical analysis plan. Specific analysis choices, including any prespecified covariates, stratification variables for the Cochran-Mantel-Haenszel analysis, and sensitivity analyses, are not reported in the registry record.

The primary population is named as the full analysis set, but its definition and the handling of participants without an observed endpoint are not reported. No missing-data method or sensitivity analysis is described. This matters because the primary endpoint is a percentage and could be affected by how incomplete follow-up is addressed. The registry’s different denominators for the primary efficacy and safety summaries are reported, but the reason is not given.

Although many secondary outcomes are listed, the registry record does not report a multiplicity strategy or a clear hierarchy for interpreting them. Secondary p-values should therefore be treated cautiously. The reported follow-up describes a specific post-treatment assessment; durability, recurrence, and outcomes beyond that assessment are not reported in the registry record. The adverse-event summaries also lack detail on timing, duration, relatedness, and event-level context. These limitations narrow the conclusions that can be drawn from the record, without changing the numerical results it reports.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Evaluation of Efficacy and Safety of BF-200 ALA Used With Photodynamic Therapy in Patients With Actinic Keratosis. — NCT02799082.
• Registry record last updated 2017-04-06; status last verified 2017-04.
• Results first posted 2017-04-06.
• 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.

23. Record Summary

The registry record describes a completed randomized, double-blind, Phase III, multicenter, parallel study of BF-200 ALA gel with photodynamic therapy versus matched Vehicle gel in participants with actinic keratosis. Enrollment was 122. The primary endpoint was complete remission of all target-area lesions 12 weeks after the last photodynamic therapy, up to 24 weeks, in the full analysis set.

The reported clearance rates were 66.3% for BF-200 ALA and 12.5% for Vehicle. The registry reports a Cochran-Mantel-Haenszel comparison with p < 0.001. The record also lists secondary clearance, lesion-size, lesion-area, and cosmetic outcomes, and provides safety summaries. Original design assumptions, missing-data methods, multiplicity handling, and several analysis details are not reported in the registry record.