Study of Intravaginal Tamoxifen in PostMenopausal Women With VVA: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Intravaginal Tamoxifen in PostMenopausal Women With VVA (NCT05378269), a randomized phase 1, phase 2 study. The primary outcome is Number of Subjects With Treatment Emergent Adverse Events.

2. Clinical Question

3. Trial Design

The registry record describes NCT05378269 as a randomized, parallel-group, placebo-controlled Phase 1/2 study of intravaginal tamoxifen. Its official title identifies it as DARE-VVA1 and describes a double-blind study of safety, pharmacokinetics, and pharmacodynamics in postmenopausal participants with vulvar and vaginal atrophy. The masking field specifies quadruple masking. The record does not explain the masking roles or the process used to maintain masking.

The arms were placebo and DARE-VVA1 vaginal inserts at 1mg, 5mg, 10mg, and 20mg. Posted arm sizes were 4 for placebo, 3 for DARE-VVA1 1mg, 4 for DARE-VVA1 5mg, 3 for DARE-VVA1 10mg, and 3 for DARE-VVA1 20mg. The recorded enrollment was 17. The registry lists the trial as completed, with a start date of 2021-11-22 and a primary completion date of 2022-12-20.

The primary outcome was the number of participants with treatment-emergent adverse events over 56 days. The description says this outcome was used to evaluate safety and tolerability. Secondary outcomes include evaluation of vaginal cytology and vaginal pH; vaginal cytology appears twice in the registry's secondary-outcome list. The record lists 6 outcome measures and 3 posted secondary outcomes, but does not provide their results in the registry record for this analysis.

The registry record does not report the randomization method, allocation concealment procedures, detailed dosing schedule, adherence, or a sample-size justification. It also does not describe an interim analysis or a prespecified statistical analysis plan. These omissions limit how fully the design and conduct can be assessed from the registry record 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

Reasons for not completing this period:

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 Subjects With Treatment Emergent Adverse Events, measured over 56 days.

The primary endpoint is the number of participants with treatment-emergent adverse events during 56 days. It is a count of participants who experienced an event, not a count of every event occurrence. A participant with multiple events may still contribute as one participant to this endpoint, though the registry record does not provide details about event counting or classification rules.

This kind of endpoint is used to describe safety and tolerability during the stated observation period. Reporting the outcome separately by randomized arm allows readers to see the observed participant counts for placebo and each DARE-VVA1 dose level. The registry lists 3 participants with an event in the placebo arm, 2 in the 1mg arm, 4 in the 5mg arm, 3 in the 10mg arm, and 3 in the 20mg arm.

These counts do not by themselves describe the event types, severity, duration, or relationship to treatment. The registry record identifies a separate serious-adverse-event outcome, but the primary endpoint combines treatment-emergent adverse events without distinguishing serious from non-serious events. Whether an event is treatment-emergent indicates its timing relative to treatment under the study's definitions; the precise definition and adjudication process are not reported in the registry record.

General: Safety endpoints are often interpreted alongside event descriptions, exposure duration, and participant-level context. A count alone cannot convey all of that information. The registry record's outcome is a descriptive measure, and no posted analysis estimates a comparative treatment effect for it.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary outcome is a binary participant-level measure: for each participant, the relevant question is whether a treatment-emergent adverse event was recorded during 56 days. The reported value for an arm is the count of participants meeting that condition. It is not an event rate per unit of person-time and does not count repeated events as separate participants. The registry record does not describe the detailed event-coding rules or how incomplete follow-up was handled.

For the primary outcome, the posted counts are 3 in placebo, 2 in DARE-VVA1 1mg, 4 in DARE-VVA1 5mg, 3 in DARE-VVA1 10mg, and 3 in DARE-VVA1 20mg. The corresponding posted arm sizes are 4, 3, 4, 3, and 3. These arm-level counts are the available descriptive results. No inferential analysis is posted in the registry record.

Why are uncertainty intervals useful?

General: An observed count is subject to sampling variability. If a study were repeated with a different set of participants, the counts could differ even if the underlying event experience were similar. A confidence interval for an estimated effect or event frequency communicates uncertainty under a stated statistical model. It is not a guarantee that the true value lies within the interval, and it does not resolve limitations in study design or data collection.

The registry record does not report confidence intervals for the primary outcome or for comparisons among arms. As a result, readers cannot use the posted primary results to assess the numerical precision of an estimated comparative effect. It would be inappropriate to reconstruct one from the counts and present it as a registry result; the record contains no such analysis.

What does randomization contribute?

General: Random allocation aims to make treatment groups comparable, on average, with respect to both measured and unmeasured baseline characteristics. In small studies, chance imbalances can remain, and randomization does not ensure that every group starts with identical characteristics. The registry record identifies the allocation as randomized, but it does not report the sequence-generation method, concealment procedure, or baseline characteristics needed to evaluate balance.

The parallel-group design means that participants were assigned to one arm rather than crossing between arms, according to the design description. The registry names placebo and four DARE-VVA1 dose levels. It does not report the protocol details needed to describe treatment duration, adherence assessment, or other design features that might affect interpretation.

How should multiple arms and outcomes be considered?

General: When a study makes several comparisons or assesses several outcomes, the chance of at least one apparently notable result can increase if all comparisons are treated as though they were the only one planned. A statistical analysis plan may specify a primary contrast, a testing sequence, or an adjustment for multiplicity. The registry record does not report such a plan, and no analyses are posted. The primary endpoint counts therefore should not be treated as the result of a reported, multiplicity-adjusted test.

The record lists 6 outcome measures and 3 posted secondary outcomes. Its secondary-outcome list includes evaluation of vaginal cytology twice and evaluation of vaginal pH. The registry entries do not provide secondary-outcome estimates, their analysis methods, or an explanation for the difference between the listed outcome-measure count and the posted secondary-outcome list. No secondary-outcome inference can be made from these primary safety counts.

What do planning illustrations mean?

General: A sample-size calculation estimates the number of participants that a future study might need to detect a specified effect under stated assumptions. It is a planning exercise, not a description of the observed data and not a measure of the probability that this completed study found an effect. The registry record does not report a sample-size justification for this trial.

The stated assumptions for the planning illustrations are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. Such illustrations are hypothetical planning scenarios and should not be described as observed power. The record does not report the trial's own design rationale or explain how the observed effect was selected for those illustrations.

General: Normal approximations can be useful for planning under specified conditions, but their adequacy depends on the outcome and the data structure. For binary outcomes with sparse counts, exact or model-based approaches may be considered, depending on the question and design. The registry record does not say which inferential approach, if any, was intended for the primary endpoint. No method should be attributed to the trial without a reported analysis plan.

What does absence of posted analysis imply?

The registry record lists 0 analyses. This means the available record does not contain an inferential result for the primary comparison. It does not establish that no analysis was performed outside the posted registry results. The statistical methods used, if any, are not reported in the registry record. The descriptive findings can be accurately presented as counts, but a claim of statistical significance, lack of significance, superiority, or equivalence would require evidence not present in the posted 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("Placebo", "DARE-VVA1 1mg", "DARE-VVA1 5mg", "DARE-VVA1 10mg", "DARE-VVA1 20mg")
n      <- c(4, 3, 4, 3, 3)
events <- c(3, 2, 4, 3, 3)
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  Placebo  4  3  75.0  19.4  99.4  30.1  95.4  28.4  94.7
ARM  DARE-VVA1 1mg  3  2  66.7  9.4  99.2  20.8  93.9  19.4  93.2
ARM  DARE-VVA1 5mg  4  4  100.0  39.8  100.0  51.0  100.0  47.8  99.5
ARM  DARE-VVA1 10mg  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  DARE-VVA1 20mg  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 6 outcome measures and 3 posted secondary outcomes. The secondary-outcome list names evaluation of vaginal cytology twice and evaluation of vaginal pH. The registry record does not report how these outcomes were prioritized, whether any secondary measures were confirmatory, or whether multiplicity was addressed in a statistical analysis plan. No analysis results are posted, so there is no reported testing hierarchy or adjustment to interpret.

Missing-data methods are not reported in the registry record. The record does not say how participants with incomplete follow-up, missed visits, or unavailable outcome assessments were handled. It also does not report imputation, sensitivity analyses, or a definition of the analysis population for the primary endpoint. The arm sizes and participant counts are posted, but the registry entries do not explain whether all randomized participants contributed to each outcome or whether any data were missing.

Analysis populations are also not described. The registry record does not specify whether results were based on all randomized participants, participants who received at least one dose, or another population. This matters because different population definitions can yield different estimates, especially when treatment discontinuation or incomplete outcome collection occurs. No such information should be inferred from the posted counts alone.

General: Multiplicity concerns arise when many endpoints, timepoints, or pairwise comparisons are examined. Predefining which questions are primary and how secondary findings will be interpreted helps distinguish confirmatory results from exploratory ones. Missing-data procedures similarly clarify how incomplete observations affect estimates. The absence of these details in the registry record limits evaluation of the analysis process; it does not indicate which procedures were used.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports 0 participants affected by serious adverse events in each arm: placebo, DARE-VVA1 1mg, DARE-VVA1 5mg, DARE-VVA1 10mg, and DARE-VVA1 20mg. Deaths are listed as 0 in each arm. No serious-event terms are listed in the registry record. These are the posted serious-safety counts, not estimates of risk beyond the study observations.

The primary outcome is broader than the serious-event measure. It counts participants with treatment-emergent adverse events, with posted counts of 3 for placebo, 2 for 1mg, 4 for 5mg, 3 for 10mg, and 3 for 20mg. The record does not provide event descriptions or severity details for those primary-outcome counts. It is therefore not possible to determine from those counts alone which events were serious or what kinds of events occurred.

General: A zero observed count means that no affected participant was recorded in the study data for that outcome; it does not establish that the underlying event risk is zero. Interpretation depends on the number of participants observed, the duration and completeness of follow-up, and how events were defined and collected. The registry record does not report additional detail about ascertainment or missing safety data. These figures describe the posted observations and should not be extended beyond them.

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

The primary outcome reports participants with treatment-emergent adverse events over 56 days. The posted counts vary across the placebo and DARE-VVA1 arms, and serious adverse events and deaths are listed as 0 in every arm. These descriptive findings characterize the safety observations recorded in this study. They do not establish that an intervention caused an event, nor do they prove that a dose is safer or less safe than placebo.

The record lists 17 as enrollment and reports small arm sizes: 4 for placebo, 3 for 1mg, 4 for 5mg, 3 for 10mg, and 3 for 20mg. With such limited arm-level observations, the posted counts cannot characterize uncommon events reliably. The registry record provides no confidence intervals, comparative tests, or posted analyses for the primary endpoint. It therefore does not quantify how precisely the observed differences between counts reflect differences in the underlying groups.

The trial's stated aims extend beyond the primary safety and tolerability measure to pharmacokinetics and pharmacodynamics. Secondary outcomes include vaginal cytology and vaginal pH. Their results are not included in the registry record, so the primary safety counts cannot answer questions about those other aims. The registry record also does not provide detailed event listings, participant characteristics, or missing-data procedures that would support a fuller assessment.

General: A trial result is most informative when the outcome definition, analysis population, effect estimate, uncertainty, and methods are considered together. A count can describe what was recorded, but without a comparative analysis it cannot establish a treatment effect. A zero count for a serious outcome is also not evidence that the event is impossible. The appropriate interpretation is limited to the observations and details reported in the registry record.

Planning illustrations, if considered, answer a different question from the observed results. They are hypothetical calculations based on assumptions about a future study, not evidence that the completed trial had a particular probability of detecting an effect. The registry record does not report a design sample-size justification or an inferential primary-outcome analysis.

14. Why This Trial Matters Statistically

This study is statistically notable for its early-phase, multi-arm structure and its focus on safety, pharmacokinetics, and pharmacodynamics. It compares placebo with multiple intravaginal tamoxifen dose levels, while the primary endpoint is a participant count over a defined 56-day period. That structure can provide descriptive information across dose groups, but it also makes clear why the analysis plan and uncertainty estimates matter.

The posted arm sizes are small, and the primary outcome counts are close to the available group sizes. Consequently, each participant's outcome has a visible influence on the arm-level description. The registry record contains no posted analyses or confidence intervals, so it does not support a precise comparative conclusion. This is a useful distinction between reporting observed counts and establishing a statistical contrast.

The record also makes a distinction between any treatment-emergent adverse event and serious adverse events. The primary endpoint counts participants with treatment-emergent events, while the serious-event figures are reported separately. Keeping those outcomes separate is important: a count for any event does not tell readers how many were serious, and the zero serious-event counts do not describe the full set of events.

General: Small studies often serve objectives other than definitive comparative efficacy testing. Their estimates can be informative for planning and for describing initial observations, while remaining imprecise. A transparent record of outcome definitions, missing-data handling, analysis populations, and uncertainty would help readers understand the strength and scope of the evidence. Those details are not reported in the registry record for this trial.

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 registry record provides limited information for judging the primary outcome beyond its participant-count definition and 56-day timeframe. It does not report the detailed treatment-emergent event definition, how events were assessed, or how multiple events in one participant were handled. Event-level descriptions, severity, duration, and attribution are not available in the registry record.

Although the study is described as randomized and quadruple-masked, the randomization method, allocation concealment, and roles covered by masking are not reported in the registry record. Baseline participant characteristics and detailed eligibility criteria are also not reported, limiting assessment of group comparability and the population to which the observations might apply.

The record contains no posted analyses. It does not report confidence intervals, comparative estimates, p-values, or the statistical model for the primary endpoint. Missing-data procedures and analysis populations are not reported either. The posted counts therefore cannot be used to assess adjusted comparisons, the influence of incomplete follow-up, or the robustness of results under alternative analysis choices.

The record lists secondary outcomes but does not provide their results in the registry record. It also does not report a sample-size justification, interim-analysis plan, or a prespecified statistical analysis plan. These omissions limit evaluation of multiplicity, outcome prioritization, and the intended inferential framework. The planning assumptions described for illustrations do not substitute for a trial-specific design justification.

The arm sizes are small and the observed primary outcome is a count. These registry entries constrain how much can be learned about uncommon adverse events and comparative differences from the posted results. The findings should be understood as limited descriptive observations from this study, not as a complete characterization of safety across broader populations or longer observation periods.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Intravaginal Tamoxifen in PostMenopausal Women With VVA — NCT05378269.
• Registry record last updated 2024-10-21; status last verified 2024-07.
• Results first posted 2024-10-21.
• 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

NCT05378269 is a completed randomized, parallel-group, placebo-controlled Phase 1/2 study of intravaginal tamoxifen in postmenopausal participants with vulvar and vaginal atrophy. The registry describes double-blind design and quadruple masking. The recorded enrollment is 17; the start date is 2021-11-22 and the primary completion date is 2022-12-20.

The arms were placebo and DARE-VVA1 vaginal inserts at 1mg, 5mg, 10mg, and 20mg. The primary outcome was the number of participants with treatment-emergent adverse events during 56 days. Posted counts were 3, 2, 4, 3, and 3, respectively. Serious adverse events and deaths were listed as 0 in each arm.

The registry record lists 6 outcome measures, 3 posted secondary outcomes, and 0 analyses. It does not report comparative statistical results, confidence intervals, missing-data methods, or analysis populations. The available primary results are descriptive and do not establish a comparative treatment effect.