This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for A Study of Increasing Strengths, Safety and Efficacy of Two Formulas of LEO 43204 on the Face or the Chest in Patients With Actinic Keratosis (NCT01922050), a randomized phase 1, phase 2 study. The primary outcome is Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01922050 |
| Phase | Phase 1, Phase 2 |
| Condition | Actinic Keratosis |
| Allocation | Randomized |
| Design model | Sequential |
| Masking | Quadruple |
| Enrollment | 320 |
| Arms in the primary outcome | n/a |
| Lead sponsor | LEO Pharma |
| Results posted | Yes |
2. Clinical Question
Population
Patients with actinic keratosis. The official title describes application to the full face or approximately 250 cm2 (40 in2) on the chest. Further eligibility details are not reported in the registry record.
Intervention
Two formulations of LEO 43204, given once daily for two consecutive days. Part 1 used escalating doses to assess dose-limiting toxicity. Part 2 compared selected doses of each formulation with its corresponding vehicle formulation.
Comparator
Part 2 included placebo vehicle formulations for the gel and cream formulations. The record describes double-blind treatment in Part 2. Part 1 is described as open-label dose escalation, without a placebo comparator.
Primary question
In Part 1, how many participants experienced a dose-limiting toxicity based on local skin responses, and what dose level met the registry’s definition of the maximum tolerated dose? The observed counts and the selected maximum tolerated dose are not reported in the registry record.
The study also had an efficacy objective in Part 2: evaluating two doses of each formulation against vehicle after the brief treatment course. The listed secondary outcomes concern complete and partial clearance of actinic keratosis lesions. Those outcome results are not reported in the registry record, so the planned comparisons cannot be interpreted as observed evidence of efficacy.
The record identifies actinic keratosis as the condition and describes topical treatment on the face or chest. It does not report enough detail to characterize the enrolled population beyond that condition, or to determine whether results differed by application site. The study’s two parts address distinct questions: dose-limiting toxicity during dose escalation, then efficacy comparisons at selected doses. The primary question is therefore about tolerability as operationally defined by local skin responses, rather than lesion clearance.
3. Trial Design
The record identifies NCT01922050 as a randomized, sequential Phase 1/Phase 2 study sponsored by LEO Pharma. Its recorded enrollment is 320, and its status is completed. The recorded start is 2013-10 and primary completion is 2014-11. These registry entries describe the study’s administrative status; they do not establish that results for the stated endpoints were posted.
The two-part design separates dose escalation from efficacy evaluation. In Part 1, participants received escalating doses of LEO 43204 Formulation 1 or Formulation 2. The arm descriptions call this treatment open-label, dose-escalation, once-daily treatment for two days. The purpose was to identify maximum tolerated dose levels using dose-limiting toxicity based on local skin responses.
In Part 2, the listed arms include two doses of each formulation and matching vehicle formulations. These arm descriptions identify treatment as double-blind, once daily for two days. The brief summary states that efficacy was to be evaluated by comparing the two formulations and doses with vehicle. The record also labels the overall study randomized and quadruple-masked. Because the arm descriptions distinguish open-label Part 1 from double-blind Part 2, those specific descriptions are important when characterizing masking across the study.
The official title describes application to the full face or approximately 250 cm2 (40 in2) on the chest. It does not report the allocation ratio, randomization sequence method, dose-selection procedures beyond the stated escalation and MTD rule, or participant flow by arm. Details of recruitment, eligibility criteria, adherence, and discontinuation are not reported in the registry record. Those omissions limit reconstruction of how the study was implemented and which participants contributed to each analysis.
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.
Only the first 6 of 14 groups are shown.
Part 1 Open-label, Dose-escalation Phase
| Stage | Part 1: LEO 43204 Gel 0.0015 | Part 1: LEO 43204 Gel 0.003 | Part 1: LEO 43204 Gel 0.006 | Part 1: LEO 43204 Gel 0.012 | Part 1: LEO 43204 Gel 0.018 | Part 1: LEO 43204 Gel 0.025 |
|---|---|---|---|---|---|---|
| STARTED | 3 | 3 | 6 | 6 | 17 | 18 |
| COMPLETED | 3 | 3 | 6 | 6 | 17 | 18 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
Part 2 Double-blind Phase
| Stage | Part 1: LEO 43204 Gel 0.0015 | Part 1: LEO 43204 Gel 0.003 | Part 1: LEO 43204 Gel 0.006 | Part 1: LEO 43204 Gel 0.012 | Part 1: LEO 43204 Gel 0.018 | Part 1: LEO 43204 Gel 0.025 |
|---|---|---|---|---|---|---|
| STARTED | 0 | 0 | 0 | 0 | 0 | 0 |
| COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
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 characteristics are provided for all randomized participants
Only the first 6 of 15 groups are shown.
| Characteristic | Unit | Part 1: LEO 43204 Gel 0.0015 | Part 1: LEO 43204 Gel 0.003 | Part 1: LEO 43204 Gel 0.006 | Part 1: LEO 43204 Gel 0.012 | Part 1: LEO 43204 Gel 0.018 | Part 1: LEO 43204 Gel 0.025 |
|---|---|---|---|---|---|---|---|
| Participants analysed | 3 | 3 | 6 | 6 | 17 | 18 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 1 | 1 | 3 | 1 | 10 | 6 |
| Age, Categorical: >=65 years | Participants | 2 | 2 | 3 | 5 | 7 | 12 |
| Sex: Female, Male: Female | Participants | 1 | 1 | 4 | 2 | 6 | 6 |
| Sex: Female, Male: Male | Participants | 2 | 2 | 2 | 4 | 11 | 12 |
| Region of Enrollment: Canada | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Region of Enrollment: United States | Participants | 3 | 3 | 6 | 6 | 17 | 18 |
6. Primary Endpoint
The registry lists the primary outcome as Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs), measured over From Day 1 up to and including Day 8.
| Element | Registry entry |
|---|---|
| Result type | Count Of Participants |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint is the number of participants experiencing a dose-limiting toxicity based on local skin responses in Part 1, assessed from Day 1 up to and including Day 8. The registry describes tabulation by treatment group. A dose-limiting toxicity could be triggered by one or more specified severe local responses, or by a combination of specified response grades. The response categories are erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration. Each category is graded from 0, indicating no presence, to 4, the highest severity grade.
This endpoint was used to identify the maximum tolerated dose. The registry defines that as the highest dose level with less than 4 out of 12 participants in cohorts 1 to 4, or less than 6 out of 18 participants in cohorts 5 and 6, experiencing a dose-limiting toxicity. This is a dose-escalation decision rule, not a measure of lesion clearance or a general measure of all possible harms.
The endpoint is a participant count: it records how many people met the specified toxicity definition, rather than the number of individual skin-response events. The rule relies on both the severity grades and how multiple local responses occur together. The registry record does not report the observed counts by dose or the resulting maximum tolerated dose. Consequently, the endpoint’s operational definition can be described, but its observed outcome cannot be evaluated from the posted record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry describes the study objectives, design, endpoint definitions, and some adverse-event summaries, but it does not report the primary endpoint results. In particular, the Part 1 counts of participants experiencing a dose-limiting toxicity and the maximum tolerated dose selected from those counts are not reported in the registry record. That means the central dose-escalation question cannot be answered from the posted primary outcome information.
The record also lists Part 2 complete and partial clearance outcomes, each described as using multiple imputation. Their results are not reported in the registry record. No treatment-effect estimates, confidence intervals, or statistical test results for these efficacy outcomes are included in the registry record for interpretation. A planned comparison with vehicle should not be mistaken for evidence that a difference was observed.
Some adverse-event counts are reported by group. For example, Part 2 gel vehicle lists 0 serious adverse events among 58 at risk, while Part 2 LEO 43204 Gel 0.006 lists 5 among 62 at risk and Gel 0.012 lists 2 among 60 at risk. These are descriptive counts in the registry record. They do not by themselves establish whether events were caused by treatment, nor do they substitute for the defined Part 1 local-skin-response endpoint. Other adverse events are also tabulated by group, but the registry record does not provide the clinical assessment needed to attribute them to treatment.
The record describes a randomized study, but randomization alone does not make the posted counts a complete comparative analysis. Interpretation would also depend on the analysis population, missing outcome handling, prespecified statistical methods, and uncertainty around estimates. Those details are not reported for the primary endpoint. The registry’s completed status does not fill in missing outcome results.
Planning illustrations based on observed effects, if consulted alongside these descriptions, should be understood as hypothetical design calculations rather than observed power or trial findings. The posted planning assumptions identify a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; they are not a report of the trial’s own design justification. The record does not report whether the original study used these assumptions or how its sample size was selected.
9. Statistical Methods Explained
Several design and analysis concepts help distinguish the questions in this study. These explanations are general; they do not fill gaps in the registry record.
What does dose escalation mean?
In a dose-escalation part, participants are assigned to successively higher dose levels according to a study’s decision process. Here, the registry describes Part 1 as open-label and dose-escalation, and states that dose-limiting toxicity counts were used to identify a maximum tolerated dose. The registry gives a threshold rule for that decision. The precise sequence in which cohorts were enrolled or doses advanced is not reported in the registry record, so the decision process should not be reconstructed beyond the stated rule.
The endpoint is a count of participants who meet a defined toxicity criterion. A count is different from a rate or percentage, which would express the count relative to a denominator. This record’s primary outcome description calls for counts by treatment group. The values for those primary outcome groups are not reported in the registry record. The listed adverse-event summaries include both the number at risk and the number affected, but they should be read as descriptive summaries, not as the primary endpoint results.
What does randomization contribute?
Randomization assigns participants to treatment groups using a chance-based procedure. In general, it can help make comparison groups similar with respect to both measured and unmeasured characteristics, though it does not guarantee balance in every trial. The registry labels this study randomized, but does not report the randomization sequence method, allocation ratio, concealment procedures, or group-specific participant flow. Those details matter when assessing whether the intended comparison was carried out as planned.
How should masking be understood?
Masking means that one or more groups involved in a study are kept unaware of treatment assignment. In general, masking can reduce the influence of expectations on care, assessment, or reporting. The record labels the overall study quadruple-masked, while the specific arm descriptions identify Part 1 as open-label and Part 2 as double-blind. These descriptions need to be read by study part; the registry does not explain how the overall masking label relates to each role in each part.
Why does the endpoint definition matter?
A composite decision rule can classify a participant as having a dose-limiting toxicity through different combinations of local response grades. Here the registry lists specific severe findings that can qualify alone and other findings that qualify in combination. This makes the definition more informative than a broad label such as skin reaction, but also means that the count depends on grading and on applying the rule consistently. General measurement error in grading could change whether a participant meets a threshold. The registry describes grades from 0 to 4, but does not report assessor training, reliability checks, or adjudication procedures.
What is a confidence interval?
In general, a confidence interval gives a range of values compatible with an estimate under a specified statistical procedure. It conveys uncertainty and precision, rather than proving that a treatment effect is present or absent. No confidence intervals for the primary or efficacy outcomes are reported in the registry record, so precision for those comparisons cannot be assessed.
For count outcomes, statistical methods may need to account for the distribution of the count and the amount of variation across groups. Over-dispersion is a general statistical issue in which observed variability exceeds what a simple count model would expect; ignoring it can make uncertainty estimates too narrow. That concept cannot be applied as a finding about this trial, because the registry does not report a model for its primary endpoint or the underlying participant-level data.
The record labels the outcome type as binary and describes its meaning as participants with an event, expressed as counts. A binary outcome records whether each participant did or did not meet a defined condition; group summaries can then report how many participants experienced the event. The primary endpoint definition is consistent with an event classification for each participant, though the reported outcome is a count. No adjusted analysis method or effect measure is reported for that primary outcome.
What does multiple imputation address?
Multiple imputation is a general method for handling missing outcome data by creating several plausible completed datasets, analyzing each, and combining the results to reflect uncertainty due to missingness. The registry identifies multiple imputation for the Part 2 complete and partial clearance outcomes. It does not report the imputation model, variables used, assumptions about the missingness process, or sensitivity analyses. Therefore the reference to multiple imputation does not by itself establish how robust an efficacy result would be to missing data, and no such result is reported in the registry record.
The registry gives planning assumptions for sample-size illustrations based on observed effects: a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effect sizes set as stated fractions of an observed effect. Such calculations are planning illustrations, not observed power. The record does not report the trial’s own sample-size justification or whether the study used those assumptions. The intended comparison and planning assumptions should therefore remain separate from any claim about what the trial demonstrated.
10. Multiplicity, Missing Data and Analysis Populations
Multiplicity arises when a study evaluates several outcomes, treatment groups, doses, or comparisons. In general, carrying out many statistical tests can increase the chance of finding at least one apparently notable result by chance. This study has separate Part 1 toxicity and Part 2 efficacy objectives, two formulations, multiple doses, and vehicle comparisons. The registry lists four outcome measures and 18 analyses. It does not report a multiplicity adjustment, a hierarchy for interpreting outcomes, or a prespecified strategy for selecting among comparisons. The effect of multiple testing on interpretation therefore cannot be assessed from the registry record.
The Part 2 secondary outcomes are complete clearance and partial clearance of actinic keratosis lesions, both identified as using multiple imputation. That names an approach to missing outcomes, but the imputation model, assumptions, missingness extent, and sensitivity analyses are not reported in the registry record. There is no corresponding missing-data description for the primary Part 1 toxicity count.
Analysis populations are also not described in detail. The registry record does not report whether the primary analysis used all randomized participants, participants who received treatment, or another defined population. It does not provide participant flow or reasons for missing data and withdrawal by arm. These details are needed to judge how the analyzed groups relate to the randomized groups and how incomplete follow-up could affect conclusions.
Although the record describes the trial as randomized and gives an overall enrollment of 320, it does not report group-specific enrollment for the primary analysis. Neither the sample-size justification nor interim-analysis procedures are reported in the registry record. These missing details should not be filled in by assuming conventional methods. They limit assessment of the planned error control, analysis population, and precision of the stated comparisons.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Part 1: LEO 43204 Gel 0.0015 | 0 | 3 | 0.0% |
| Part 1: LEO 43204 Gel 0.003 | 0 | 3 | 0.0% |
| Part 1: LEO 43204 Gel 0.006 | 1 | 6 | 16.7% |
| Part 1: LEO 43204 Gel 0.012 | 0 | 6 | 0.0% |
| Part 1: LEO 43204 Gel 0.018 | 1 | 17 | 5.9% |
| Part 1: LEO 43204 Gel 0.025 | 0 | 18 | 0.0% |
| Part 1: LEO 43204 Cream 0.0015 | 0 | 3 | 0.0% |
| Part 1: LEO 43204 Cream 0.003 | 0 | 3 | 0.0% |
| Part 1: LEO 43204 Cream 0.006 | 0 | 6 | 0.0% |
| Part 1: LEO 43204 Cream 0.012 | 0 | 12 | 0.0% |
| Part 2: LEO 43204 Gel Vehicle | 0 | 58 | 0.0% |
| Part 2: LEO 43204 Gel 0.006 | 5 | 62 | 8.1% |
| Part 2: LEO 43204 Gel 0.012 | 2 | 60 | 3.3% |
| Part 2: LEO 43204 Gel 0.018 | 0 | 62 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Part 1: LEO 43204 Gel 0.0015 | 3 of 3 |
| Part 1: LEO 43204 Gel 0.003 | 1 of 3 |
| Part 1: LEO 43204 Gel 0.006 | 5 of 6 |
| Part 1: LEO 43204 Gel 0.012 | 5 of 6 |
| Part 1: LEO 43204 Gel 0.018 | 10 of 17 |
| Part 1: LEO 43204 Gel 0.025 | 11 of 18 |
Most frequent serious adverse event terms
| Event term | Organ system | Part 1: LEO 43204 Gel 0.0015 | Part 1: LEO 43204 Gel 0.003 | Part 1: LEO 43204 Gel 0.006 | Part 1: LEO 43204 Gel 0.012 | Part 1: LEO 43204 Gel 0.018 | Part 1: LEO 43204 Gel 0.025 |
|---|---|---|---|---|---|---|---|
| Squamous cell carcinoma of skin | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 of 3 | 0 of 3 | 1 of 6 | 0 of 6 | 0 of 17 | 0 of 18 |
| Breast Cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 of 3 | 0 of 3 | 0 of 6 | 0 of 6 | 1 of 17 | 0 of 18 |
| Bradycardia | Cardiac disorders | 0 of 3 | 0 of 3 | 0 of 6 | 0 of 6 | 0 of 17 | 0 of 18 |
| Myocardial infarction | Cardiac disorders | 0 of 3 | 0 of 3 | 0 of 6 | 0 of 6 | 0 of 17 | 0 of 18 |
| Ventricular fibrillation | Cardiac disorders | 0 of 3 | 0 of 3 | 0 of 6 | 0 of 6 | 0 of 17 | 0 of 18 |
| Chest pain | General disorders | 0 of 3 | 0 of 3 | 0 of 6 | 0 of 6 | 0 of 17 | 0 of 18 |
| Hip fracture | Injury, poisoning and procedural complications | 0 of 3 | 0 of 3 | 0 of 6 | 0 of 6 | 0 of 17 | 0 of 18 |
| Convulsion | Nervous system disorders | 0 of 3 | 0 of 3 | 0 of 6 | 0 of 6 | 0 of 17 | 0 of 18 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Part 1: LEO 43204 Gel 0.0015 | Part 1: LEO 43204 Gel 0.003 | Part 1: LEO 43204 Gel 0.006 | Part 1: LEO 43204 Gel 0.012 | Part 1: LEO 43204 Gel 0.018 | Part 1: LEO 43204 Gel 0.025 |
|---|---|---|---|---|---|---|---|
| Application site pain | General disorders | 1 of 3 | 1 of 3 | 2 of 6 | 3 of 6 | 3 of 17 | 8 of 18 |
| Application site pruritus | General disorders | 1 of 3 | 1 of 3 | 2 of 6 | 4 of 6 | 2 of 17 | 1 of 18 |
| Application site erythema | General disorders | 0 of 3 | 0 of 3 | 2 of 6 | 1 of 6 | 2 of 17 | 1 of 18 |
| Headache | Nervous system disorders | 0 of 3 | 1 of 3 | 0 of 6 | 0 of 6 | 2 of 17 | 1 of 18 |
| Eye irritation | Eye disorders | 0 of 3 | 0 of 3 | 0 of 6 | 1 of 6 | 1 of 17 | 0 of 18 |
| Application site discolouration | General disorders | 0 of 3 | 0 of 3 | 0 of 6 | 0 of 6 | 0 of 17 | 1 of 18 |
| Application site discomfort | General disorders | 0 of 3 | 0 of 3 | 0 of 6 | 0 of 6 | 0 of 17 | 1 of 18 |
| Application site exfoliation | General disorders | 0 of 3 | 0 of 3 | 0 of 6 | 0 of 6 | 1 of 17 | 0 of 18 |
| Application site oedema | General disorders | 0 of 3 | 0 of 3 | 0 of 6 | 0 of 6 | 1 of 17 | 0 of 18 |
| Application site photosensitivity reaction | General disorders | 0 of 3 | 0 of 3 | 0 of 6 | 0 of 6 | 1 of 17 | 0 of 18 |
Serious events with the highest arm-level rate: squamous cell carcinoma of skin (16.7%), breast cancer (5.9%), chest pain (3.2%), bradycardia (1.7%), hip fracture (1.7%).
The registry’s adverse-event summaries distinguish serious adverse events from other adverse events and report counts of participants at risk and affected by group. For example, Part 2 LEO 43204 Gel 0.006 lists 5 serious adverse events among 62 at risk, and Part 2 LEO 43204 Gel 0.012 lists 2 among 60 at risk. Part 2 LEO 43204 Gel Vehicle lists 0 among 58 at risk. These are posted group summaries, not estimates of causal effects.
Serious adverse events are not the same endpoint as dose-limiting toxicity. The primary endpoint applies a specific rule to graded local skin responses during the period from Day 1 up to and including Day 8. The adverse-event summaries have a different scope in the registry and should not be used to infer the Part 1 DLT counts or the selected maximum tolerated dose. The deaths fields are not reported in the registry record.
The listed serious-event terms include Squamous cell carcinoma of skin at 16.7%, Breast Cancer at 5.9%, Chest pain at 3.2%, Bradycardia at 1.7%, Hip fracture at 1.7%, and Myocardial infarction at 1.6%. The denominator and the basis for these percentages are not reported in the registry record, so they should not be treated as group-specific risks or compared directly with the at-risk counts. The record does not establish whether any event was caused by study treatment. Without that attribution, follow-up context, and a complete comparative analysis, these figures are descriptive rather than evidence of a treatment effect.
12. What the Result Does, and Does Not, Mean
The record establishes that a randomized, sequential Phase 1/Phase 2 study was conducted to investigate two LEO 43204 formulations in actinic keratosis. It specifies a Part 1 dose-limiting toxicity endpoint based on local skin responses and a Part 2 objective of comparing selected doses with vehicle for lesion clearance. It also gives the operational MTD rule and identifies the planned secondary clearance outcomes.
It does not report the observed primary endpoint counts, the MTD identified, or the Part 2 clearance results. Therefore the posted registry information does not establish which dose met the study’s toxicity criterion, how the formulations compared with vehicle, or how precisely any efficacy difference was estimated. Those are the key outcome questions the design was intended to address, but they cannot be answered from the recorded results available in this account.
Some adverse-event summaries are present, including counts of serious and other events in named groups. These counts describe the registry entries; they do not show whether events were caused by a formulation or whether rates differed in a way that could be attributed to treatment. The listed serious-event percentages also lack a reported denominator in this record. They should not be interpreted as a complete safety comparison.
In general, a completed trial status means the registry records the study as completed, not that every result needed for interpretation is available in the record. Likewise, a randomized design can support fair comparisons when implemented and analyzed appropriately, but it cannot replace the outcome estimates, uncertainty measures, and analysis details needed to evaluate those comparisons.
The study’s record is therefore informative about its structure and endpoint definitions, but incomplete as a report of its main findings. It does not justify a conclusion about treatment efficacy or overall safety. Additional results and analysis details would be needed to assess the magnitude and precision of the planned comparisons and the relationship of adverse events to treatment.
13. Why This Trial Matters Statistically
This trial is statistically notable because it joins a dose-escalation question to later efficacy comparisons within a sequential design. The Part 1 decision depends on a prespecified clinical classification of local skin responses and the stated threshold rule for identifying a maximum tolerated dose. The classification is not simply a count of any skin response: it relies on response categories, severity grades, and combinations of findings. That makes transparent endpoint definitions essential for reproducibility.
The transition from escalation to a later comparative part also illustrates why the objectives must be kept distinct. Part 1 asks whether doses meet the toxicity rule; Part 2 evaluates lesion clearance against vehicle. Evidence answering one objective does not automatically answer the other. Part 2’s double-blind descriptions and Part 1’s open-label descriptions also show why masking should be described by part rather than treated as a single uniform feature.
Statistically, dose selection and multiple efficacy comparisons raise different interpretive issues. A dose-escalation threshold is a decision rule, while efficacy comparisons require effect estimates and uncertainty. Multiple doses and outcomes also make it important to understand the analysis hierarchy and any multiplicity strategy. These details are not reported in the registry record, so the strength of the intended statistical safeguards cannot be assessed.
The record demonstrates why trial status and trial results are not interchangeable. It reports a completed study and gives some descriptive adverse-event counts, yet omits the key primary and efficacy outcome results. Without those results, neither the dose-escalation conclusion nor the precision of the efficacy comparisons can be evaluated. This is a useful distinction for registry readers: design information explains what a study set out to learn, while outcome data and analysis details are needed to determine what its observations show.
14. 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.
A central limitation is that the registry record does not report results for the primary endpoint. The Part 1 DLT counts and selected MTD are unavailable, preventing assessment of the dose-escalation objective. The Part 2 complete and partial clearance results are also not reported, so no efficacy comparison can be evaluated from the record.
The record gives overall enrollment but not group-specific participant flow for the primary outcome. It does not describe the primary analysis population, missingness, or reasons for withdrawal. Although multiple imputation is named for the Part 2 clearance outcomes, the method, assumptions, and sensitivity analyses are not reported. These omissions make it difficult to assess the role of incomplete outcome data.
The registry identifies the study as randomized and quadruple-masked overall, while Part 1 is described as open-label and Part 2 as double-blind. It does not explain the masking label across study roles or provide details of allocation procedures. Further, the analysis plan, multiplicity approach, interim analyses, and sample-size justification are not reported in the registry record. The planning assumptions listed for illustrations should not be treated as the original trial design rationale.
The adverse-event summaries are descriptive and do not provide treatment attribution. The listed serious-event percentages have no reported denominator, and death counts are not reported in the registry record. The primary DLT endpoint has a specific local-response definition, so broad adverse-event counts cannot serve as a replacement. These record-level limitations constrain interpretation independently of the study’s completed status.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study of Increasing Strengths, Safety and Efficacy of Two Formulas of LEO 43204 on the Face or the Chest in Patients With Actinic Keratosis — NCT01922050.
- Registry record last updated 2025-03-06; status last verified 2019-02.
- Results first posted 2019-02-27.
- 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.
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18. Record Summary
NCT01922050 is recorded as a completed, randomized, sequential Phase 1/Phase 2 study sponsored by LEO Pharma, with enrollment of 320. The study concerned two LEO 43204 formulations in patients with actinic keratosis, with treatment once daily for two consecutive days.
Part 1 used open-label dose escalation and assessed the number of participants with local-skin-response DLTs from Day 1 up to and including Day 8. Part 2 was described as double-blind and planned comparisons of two doses of each formulation with vehicle for lesion clearance. The primary endpoint counts, selected MTD, and Part 2 efficacy results are not reported in the registry record. Some adverse-event counts are listed, but they do not establish causation or provide a substitute for the missing outcome results.