Dose Escalation Trial to Evaluate Dose Limiting Toxicity/Maximum Tolerated Dose of Microneedle Arrays Containing Doxorubicin (D-MNA) in Basal Cell Carcinoma (BCC): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dose Escalation Trial to Evaluate Dose Limiting Toxicity/Maximum Tolerated Dose of Microneedle Arrays Containing Doxorubicin (D-MNA) in Basal Cell Carcinoma (BCC) (NCT03646188), a non-randomized phase 1 study. The primary outcome is Number of Participants With Dose Limiting Toxicities as Assessed by Local Skin Response (LSR) Grading Scale.

2. Clinical Question

The study was intended to assess dose-limiting toxicity and maximum tolerated dose, as well as safety and tolerability. Its summary also names efficacy as an objective, and a secondary outcome concerns complete response of eradicated basal cell carcinoma measured by histological analysis. The registry record does not give numerical results for that secondary outcome either. As a result, the record describes the questions the trial set out to address, but does not establish what the primary endpoint or secondary outcome showed.

3. Trial Design

This was an open-label Phase I study with non-randomized allocation and a sequential model. The record lists a placebo-containing microneedle array and doxorubicin-containing arrays at 25 µg, 50 µg, 100 µg, and 200 µg. Because participants were not randomly allocated, differences between the groups cannot be interpreted as though the groups were exchangeable randomized arms. The record does not report the sequence or decision rules used to move between doses.

The study enrolled 13 participants. It began on 2020-06-10, and its primary completion date is listed as 2021-03-01. Its status is terminated. The reason for termination, the date of termination, and any consequences of termination for follow-up or data collection are not reported in the registry record. The record does not report how many participants were assigned to each study arm for the primary endpoint, or how many were evaluable for that endpoint.

The main endpoint was the number of participants with dose-limiting toxicities assessed by Local Skin Response grading over 4 weeks. The record describes a 0-4 grading scale, with 4 representing the worst dermal response. A secondary outcome was complete response of eradicated basal cell carcinoma measured by histological analysis. The record lists two outcome measures but reports no analysis entries.

The study's dose-escalation objective differs from a randomized treatment comparison. It focuses on tolerability and toxicity across planned dose levels, while random allocation would be used to support a balanced comparison of treatment groups. The registry record does not report the protocol's dose-escalation algorithm, stopping rules, criteria for determining maximum tolerated dose, or the planned statistical methods. These design details should not be inferred from the listed sequence of doses alone.

4. Participant Flow and Accounting

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

Overall Study

Analysis population for the primary outcome, as defined in the registry: All evaluable subjects

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 Number of Participants With Dose Limiting Toxicities as Assessed by Local Skin Response (LSR) Grading Scale, measured over 4 weeks.

The primary endpoint counts participants with dose-limiting toxicities, assessed using a Local Skin Response grading scale. The stated timeframe is 4 weeks, and the endpoint population is all evaluable subjects. The scale runs from 0 to 4, with 4 described as the worst dermal response. The registry record does not provide a threshold defining which grades or patterns qualified as a dose-limiting toxicity, beyond naming the grading scale and endpoint.

In a dose-escalation study, a toxicity endpoint can help characterize whether an exposure level is tolerable under the study's assessment rules. Such an endpoint is relevant to evaluating maximum tolerated dose, one of the stated study objectives. This is a general explanation of the role of a toxicity endpoint; it does not establish how this trial's investigators applied their criteria. The protocol-level definition and decision process are not reported in the registry record.

The endpoint is a participant count, not a continuous measure of skin response severity. It therefore does not, by itself, communicate the full distribution of grades or the timing and duration of individual reactions. Those details are not reported in the registry record. More importantly, the record gives no observed primary endpoint count or analysis. The endpoint's definition can be described, but the data needed to assess the observed frequency of dose-limiting toxicity are absent.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods should be interpreted in light of the design and the outcomes actually reported. Here, the record identifies a Phase I, open-label, non-randomized, sequential trial. It describes a participant-count primary endpoint and gives adverse-event counts by arm, but it does not report primary endpoint results or analysis entries. The distinction between a study's stated objectives and its analyzed results is important: an endpoint can be registered without a numerical finding being available in the registry record.

What does a participant count tell a reader?

The primary endpoint is expressed as the number of participants with dose-limiting toxicities, not as a mean score on the Local Skin Response scale. A count can be clinically and statistically interpretable when its population, event definition, and observation period are clear. The record identifies the endpoint population as all evaluable subjects, gives a timeframe of 4 weeks, and describes the scale as running from 0 to 4. However, it does not report the number of evaluable participants, the number with the primary endpoint, or the exact rule translating grades into a dose-limiting toxicity. Without those details, the event count and its precision cannot be reconstructed.

More generally, event counts are often accompanied by a denominator and an interval estimate. A confidence interval expresses the uncertainty around an estimated quantity under a statistical model; it is not a guarantee that the true value falls within that interval. With limited observations, intervals can be broad, and a count alone can convey little about precision. This is general statistical context, not a claim about an unreported interval for this study. The registry record gives no confidence interval for the primary endpoint.

What does the non-randomized design imply?

Random allocation is a method for making comparison groups more similar, on average, with respect to both measured and unmeasured characteristics. This study is explicitly non-randomized, so the listed arms should not be treated as balanced randomized groups. In a sequential dose-escalation design, the dose levels and enrollment may follow a planned order. The record does not describe the order of assignment, the escalation rules, or participant characteristics by arm. A contrast between the listed groups would therefore be descriptive unless supported by further design and analysis details, which are not reported in the registry record.

Sequential designs are commonly used to evaluate tolerability as doses are considered in order, but the exact statistical implications depend on the prespecified algorithm and the observed outcomes. This is a general description of such designs, not a statement about the algorithm used in this trial. The registry record does not report a dose-escalation algorithm, stopping rules, or the criteria used to declare a maximum tolerated dose. The dose list alone does not show how decisions were made.

How should the safety counts be understood?

The adverse-event record distinguishes serious adverse events from other adverse events. These categories should not be merged: seriousness is a specific classification, and an event counted among other adverse events is not thereby shown to be serious. The record reports no serious adverse events in the listed arms. It also reports other adverse events in two arms. These are counts as recorded, not comparative effect estimates. They do not reveal event type, severity, timing, duration, attribution, or whether events overlapped within a participant. Those details are not reported in the registry record.

In general, over-dispersion describes variability greater than a simple statistical model expects. It can matter when outcomes are clustered or when participants have differing underlying risks, because a model that assumes less variability may overstate precision. This is general statistical context only. The registry record does not report a model for the primary endpoint or enough primary endpoint data to assess whether over-dispersion is relevant.

What can be said about sample-size planning?

The record describes a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It states that the effect to detect is a stated fraction of the observed effect. The illustration is described as planning, not as the trial's original design, and it is not observed power. The record does not report a trial-specific sample-size justification. Since the primary endpoint result and its observed effect are not reported, no sample-size illustration or effect estimate can be independently interpreted from the registry record.

In general, a sample-size calculation depends on the target effect, variability or event rate, allocation, and chosen error criteria. Changing the target effect changes the amount of information needed to detect it under the assumptions. Planning calculations do not show that a study had a particular probability of finding a result after the data have been observed. This distinction matters especially in a small dose-escalation study, where the purpose may center on safety characterization rather than a definitive efficacy comparison. The registry record does not state the original enrollment target or a formal justification for the enrollment of 13 participants.

No p-value, confidence interval, adjusted estimate, or prespecified statistical analysis is reported for the primary endpoint. The record does not report whether there were interim analyses, how missing observations were handled, or what analysis population was used beyond the phrase all evaluable subjects for the endpoint definition. These omissions mean that a formal inferential interpretation cannot be recovered from the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary outcome and a secondary outcome, but it does not report an analysis plan or results for either. It therefore does not explain how the investigators intended to handle multiplicity, meaning the increased chance of a misleading finding when several outcomes or comparisons are tested. General approaches can include designating one primary test, adjusting significance thresholds, or treating additional analyses as exploratory. Which approach, if any, was planned for this trial is not reported in the registry record.

The design lists placebo and several doxorubicin dose groups. If multiple dose comparisons or dose-related hypotheses were tested, that could also raise multiplicity questions. However, the record gives no inferential comparisons, p-values, or analysis entries, so it does not show whether such testing occurred. The dose groups should not be read as a set of randomized pairwise comparisons.

Missing-data handling is also not reported. The primary endpoint population is described as all evaluable subjects, but the record does not define evaluability, state how many participants met that definition, or say how participants with incomplete endpoint assessment were treated. It does not report withdrawals, missing endpoint observations, or imputation methods. The overall enrollment is 13, but the record does not provide the number evaluable for the primary endpoint.

The record does not describe an intention-to-treat population, a per-protocol population, or any other analysis population beyond the endpoint's all-evaluable wording. It also does not report interim analyses, stopping decisions based on accumulating outcomes, or statistical methods for the secondary outcome. These are unreported analysis details, not evidence that a particular procedure was or was not used outside the registry record.

11. 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 1% reporting threshold.

Most frequent non-serious adverse event terms

The registry record separates serious adverse events from other adverse events. For serious adverse events, the reported count is 0 among 3 participants at risk in the placebo-containing MNA group, 0 among 3 at risk in the 25 µg group, 0 among 3 at risk in the 50 µg group, 0 among 3 at risk in the 100 µg group, and 0 among 1 at risk in the 200 µg group. Deaths are reported as 0 in each listed group.

For other adverse events, the record reports 0 among 3 at risk in the placebo-containing MNA group, 1 among 3 at risk in the 25 µg group, 0 among 3 at risk in the 50 µg group, 0 among 3 at risk in the 100 µg group, and 1 among 1 at risk in the 200 µg group. These are descriptive counts in groups that were not randomized for a like-for-like comparison. They should not be interpreted as evidence of a dose-related pattern or as causal estimates.

The registry record does not list serious adverse-event terms, and it does not describe the types, severity, timing, duration, or attribution of the other adverse events. These safety counts are not the primary endpoint results: the record does not report the number of participants with dose-limiting toxicity under the Local Skin Response grading definition.

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

The record establishes that a Phase I, open-label, sequential dose-escalation study was conducted in participants with basal cell carcinoma, with a primary focus on dose-limiting toxicity assessed using a Local Skin Response grading scale. It identifies a 4-week assessment timeframe and lists placebo and four doxorubicin doses. Those details describe what the trial was designed to investigate; they do not establish the findings.

The primary endpoint count is not reported in the registry record. Neither is an estimate of maximum tolerated dose. Complete response, the listed secondary outcome measured by histological analysis, also has no numerical result in the record. Thus, the posted information cannot establish the frequency of the primary endpoint, the degree of precision around it, or the observed secondary outcome. It cannot support a conclusion about efficacy.

The adverse-event entries provide limited descriptive information: no serious adverse events or deaths are reported in the listed groups, while other adverse events are recorded in the 25 µg and 200 µg groups. These entries do not give event descriptions or establish that any event was caused by the study intervention. They also do not replace the missing primary endpoint result.

The study's non-randomized design matters when interpreting differences across doses. The groups are not randomized comparison arms, and the registry record does not provide a comparative statistical analysis. A pattern in the listed adverse-event counts, if one is perceived, cannot by itself establish a dose effect. The record also does not report why the study was terminated, the dose-escalation rules, or how missing observations were handled.

Overall, the registry record documents the study's objectives, design, outcome definitions, and some safety counts. It does not provide enough outcome or analysis information to determine what the trial found about dose-limiting toxicity, maximum tolerated dose, or histological complete response. The absence of a reported result should be understood as an information limitation, not as evidence for or against any clinical effect.

13. Why This Trial Matters Statistically

This study illustrates why a trial's design, endpoint definition, and posted results need to be read together. A dose-escalation study asks questions about tolerability across dose levels, rather than necessarily estimating a treatment effect through a randomized comparison. The non-randomized, sequential design is therefore central to interpreting the listed arms and any safety counts.

The endpoint is also important. The study identifies dose-limiting toxicity as the primary outcome and specifies a Local Skin Response grading scale and a 4-week timeframe. Yet the registry record does not report the endpoint result, the number evaluable, or the operational threshold for a dose-limiting toxicity. Without those elements, the central statistical question remains unanswered in the record, despite the presence of a defined endpoint.

It also demonstrates the difference between safety counts and a dose-limiting toxicity analysis. Serious and other adverse events are recorded separately, but the record does not indicate which events, if any, met the primary endpoint definition. Readers should not assume those safety categories correspond directly to the endpoint.

Finally, registration details and outcome reporting serve different purposes. A registered objective describes what a study intended to assess; numerical results and a statistical analysis are needed to understand what the data showed and with what precision. The termination status adds context, but without a reported reason it cannot explain the missing analysis. This record is therefore useful for understanding the planned clinical and statistical questions, while also showing how limited interpretation becomes when endpoint results and analysis details are not reported.

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.

Several trial-specific limitations restrict interpretation of the registry record. The study is non-randomized and sequential, so the arms are not a like-for-like randomized comparison. The record does not describe the sequence in which doses were evaluated, allocation procedures, escalation criteria, or stopping rules. Without those details, the listed doses do not reveal how decisions were made or how each group came to be represented.

The primary endpoint result is not reported, despite its central role in the study objective. The registry record does not provide the count of dose-limiting toxicities, the number of evaluable participants, or the criteria used to classify a response as dose-limiting. It also does not provide the result for the histologically measured complete-response outcome. The record lists two outcome measures and no analysis entries.

The adverse-event information is limited to counts by category and group. Serious adverse-event terms are not listed, and the record does not describe the other events, their severity, timing, duration, or attribution. The counts do not establish a causal relationship or substitute for the primary endpoint.

The study status is terminated, but the reason and timing of termination are not reported in the registry record. Nor does the record explain whether termination changed planned follow-up or outcome collection. Missing-data rules, analysis populations, multiplicity handling, confidence intervals, and statistical tests are also not reported. These gaps mean that the precision, completeness, and inferential basis of the results cannot be assessed from the posted information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Dose Escalation Trial to Evaluate Dose Limiting Toxicity/Maximum Tolerated Dose of Microneedle Arrays Containing Doxorubicin (D-MNA) in Basal Cell Carcinoma (BCC) — NCT03646188.
• Registry record last updated 2026-04-16; status last verified 2026-03.
• Results first posted 2022-08-17.
• 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.

18. Record Summary

NCT03646188 is a Phase I, open-label, non-randomized, sequential dose-escalation trial in participants with superficial or nodular basal cell carcinoma. The study enrolled 13 participants and is listed as terminated. Its primary objective concerned dose-limiting toxicity and maximum tolerated dose for doxorubicin-containing microneedle arrays, with placebo and 25 µg, 50 µg, 100 µg, and 200 µg dose groups.

The primary endpoint was the number of participants with dose-limiting toxicities assessed using Local Skin Response grading over 4 weeks. A histologically measured complete-response outcome was also listed. Neither outcome has a numerical result in the registry record, which reports no analysis entries. Adverse-event counts are listed by arm, but they do not provide the missing primary endpoint analysis. The record does not report the reason for termination, the dose-escalation rules, or the statistical analysis plan.