ET-01 in Subjects With Lateral Canthal Lines: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for ET-01 in Subjects With Lateral Canthal Lines (NCT03326856), a randomized phase 2 study. The primary outcome is Number of Participants With a Response Defined as IGA-C (Investigators Global Assessment) Score ≤ 2 and a SSA-C (Subject Self-Assessment) Score ≤ 2.

2. Clinical Question

The clinical question is therefore about the number of participants in each arm meeting a joint assessment threshold at a specified follow-up. The registry lists random allocation and quadruple masking, but does not report the allocation procedure, the identities of those masked, or the details of how treatment was applied. Those omissions limit how fully the conduct of the comparison can be reconstructed from the registry record.

3. Trial Design

This was a randomized, quadruple-masked Phase 2 study of ET-01 in subjects with lateral canthal lines. The listed design model is sequential. That classification does not, by itself, explain how participants entered the dose arms, whether treatment stages were planned, or how decisions between stages were made; those details are not reported in the registry record. The trial status is completed.

The study began on 2017-10-25, and the primary completion date was 2018-06-11. Enrollment was 48. The five listed arms were vehicle and four dose levels of topical botulinum toxin, Type A. The record does not state the dose amounts, treatment schedule, duration of treatment, or the procedures used to maintain masking. It also does not identify which groups of people were included in the quadruple masking.

The primary outcome was assessed at Week 4. The analysis population was defined as treated subjects who had at least one post-baseline visit, described as the Per Protocol population. The arm-level participant counts for this endpoint were Vehicle 13, Dose 1 8, Dose 2 9, Dose 3 9, and Dose 4 8. These are the endpoint analysis counts, not a complete account of participant flow. Reasons for differences between enrollment, treatment, and endpoint analysis counts are not reported in the registry record.

The record lists two secondary outcomes: response based on the Investigators Global Assessment alone and response based on the Subject Self-Assessment alone. It also reports three outcome measures overall, but the available results do not include analyses for these outcomes. The registry record does not report the planned statistical analysis methods, the allocation ratio, a sample-size justification, interim analyses, or rules for handling multiple dose comparisons.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Per Protocol (PP) population defined as all treated subjects who had at least one post-baseline visit. No imputation was performed when only incomplete data were available.

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 a Response Defined as IGA-C (Investigators Global Assessment) Score ≤ 2 and a SSA-C (Subject Self-Assessment) Score ≤ 2, measured over Week 4.

The primary endpoint counts participants who met both parts of a composite response definition at Week 4. The investigator-rated and subject-rated assessments each used a Crow’s Feet Wrinkle Scale ranging from 0, absent, to 4, severe. A participant counted as a responder only if both scores on contraction were 2 or less. This joint definition requires agreement across the two assessments at the specified threshold; meeting only one assessment criterion is not enough.

A composite can bring more than one perspective into a single outcome. In this trial, the investigator assessment and the subject’s own assessment are both represented. That makes the endpoint a count of participants meeting the combined criterion, rather than a measure of change in either score considered separately. The registry record does not report the separate score distributions, baseline values, or changes from baseline for this primary outcome.

The endpoint is binary at the participant level: each person either met the composite response definition or did not. The posted results report the number of responders and the endpoint analysis population in each arm. They do not report a modeled effect estimate, confidence interval, or inferential test for the primary comparison. The threshold and assessment time are specified, but the record does not provide further detail about assessment procedures, assessor training, or whether the Week 4 assessment was selected in advance as the key time point in a statistical plan.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary participant-level endpoint. Each participant is classified according to whether both assessment scores satisfy the response threshold. The reported count is the number classified as responders in an arm; the accompanying arm size identifies the participants included in that endpoint analysis. A count is directly descriptive, but it does not, on its own, quantify the uncertainty in an arm’s response probability or the comparative effect between arms.

What does a confidence interval communicate?

In general, a confidence interval expresses the uncertainty associated with an estimated effect under a specified statistical method. It can show which effect sizes remain reasonably compatible with the observed data and the assumptions of that method. A narrow interval indicates greater precision than a wide interval, while an interval spanning effects in different directions can indicate substantial uncertainty about the comparison. The registry record does not report confidence intervals for the primary outcome.

Why is a comparison different from arm-level counts?

A comparative analysis must define a contrast between an intervention arm and a comparator, and specify how the observed data are used to estimate that contrast. Different approaches can be appropriate for binary outcomes, but their results depend on the chosen effect measure, model, analysis population, and assumptions. The record identifies Vehicle as control but does not report a sponsor analysis for the primary comparison. It also notes that a two-arm comparison was not estimable from the posted endpoint results. Therefore, the arm counts should remain descriptive rather than being treated as a formal test of a dose-versus-vehicle effect.

How does randomization relate to interpretation?

In general, random allocation is intended to create groups whose differences at the start of a study are not systematically determined by treatment choice. This supports a causal comparison when allocation is implemented as planned and the analysis appropriately accounts for the randomized population. The registry record identifies the study as randomized, but does not report the sequence-generation method, allocation concealment, or a participant-flow account sufficient to assess departures from the planned groups. The primary endpoint analysis uses a Per Protocol population rather than an explicitly described intention-to-treat population, so the reported counts should be interpreted in light of that restriction.

What does masking add?

In general, masking can reduce the influence of treatment knowledge on participant reports, investigator ratings, and study conduct. The record labels the study quadruple-masked, but does not say which roles were masked or describe the masking procedures. It is therefore possible to report the registry’s design classification, but not to assess from this record how masking was maintained or whether it could have been compromised.

What does the sequential model establish?

The registry lists a sequential model. In general, sequential designs may organize a study or its decision process in stages, but the label alone does not establish what was planned or implemented. The registry record does not report stage definitions, decision boundaries, stopping criteria, or whether any interim analyses occurred. No assumptions about those features should be made from the model label alone.

How should planning illustrations be read?

General sample-size planning translates a chosen effect, significance level, allocation scheme, and statistical approximation into an illustrative number of participants or events. Such an illustration is conditional on those assumptions and is not an observed result or a measure of the probability that the completed trial detected an effect. The planning assumptions associated with this record specify a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. For non-time-to-event outcomes, the illustration is expressed as participants per arm; time-to-event calculations use total events. These are planning conventions, not the trial’s reported design justification. The actual illustration values are not reported in the registry record, and a sample-size justification for the trial is not reported in the registry record.

For binary outcomes, sparse counts can make estimates unstable and precision limited. General methods may use exact or approximate procedures, or a regression model, depending on the design and the planned estimand. The choice should be specified in an analysis plan; it cannot be recovered from the arm counts. The registry record reports no primary analysis method, no confidence interval, and no p-value. Consequently, no particular inferential method or conclusion about statistical significance can be attributed to the posted primary results.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Vehicle", "Dose 1", "Dose 2", "Dose 3", "Dose 4")
n      <- c(13, 8, 9, 9, 8)
events <- c(2, 3, 4, 2, 1)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Vehicle  13  2  15.4  1.9  45.4  4.3  42.2  4.7  42.8
ARM  Dose 1  8  3  37.5  8.5  75.5  13.7  69.4  13.7  70.1
ARM  Dose 2  9  4  44.4  13.7  78.8  18.9  73.3  18.7  73.8
ARM  Dose 3  9  2  22.2  2.8  60.0  6.3  54.7  6.7  55.6
ARM  Dose 4  8  1  12.5  0.3  52.7  2.2  47.1  2.8  48.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary composite outcome and two secondary outcomes: response based on the investigator assessment alone and response based on the subject self-assessment alone. It reports three outcome measures overall. Testing multiple outcomes or comparing multiple dose arms can increase the chance of a false-positive finding if results are interpreted without an appropriate plan. The registry record does not report a multiplicity strategy, a hierarchy among outcomes, or a procedure for adjusting comparisons across dose arms. The listed outcomes therefore should not be treated as if a particular adjustment had been used.

The primary endpoint population was the Per Protocol population, defined as treated subjects who had at least one post-baseline visit. The record states that no imputation was performed when only incomplete data were available. This means the registry describes an analysis restricted to the defined population and gives a specific rule for incomplete data, but it does not provide enough detail to determine the extent or pattern of missingness. Reasons for missing assessments, the number with incomplete data, and any sensitivity analyses are not reported in the registry record.

Missing data can affect interpretation when the availability of an outcome is related to treatment assignment or participant characteristics. In general, excluding participants or leaving incomplete values unfilled can lead to a result that differs from one based on all randomized participants, depending on why observations are missing. The record does not report an intention-to-treat analysis or sensitivity analyses to assess that possibility.

The registry reports zero posted analyses for the outcome measures. The two secondary outcomes are named, but their results are not reported in the registry record. The available primary counts thus do not establish whether a broader analysis plan was completed, how multiplicity was handled, or how missing observations might have affected the findings.

12. 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 5% reporting threshold.

Most frequent non-serious adverse event terms

The adverse-event summary reports no serious adverse events in any listed arm and no deaths. The numbers at risk for serious adverse events were Vehicle 13, Dose 1 9, Dose 2 9, Dose 3 9, and Dose 4 8. The summary also reports no serious adverse-event terms. These are descriptive counts for the adverse-event groups, not comparative estimates of risk.

For other adverse events, the registry reports none in Vehicle, Dose 1, or Dose 3; one affected participant in Dose 2 and one in Dose 4. The numbers at risk for these summaries were Vehicle 13, Dose 1 9, Dose 2 9, Dose 3 9, and Dose 4 8. The record does not provide further detail about the events, their timing, severity, duration, or attribution. It also does not report an inferential comparison of adverse events between arms.

Zero observed serious events in these groups does not demonstrate that serious events are impossible or rule out risks that might not appear in a study of this size. Likewise, the small number of other events cannot establish a difference between treatments. Safety counts should be read as events recorded during the study in the stated groups, not as proof of safety or harm.

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

The posted results establish that the registry contains Week 4 counts for the primary composite response in the Per Protocol population, along with arm-specific adverse-event summaries. The composite requires both the investigator and subject assessments on contraction to meet the score threshold. The counts vary across the five listed arms, but the record does not provide a comparative estimate or uncertainty interval for the primary endpoint.

These data do not establish a statistically reliable difference between any dose arm and vehicle. No p-value, confidence interval, or sponsor-reported primary comparison is available in the registry record. Nor do the counts alone establish the size or direction of an underlying treatment effect. The registry notes that a two-arm comparison for this binary endpoint was not estimable from the posted results. The arm-level observations should therefore not be converted into an unsupported claim of efficacy or lack of efficacy.

The result is also limited to a particular time point, analysis population, and combined threshold. It does not describe separate responses on the investigator and subject assessments, changes in scale scores, or results at other follow-up times. The secondary outcome results are not reported in the registry record. No treatment recommendation follows from these descriptive results.

For safety, the posted summaries report no serious adverse events and no deaths in the listed groups, with two other adverse events recorded across the dose arms. These observations are limited to the participants and events recorded in this trial. They do not rule out uncommon or unobserved events, and the registry record does not provide enough detail for a broader safety characterization.

The most defensible reading is narrow: the registry reports participant counts for a defined composite and event counts for safety, but does not report the analysis needed to quantify a treatment-versus-vehicle effect. Interpretation should preserve that distinction between observed counts and inferential conclusions.

14. Why This Trial Matters Statistically

This trial illustrates why endpoint definitions and analysis populations matter when reading clinical results. The primary outcome is not simply an investigator rating or a subject rating. A participant must meet the response threshold on both assessments, so the count represents a stricter joint classification than either secondary measure considered alone. Knowing that distinction is essential to understanding what the reported responders represent.

The registry also makes visible a common interpretive boundary: a randomized study can have posted arm-level observations without a posted comparative analysis. Counts help describe the recorded data, but an estimate of the treatment contrast and its precision is needed to assess how much the data support a difference. Here, the record does not report that estimate, a confidence interval, or a p-value, and identifies the binary comparison as not estimable from the posted results.

The Per Protocol definition and the rule against imputing incomplete data are also consequential. They tell readers who contributed to the primary endpoint counts and how incomplete observations were treated at a high level. They do not, however, explain missingness or establish how results would compare under another analysis population. The distinction between enrollment and endpoint analysis counts makes participant flow and analysis-population choice important to interpretation.

Finally, a sequential model label, multiple dose arms, and multiple outcomes all raise questions that require a statistical plan to answer. The registry does not report stage rules or multiplicity procedures. This record therefore demonstrates the value of separating design labels and descriptive results from details that must be explicitly documented before strong statistical conclusions can be drawn.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary result is reported as counts without a comparative effect estimate, confidence interval, or p-value. This prevents assessment of the precision of the treatment-versus-vehicle comparison from the registry results. The record specifically indicates that a two-arm comparison for this binary outcome was not estimable from the posted data.

The endpoint analysis used a Per Protocol population of treated participants with at least one post-baseline visit. The registry does not provide a complete participant-flow account or explain why the arm-level analysis counts differ. It states that no imputation was performed for incomplete data, but does not report the number or pattern of incomplete assessments or sensitivity analyses.

The primary outcome is a composite at Week 4. Separate results for the investigator and subject assessments, results at other times, and the posted results for the two secondary outcomes are not reported in the registry record. The record does not describe dose amounts, treatment procedures, allocation methods, masking procedures, or the identities of masked roles. It also does not report a statistical analysis plan, multiplicity adjustments, interim analyses, sequential decision rules, or a sample-size justification.

The adverse-event summaries are counts, with limited event detail. The record does not provide timing, severity, duration, or attribution for the other adverse events. The reported absence of serious events and deaths is descriptive and cannot resolve the possibility of events not observed in the study. These limitations constrain both efficacy and safety interpretation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: ET-01 in Subjects With Lateral Canthal Lines — NCT03326856.
• Registry record last updated 2022-04-21; status last verified 2022-04.
• Results first posted 2021-09-10.
• 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.

19. Record Summary

NCT03326856 is a completed randomized, quadruple-masked Phase 2 study of topical botulinum toxin, Type A, identified as ET-01, for lateral canthal lines. Enrollment was 48. The study began on 2017-10-25, with primary completion on 2018-06-11. The listed arms were Vehicle and four dose arms.

The primary endpoint counted participants at Week 4 who met both the investigator and subject assessment threshold on contraction. The registry reports arm-level responder counts for the Per Protocol population, but no estimable two-arm comparison, confidence interval, or p-value. Two secondary outcomes are listed without posted results. No imputation was performed for incomplete data in the described primary population.

The adverse-event summary reports no serious adverse events and no deaths, and one other adverse event in each of Dose 2 and Dose 4. The record does not report the statistical plan, multiplicity handling, sequential decision rules, or sample-size justification. The posted results are therefore primarily descriptive and do not establish a comparative treatment effect.