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 Phase 2, Muti-Center Study of Repeat Dosing of Squaric Acid Dibutyl Ester in Subjects With Herpes Labialis (NCT03521479), a randomized phase 2 study. The primary outcome is Local and Generalized Adverse Events.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03521479 |
| Phase | Phase 2 |
| Condition | Herpes Labialis, HSV |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 40 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Squarex, LLC |
| Results posted | Yes |
2. Clinical Question
Population
The study concerned subjects with frequent herpes labialis, defined in the registry record as 4 or more episodes in the previous 12 months. Herpes labialis and HSV are listed as conditions. The record does not provide further eligibility details or describe the characteristics of participants enrolled.
Intervention
All four groups began with 2% squaric acid dibutyl ester (SADBE) on day 0. Group A received 2% again at week 3, week 6, week 9, and month 8. Group B received 0.5% at those later visits. Group C received 2% on day 0, month 3, and month 6. Group D received 2% on day 0 and month 6.
Comparator
The randomized, parallel groups differed in the concentration and schedule of repeat SADBE applications. These are active-regimen comparisons; the registry record does not list a placebo or no-treatment group. The record does not specify a single primary pairwise comparison among the four groups.
Primary question
The primary objective was to assess local and generalized adverse events with repeat topical SADBE application over 9 months. The secondary objective was to assess efficacy in preventing herpes labialis episodes. The posted primary outcome is a number of adverse events, but no inferential comparison of the groups is reported in the registry record.
3. Trial Design
This was a Phase 2, randomized, quadruple-masked, parallel-group study of repeat SADBE dosing in subjects with frequent herpes labialis. The registry lists enrollment of 40. Its status is terminated. The study start date is 2018-03-12, and the primary completion date is 2018-10-05.
The four groups used different repeat-dose schedules after a shared 2% application on day 0. Group A continued with 2% at week 3, week 6, week 9, and month 8; Group B used 0.5% at those same visits. Group C received 2% on day 0, month 3, and month 6, while Group D received 2% on day 0 and month 6. The registry identifies the intervention as a drug and does not list a placebo or untreated group.
Random allocation means group assignment was intended to occur by chance; the registry does not report the allocation procedure. Quadruple masking indicates that the record classifies the study as masked at four roles, but does not identify those roles or describe how masking was maintained. The parallel model means the groups are described as separate treatment groups rather than as a crossover sequence.
The primary objective concerned local and generalized adverse events over 9 months. The secondary objective concerned prevention of herpes labialis episodes. The registry record does not report the reason for termination, actual treatment exposure, participant flow, protocol deviations, or whether all planned visits were completed. It also does not report the sample-size justification or the intended primary contrast.
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
| Stage | Group A | Group B | Group C | Group D |
|---|---|---|---|---|
| STARTED | 10 | 10 | 10 | 10 |
| COMPLETED | 10 | 10 | 10 | 10 |
| NOT COMPLETED | 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.
| Characteristic | Unit | Group A | Group B | Group C | Group D | Total |
|---|---|---|---|---|---|---|
| Participants analysed | 10 | 10 | 10 | 10 | 40 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 10 | 10 | 10 | 10 | 40 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 0 | 0 | 0 |
| Age, Continuous | years | 42.3 (SD 11.3) | 39.2 (SD 10.1) | 47.1 (SD 12.4) | 47.2 (SD 13.1) | 43.94 (SD 11.83) |
| Sex: Female, Male: Female | Participants | 7 | 5 | 5 | 6 | 23 |
| Sex: Female, Male: Male | Participants | 3 | 5 | 5 | 4 | 17 |
| Race/Ethnicity, Customized: Asian | Participants | 1 | 1 | 0 | 0 | 2 |
| Race/Ethnicity, Customized: African American or Black | Participants | 0 | 0 | 1 | 1 | 2 |
| Race/Ethnicity, Customized: White | Participants | 8 | 9 | 7 | 8 | 32 |
| Race/Ethnicity, Customized: Hispanic or Latino | Participants | 1 | 0 | 2 | 1 | 4 |
| Region of Enrollment: United States | participants | 10 | 10 | 10 | 10 | 40 |
6. Primary Endpoint
The registry lists the primary outcome as Local and Generalized Adverse Events, measured over 9 months.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | events |
| Endpoint classification | not reduced to a single comparison |
The primary outcome is titled “Local and Generalized Adverse Events.” It is expressed as a number of events, with a 9-month timeframe. Its description focuses on local and generalized adverse events associated with repeat topical application of 2% and 0.5% SADBE in subjects with frequent herpes labialis.
A safety outcome is used to describe unwanted events during treatment and follow-up. Counts can help characterize the amount of reported harm, while separate categories such as serious and other adverse events can communicate different aspects of safety. The registry record does not define how an event was classified as local, generalized, or serious, nor does it describe how events were collected, verified, or attributed to treatment.
The distinction between an event count and the number of participants affected matters. The primary outcome is described as a number of events, whereas the posted safety summaries report counts of participants affected within serious and other adverse-event categories. Those figures do not, by themselves, give the number of events per participant or the timing and duration of each event. No arm-level result for the primary outcome as a total event count is reported in the registry record.
The secondary objective was efficacy in preventing herpes labialis episodes. A numerical result for that objective is not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted safety summaries report no serious adverse events among the 10 participants at risk in each group, and no deaths in any group. For other adverse events, the affected-participant counts are 13 among 30 at risk in Group A, 12 among 30 in Group B, 6 among 30 in Group C, and 4 among 30 in Group D. These are descriptive counts, not estimates accompanied by uncertainty intervals or results from a reported statistical comparison.
The pattern of counts differs across groups, but the registry record does not establish whether those differences are meaningful, precise, or attributable to the dosing schedules. The record contains no posted comparative analysis, confidence intervals, hypothesis tests, or adjustment for differences in participant characteristics. The small group counts make it especially important not to treat the observed ordering as a definitive ranking. No such ranking is reported by the sponsor.
The serious-event figures need a measured reading. Zero reported serious events in a group is not proof that the underlying risk is zero. With limited information about event ascertainment and follow-up, the figures cannot establish how often serious events might occur outside the observed study. They also do not identify the specific types of other events, their severity, their timing, or whether the same participant experienced more than one event.
The record lists enrollment of 40, but the safety summary reports 10 at risk for serious events and 30 at risk for other events in each group. Those category-specific denominators should be read as posted, not assumed to be interchangeable or reconciled into a single analysis population. The registry record does not explain why the denominators differ or provide participant-flow details that would clarify them.
The primary objective was safety over 9 months. The secondary objective was prevention of herpes labialis episodes, but no efficacy result is reported. Accordingly, the posted counts address only part of the stated objectives. The study status is terminated; the reason and its relation, if any, to the results are not reported in the registry record. None of these summaries supports a causal conclusion that one regimen is safer or more effective than another.
9. Statistical Methods Explained
Statistical interpretation requires separating what is directly counted from what would require a model or comparison. The registry describes the primary endpoint as a number of local and generalized adverse events over 9 months. Its safety summaries, however, present participants affected in serious and other adverse-event categories. These measures answer related but distinct questions: event totals count occurrences, while affected-participant counts indicate how many people experienced at least one event in a category. The registry record does not report event-level detail that would connect the two.
What a count can and cannot show
For a count outcome, the basic descriptive information is the number of events observed during the relevant follow-up. A comparison might also account for how long participants were observed, since participants with more follow-up time have more opportunity to experience an event. General statistical practice may use count models when outcomes are counts, but a model choice depends on the data structure and assumptions. The registry record does not report an event-rate analysis, person-time, or a statistical model for the primary outcome.
In general, count data can vary more than a simple Poisson model expects; this is called over-dispersion. If present, over-dispersion can make standard errors from an overly restrictive model too small and confidence intervals too narrow. This is a general consideration, not a finding about this study: the registry record does not report a count distribution, a dispersion estimate, or any fitted model with which to assess it.
Why uncertainty matters
A confidence interval is a range of values compatible with the observed data under a specified statistical method and its assumptions. It conveys precision, not certainty, and it is not the probability that a particular treatment effect is true. A comparison based only on observed counts can conceal substantial uncertainty, especially when the amount of information is limited. No confidence intervals are reported for the adverse-event summaries, so their precision cannot be assessed from the registry results alone.
A hypothesis test evaluates data relative to a specified null hypothesis and analysis method. A p-value, when reported, describes how unusual data at least as incompatible with that null would be under the model assumptions; it does not measure the size or clinical importance of an effect. The registry record lists no posted statistical analyses for the outcome. Therefore, no p-value or inferential conclusion should be attributed to the study from the reported counts.
Planning illustrations and observed findings
The planning assumptions described for the accompanying sample-size illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They base the effect to detect on a stated fraction of the observed effect. These are planning illustrations rather than the trial’s own design justification, and any resulting sample sizes would be planning quantities, not observed power. The registry record does not report the trial’s original sample-size rationale or a complete statistical analysis plan. No specific planning sample-size values are stated in the registry record details.
Equal allocation between two arms is an assumption for those illustrations; it does not establish the allocation actually achieved across this four-group study. The registry record gives overall enrollment and arm-level safety denominators, but does not report a full enrollment breakdown or the randomization scheme. A normal approximation is a general method that may be used for certain comparisons when its conditions are reasonable. The registry record does not say that such an approximation was used for the trial’s primary analysis.
Multiple groups and comparisons
With multiple groups, analysts may consider several possible contrasts. In general, carrying out many tests can increase the chance of at least one false-positive result if no adjustment or prespecified strategy is used. A multiplicity plan might define a primary contrast, order tests, or adjust significance thresholds. The registry record does not identify a primary pairwise contrast or report a multiplicity strategy. It would therefore be inappropriate to infer that any particular comparison was the study’s intended confirmatory test.
The record indicates that the primary outcome was not reduced to one comparison because it has several categories or time points. It also reports no posted analysis records. This leaves the target estimand—the precise group difference the analysis was meant to estimate—unclear. General statistical principles can explain how such an analysis might be designed, but they do not fill in the missing study-specific plan.
Interpretation also depends on the population analyzed. In general, an intention-to-treat analysis retains participants in their randomized groups, while a per-protocol analysis may restrict analysis to those meeting specified treatment or follow-up criteria. The registry record does not identify an analysis population or report how missing observations, withdrawals, or incomplete follow-up were handled. No such approach should be assumed.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists four randomized groups and a primary safety objective, but it does not report a primary pairwise comparison, a hierarchy of comparisons, or a multiplicity adjustment. In general, when several comparisons are tested, the chance of at least one false-positive result can increase unless the analysis plan accounts for the number and structure of tests. That general concern does not establish that any particular testing strategy was planned or used in this study.
No posted statistical analyses are reported. The record also indicates that the primary outcome was not reduced to one comparison because it has several categories or time points. The intended estimand, analysis model, and approach to repeated measurements or multiple categories are not reported in the registry record. The sample-size illustration assumptions are not a substitute for the trial’s statistical analysis plan.
Missing-data handling is not reported in the registry record. It does not describe missing outcome values, withdrawals, incomplete follow-up, or methods such as imputation or sensitivity analysis. The record also does not identify analysis populations, including whether results were intended to follow randomized assignment or a different population definition. These omissions limit assessment of potential bias: if missingness is related to outcomes or treatment, the analyzed participants may not represent everyone randomized. This is a general methodological concern, not evidence that such bias occurred in this study.
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 |
|---|---|---|---|
| Group A | 0 | 10 | 0.0% |
| Group B | 0 | 10 | 0.0% |
| Group C | 0 | 10 | 0.0% |
| Group D | 0 | 10 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Group A | 0 of 10 |
| Group B | 0 of 10 |
| Group C | 0 of 10 |
| Group D | 0 of 10 |
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 |
|---|---|
| Group A | 13 of 30 |
| Group B | 12 of 30 |
| Group C | 6 of 30 |
| Group D | 4 of 30 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Group A | Group B | Group C | Group D |
|---|---|---|---|---|---|
| Rash | Skin and subcutaneous tissue disorders | 3 of 10 | 6 of 10 | 6 of 10 | 4 of 10 |
| Rash | Skin and subcutaneous tissue disorders | 6 of 10 | 6 of 10 | 0 of 10 | 0 of 10 |
| Rash | Skin and subcutaneous tissue disorders | 4 of 10 | 0 of 10 | 0 of 10 | 0 of 10 |
The serious adverse-event summaries report 0 affected participants among 10 at risk in each of Groups A, B, C, and D. Deaths are reported as 0 in each group. The other adverse-event summaries report 13 affected among 30 at risk in Group A, 12 among 30 in Group B, 6 among 30 in Group C, and 4 among 30 in Group D.
These figures are category-specific counts of participants affected, not a complete account of event frequency, duration, or severity. A participant may have had more than one event, but the summaries do not specify event totals or overlap between categories. The record does not explain why the serious-event and other-event denominators differ, and those denominators should not be treated as a common population without further information.
Zero reported serious events is an observation in this study, not evidence that serious events cannot occur. The registry record does not provide uncertainty intervals, event descriptions, or comparative analyses. The group counts should therefore be read descriptively rather than as proof of a difference between dosing regimens.
12. What the Result Does, and Does Not, Mean
The registry record establishes that a randomized, quadruple-masked, parallel Phase 2 study evaluated four repeat topical SADBE schedules in subjects with frequent herpes labialis. It reports safety counts over a stated 9-month timeframe and identifies prevention of herpes labialis episodes as a secondary objective. The reported safety summaries show no serious adverse events or deaths in any group, alongside different counts of participants affected by other adverse events.
Those observations do not establish that one regimen is safer than another. The record does not report comparative tests, uncertainty intervals, event-level descriptions, or a prespecified primary contrast. The affected-participant counts alone cannot indicate how many events occurred, how severe they were, when they occurred, or whether participants experienced multiple events. The differing denominators for serious and other adverse events also remain unexplained in the registry record.
The record’s efficacy objective should not be confused with an efficacy finding. No numerical result for prevention of herpes labialis episodes is reported. The study status is terminated, but the reason for termination is not reported in the registry record, so the status cannot be used to infer a result or an explanation for the available data.
More generally, a study result describes what was observed under its definitions, follow-up, and analysis methods. Inference beyond those observations depends on design details, completeness of follow-up, and statistical analysis. Important information about those matters is not reported in the registry record. The safety figures are therefore best understood as descriptive registry results, not as a definitive comparison or a basis for treatment decisions.
13. Why This Trial Matters Statistically
This study illustrates why endpoint wording and reported results need to be read together. The primary endpoint is described as a number of adverse events, while the posted safety summaries count participants affected in serious and other categories. Those quantities are related but not interchangeable. Without event-level data, follow-up details, and a clear analysis description, a reader cannot determine whether the summaries fully represent the stated endpoint.
It also shows the statistical challenge of interpreting several randomized groups when the registry record does not identify a primary contrast. Different schedules and concentrations create possible comparisons, but a reader should not select one after seeing the counts and treat it as the prespecified test. A planned comparison and multiplicity strategy are important for interpreting evidence across multiple arms.
The safety summaries demonstrate why observed counts need uncertainty and context. Zero serious events in each group is a useful description of what was reported, but it does not by itself establish a zero underlying risk. Counts of other adverse events also do not provide a comparative conclusion without a defined analysis and an account of the populations contributing to each denominator.
Finally, a terminated study with no posted inferential analyses leaves important questions unresolved. The registry record does not report a reason for termination, analysis populations, missing-data handling, or an outcome result for the secondary efficacy objective. Recognizing these gaps is part of statistical interpretation: it distinguishes observed registry information from conclusions that would require additional evidence.
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.
The registry record gives limited information for evaluating the safety counts. It does not define adverse-event classification, describe event collection or adjudication, or provide event-level details such as type, timing, duration, severity, or attribution. It reports affected-participant counts in serious and other categories, while the primary endpoint is described as a number of events. This limits direct interpretation of how the posted summaries relate to the primary outcome.
The denominators differ by adverse-event category: 10 participants at risk for serious events and 30 at risk for other events in each group. Although the record lists enrollment of 40, it does not explain these denominators or provide participant flow, group-specific enrollment, or follow-up completion. The extent of missing safety information and the number of participants exposed to each regimen cannot be determined from the registry record.
The record reports no comparative statistical analyses, confidence intervals, analysis populations, or missing-data methods. It does not identify a primary contrast, explain multiplicity handling, or provide the statistical analysis plan. The secondary objective concerns episode prevention, but its numerical result is not reported. The reason for termination is also not reported in the registry record.
These limitations are specific to the information available in the registry record. They do not establish that an analysis was never conducted or that unreported information does not exist elsewhere; they mean that those details cannot be assessed from this record.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Phase 2, Muti-Center Study of Repeat Dosing of Squaric Acid Dibutyl Ester in Subjects With Herpes Labialis — NCT03521479.
- Registry record last updated 2021-08-06; status last verified 2021-08.
- Results first posted 2021-06-15.
- 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
NCT03521479 is a Phase 2 randomized, quadruple-masked, parallel study of repeat SADBE dosing in subjects with frequent herpes labialis. The registry lists enrollment of 40 and status as terminated. The study began on 2018-03-12, with primary completion on 2018-10-05.
Four groups received different repeat-dose schedules after a 2% application on day 0. The primary objective was to assess local and generalized adverse events over 9 months; the secondary objective was prevention of herpes labialis episodes. The safety summaries report 0 serious adverse events among 10 at risk and 0 deaths in each group. Other adverse events affected 13 among 30 in Group A, 12 among 30 in Group B, 6 among 30 in Group C, and 4 among 30 in Group D.
No comparative statistical analyses are reported. The registry record does not report the reason for termination, an efficacy result, a sample-size justification, analysis populations, missing-data handling, or a statistical analysis plan.