Study to Evaluate the Equivalence of Estradiol Vaginal Cream to Reference Standard in the Treatment of Vaginal Atrophy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate the Equivalence of Estradiol Vaginal Cream to Reference Standard in the Treatment of Vaginal Atrophy (NCT03332303), a randomized phase 3 study. The primary outcome is The Primary Efficacy Endpoint.

2. Clinical Question

The registry describes two distinct aims for the primary endpoint: therapeutic equivalence between the experimental and active comparator arms, and superiority over placebo. Those aims use different analysis populations: the per-protocol population for the equivalence assessment and a modified intent-to-treat population for the placebo comparison. The record does not report the resulting responder counts or comparison estimates, so the results of either aim cannot be characterized from the endpoint description alone.

The responder definition requires both a cytology change and a vaginal pH criterion. A participant must have at least a 25% reduction from baseline in the sum of the percentages of basal/parabasal and intermediate cells, and vaginal pH must be < 5.0 with a reduction from baseline of at least 0.5. A participant who withdrew because of lack of efficacy was counted as a non-responder. These rules define the question being measured; they do not reveal how many participants met the criteria.

3. Trial Design

This was a Phase 3, randomized, quadruple-masked, parallel-design, multi-site study. The registry lists enrollment of 540 and status as completed. The study compared Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC), with Estrace® Cream and with placebo vehicle cream. Each treatment description specifies once-daily administration for 7 days.

Random allocation is intended to reduce systematic differences between treatment groups at the point of assignment. Masking is intended to limit the influence of treatment knowledge on participant experience, study conduct, or outcome assessment. The registry labels masking as quadruple, but the roles included in that label are not reported in the registry record. A parallel design means the treatment groups are followed as separate groups rather than participants crossing between assigned treatments.

The stated objective was to evaluate therapeutic equivalence of the experimental formulation to the marketed reference product and to compare the safety of the test, reference, and placebo treatments. The primary endpoint record specifies an equivalence analysis between the experimental and active comparator arms using the per-protocol population, as well as a superiority comparison with placebo using a modified intent-to-treat population. The complete definition of that modified intent-to-treat population is not reported in the registry record: the available description says participants were randomized, received at least one dose, and had a post-randomization assessment, but the wording ends before the assessment definition is complete.

The registry record gives a study start date of 2017-10-26 and a primary completion date of 2018-03-15. It does not report the treatment allocation ratio or the roles covered by quadruple masking. Although the study is marked completed, the primary efficacy counts and estimates are not reported in the registry record.

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.

Before assignment: Following the 28-day screening period, participants who continued to meet the inclusion/exclusion (I/E) criteria were randomly assigned to treatment on a 2:2:1 ratio of test Estradiol Vaginal Cream USP, 0.01%; Estrace Vaginal Cream USP, 0.01%; or Placebo test vehicle vaginal cream.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Therapeutic Equivalence Between Experimental and Active Comparator Arms: Per Protocol (PP) Population Superiority over Placebo: Modified Intent-to-treat population (mITT, all randomized study participants who administered at least one dose of randomized study product and had a post-randomization evaluation)

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: All participants who were randomized and administered at least 1 dose of study drug (Safety Population).

6. Primary Endpoint

The registry lists the primary outcome as The Primary Efficacy Endpoint, measured over Study Day 8 or Study Day 9.

The primary efficacy endpoint is the number of participants in each treatment group identified as responders at the end of treatment, assessed on Study Day 8 or Study Day 9. It is a binary outcome at the participant level: each participant either meets the stated response definition or does not. The endpoint combines vaginal cytology and vaginal pH rather than treating either measure alone as sufficient.

A responder must have at least a 25% reduction from baseline in the combined percentage of basal/parabasal and intermediate cells. The participant must also have vaginal pH < 5.0 and a change from baseline of at least 0.5. Both conditions are required. A participant who withdrew because of lack of efficacy is classified as a non-responder under the registry definition.

As a general measurement principle, a composite endpoint can represent more than one dimension of response in a single classification. That can make the endpoint clinically interpretable as a combined criterion, while also meaning that failure to satisfy either component prevents classification as a responder. The registry record does not report separate primary results for the cytology and pH components, nor does it report the number of responders. The rationale for choosing this exact composite is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is binary at the participant level: a participant is classified as a responder or a non-responder using the stated combined cytology and pH criteria. The registry gives the outcome unit as participants and the parameter as a number. That means the measure of interest is a count of participants meeting the rule, rather than a continuous average of cytology or pH values. The corresponding group denominator is important for interpreting a count, but the primary efficacy denominators and counts are not reported in the registry record.

What does a binary endpoint capture?

As a general statistical explanation, a binary outcome simplifies an individual result into two categories. This can make a treatment comparison straightforward to communicate, but it also discards detail about how far a participant's measurements were from the response threshold. A participant just meeting the full definition and a participant exceeding both criteria substantially are both counted as responders. Conversely, a participant who meets one component but not the other is not a responder under this composite rule.

For this endpoint, the response category depends on both a cytology change from baseline and the pH requirements. The conjunction matters: each condition must be met. A withdrawal due to lack of efficacy is specifically counted as a non-response. The handling of other missing or unavailable endpoint measurements is not reported in the registry record. It would be inappropriate to assume that all such cases were treated the same way as the specified lack-of-efficacy withdrawals.

How should the equivalence objective be understood?

As a general statistical principle, equivalence is not established simply because a test finds no statistically significant difference. An equivalence assessment asks whether the plausible range of the treatment contrast lies within a prespecified interval of differences considered acceptably small. The margin, contrast definition, confidence interval procedure, and formal decision rule are not reported in the registry record. The record does identify the per-protocol population for the equivalence assessment, but it does not give the population's detailed eligibility or analysis rules.

The placebo objective is described as superiority, using a modified intent-to-treat population. As a general concept, a superiority comparison asks whether the data support a difference in a specified direction, with uncertainty assessed using a suitable inferential procedure. The test, significance threshold for the efficacy comparison, and estimate of the contrast are not reported in the registry record. The 0.05 significance level stated for a planning illustration is not evidence of the test or threshold used in the trial's own analysis.

What do the planning assumptions mean?

The registry describes a sample-size planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It describes planning for fractions of the observed effect. These are planning assumptions, not a report of the trial's original design calculation. The registry does not report the trial's own sample-size justification, so the planning illustration should not be used to infer why enrollment was set at its recorded value.

As a general explanation, a planning calculation estimates the number of participants needed under stated assumptions to detect an effect at a chosen power and significance level. Such an illustration depends on the assumed effect and analysis conditions. It is not observed power, and it does not establish whether the trial was adequately planned for an equivalence objective. No planning output values are reported in the registry record in the registry record used for this interpretation.

The general normal approximation treats the estimated effect as having a distribution that can be approximated by a normal curve under specified conditions. The equal-allocation assumption means the planning illustration sets the same planned allocation to each of the two arms considered. Neither assumption establishes that the actual allocation or analysis followed those conditions. The registry states the study had three arms, while the planning assumption refers to equal allocation between two arms; the particular pair intended for any planning comparison is not reported in the registry record.

Why do confidence intervals and dispersion matter?

In general, a confidence interval expresses the uncertainty around an estimated effect using a range of values compatible with the data under the method's assumptions. For an equivalence question, the interval is particularly relevant because its position relative to the equivalence limits informs the conclusion. No primary efficacy confidence interval is reported in the registry record. The primary endpoint is a count, and the registry does not specify an inferential model or dispersion parameter for the primary analysis.

As a general statistical concept, over-dispersion occurs when observed variability exceeds what a model assumes. If a count-based model fails to account for extra variability, its uncertainty estimates may be too narrow and its inference too confident. This concept does not establish that over-dispersion occurred in this trial. The record does not report a count model, a dispersion assessment, or an adjustment for over-dispersion, and the endpoint description itself defines the outcome as participant counts.

The registry lists 3 outcome measures and 6 analyses. These counts alone do not identify which analyses were confirmatory, how they were related, or which methods were applied. The primary endpoint description also indicates that more than one treatment objective was considered. Without the analysis specification and result estimates, statistical method choices cannot be reconstructed from the objective labels alone.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures and 6 analyses, and the primary endpoint is linked to an equivalence objective against the active comparator and a superiority objective against placebo. Multiple endpoints, comparisons, or analyses can create a multiplicity concern: as a general statistical principle, conducting several inferential tests can increase the chance of at least one apparently positive result if the testing strategy does not account for that structure. The record does not report a multiplicity adjustment, a hierarchy of tests, or which analyses were confirmatory. The listed counts alone are not enough to determine which results, if any, were adjusted.

The analysis populations differ by objective. The registry specifies the per-protocol population for therapeutic equivalence and the modified intent-to-treat population for superiority over placebo. It describes the modified intent-to-treat population as randomized participants who took at least one dose and had a post-randomization assessment, but the definition ends before the assessment wording is complete. The detailed per-protocol criteria are not reported in the registry record.

The primary endpoint definition specifies that participants who withdrew because of lack of efficacy were counted as non-responders. This is a particular missing-outcome rule, not a complete description of missing-data handling. The record does not report how other missing measurements, missed study visits, or withdrawals for other reasons were handled. It also does not report sensitivity analyses for missing data.

As a general principle, missing-data methods and analysis populations can affect estimates and their interpretation. This is especially relevant when the endpoint requires multiple measurements to classify response. With no complete analysis rules or efficacy results, the effect of missingness and multiplicity cannot be evaluated from 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: exacerbation of chronic obstructive pulmonary disease (0.5%).

The safety record lists serious adverse events affecting 0 of 215 participants in the experimental group, 1 of 216 in the Estrace® Cream group, and 0 of 109 in the placebo group. The listed deaths are 0 in each group. These are participant counts as recorded; they are not calculated rates, and no additional percentages should be inferred from them.

For other adverse events, the registry lists 66 of 215 participants in the experimental group, 59 of 216 in the Estrace® Cream group, and 23 of 109 in the placebo group. These counts describe participants affected, not the total number of individual events. The record does not provide further event-level detail in the registry record used for this interpretation, so the number of events per participant or the distribution by event type cannot be described.

The top serious-event term is listed as “Exacerbation of Chronic Obstructive Pulmonary Disease” with 0.5%. The registry listing does not identify the treatment-arm context for that term in the available record. As a general interpretation point, sparse serious-event counts can be imprecise, and raw counts alone do not establish a treatment difference. The record does not report comparative safety estimates or uncertainty intervals.

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

The registry record establishes that this was a randomized, quadruple-masked, parallel, Phase 3 study comparing Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC), with Estrace® Cream and placebo vehicle cream. It describes an endpoint based on a combined cytology and pH response, with assessments at the end of treatment on Study Day 8 or Study Day 9. It also states how lack-of-efficacy withdrawals were classified.

Those details explain what the study was designed to ask, but they do not show the answer. The record does not report the primary responder counts, the treatment contrasts, confidence intervals, p-values, or the equivalence margin. Therefore, the posted information cannot establish whether the experimental formulation met the stated equivalence objective or whether either active treatment was superior to placebo on the primary endpoint.

Equivalence and superiority are different statistical claims. In general, equivalence requires evidence that the treatment difference is sufficiently contained within a prespecified margin; a failure to detect a difference is not enough. Superiority requires evidence supporting a difference under the chosen analysis. The registry does not include the result estimates or complete analysis specifications required to assess either claim.

The safety counts are also limited in what they establish. They report the number of participants affected by serious and other adverse events and the number of deaths in each listed group. They do not, by themselves, provide a complete assessment of the type, severity, timing, or comparative uncertainty of events. The serious-event term listed with a percentage lacks a reported arm context in the record available for this analysis.

Accordingly, the appropriate interpretation is descriptive: the record provides design information, a composite endpoint definition, analysis-population labels, and selected safety counts. It does not provide enough primary efficacy results to support a conclusion about therapeutic equivalence, placebo superiority, or the magnitude and precision of a treatment effect.

13. Why This Trial Matters Statistically

This study illustrates an important distinction between a stated trial objective and a reported statistical result. The record names therapeutic equivalence as an objective, but the evidence needed to assess equivalence—an explicit margin and a treatment contrast with uncertainty—is not reported in the registry record. A reader therefore cannot treat the objective or the completed status as a finding.

The endpoint also demonstrates how a composite binary response can shape interpretation. The response rule requires both a cytology change and a vaginal pH criterion. That rule supplies a clear classification, but it means the overall responder count alone would not show which component determined response unless component-specific results were also reported. Those component results are not reported in the registry record.

The separate use of a per-protocol population for equivalence and a modified intent-to-treat population for placebo superiority makes the analysis population part of the scientific question. In general, the population definition affects which participants contribute to an estimate and how broadly it can be interpreted. The registry provides only a partial modified intent-to-treat definition and no detailed per-protocol criteria.

Finally, the safety summaries show why counts need context. The record lists serious-event and other-event participants by group, but does not include comparative uncertainty or detailed event-level results in the registry record used. Statistical interpretation depends not just on an endpoint and a design label, but also on complete outcome estimates, analysis rules, and precision. Those elements are essential for evaluating the trial's stated aims.

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 primary efficacy results are not reported in the registry record. In particular, no responder counts, treatment contrasts, confidence intervals, or p-values are available in the registry record used for this interpretation. The equivalence margin and the formal decision rule are also not reported, so the equivalence objective cannot be independently assessed.

Analysis descriptions are incomplete. The modified intent-to-treat population wording ends before its definition is complete, and detailed per-protocol criteria are not reported. The record also does not describe the trial's statistical analysis plan, the test used for either primary comparison, or the approach to multiplicity. The listed numbers of outcome measures and analyses do not clarify those decisions.

Missing-data handling is only partly described. The endpoint definition says that withdrawals due to lack of efficacy were classified as non-responders, but the approach for other missing endpoint data is not reported in the registry record. No sensitivity analysis information is available. The registry also does not report the roles covered by quadruple masking or the treatment allocation ratio.

The safety summary is limited to selected counts and one serious-event term with a percentage. The available record does not identify the treatment-arm context for that term, and does not give comparative safety estimates or uncertainty intervals. Finally, the sample-size description is a planning illustration based on the observed effect, not the trial's own design justification. The trial's original sample-size rationale is not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study to Evaluate the Equivalence of Estradiol Vaginal Cream to Reference Standard in the Treatment of Vaginal Atrophy — NCT03332303.
• Registry record last updated 2024-05-30; status last verified 2024-03.
• Results first posted 2024-05-30.
• 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

NCT03332303 is a completed Phase 3 randomized, quadruple-masked, parallel-design, multi-site study sponsored by Prasco LLC. It lists enrollment of 540 and compares Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC), with Estrace® Cream and placebo vehicle cream. Each intervention was described as once daily for 7 days.

The primary endpoint is the number of participants meeting a combined cytology and vaginal pH responder definition at the end of treatment, assessed on Study Day 8 or Study Day 9. The registry assigns the per-protocol population to the equivalence comparison and a modified intent-to-treat population to the placebo superiority comparison.

Primary efficacy counts and estimates, the equivalence margin, and full analysis details are not reported in the registry record. Safety listings include serious adverse events affecting 0, 1, and 0 participants and deaths of 0 in each group, alongside counts for other adverse events.