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 Trial to Evaluate the Efficacy of Low Dose Vaginal Estrogens in the Treatment of Atrophic Vaginitis (NCT00816556), a randomized phase 3 study. The primary outcome is Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00816556 |
| Phase | Phase 3 |
| Condition | Atrophic Vaginitis |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 63 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Maire Mac Bride |
| Results posted | Yes |
2. Clinical Question
Population
Participants were enrolled in a trial addressing atrophic vaginitis. The registry describes symptoms including dryness, itching, and burning, and explains that the primary questionnaire asked participants to rate those symptoms. The record does not give further eligibility details or a fuller description of the enrolled population, so characteristics such as age distribution and symptom severity at entry are not reported in the registry record.
Intervention
The active creams contained estriol or estradiol valerate, each at 10 micrograms added to Vanicream Lite 0.5 grams. Both were applied to the vaginal introitus daily for two weeks and then twice weekly for 10 weeks. The study description frames the low dose and external application as questions to evaluate, rather than as established effects.
Comparator
The comparison group received Vanicream Lite 0.5 grams applied to the vaginal introitus on the same schedule: daily for two weeks and then twice weekly for 10 weeks. This provides a cream-only comparator for the two estrogen-containing regimens. The record does not describe whether application adherence was measured or how it was incorporated into the analysis.
Primary question
The primary outcome was change in Vulvovaginal Atrophy Questionnaire scores from baseline to week 12. The statistical question is whether the observed change in scores differed among the estriol, estradiol, and placebo groups. The registry record does not report the group-level changes, the estimated between-group comparisons, or their uncertainty, so the direction and precision of any primary-outcome difference cannot be assessed from the posted results.
3. Trial Design
The registry identifies this as a Phase 3, randomized, quadruple-masked, parallel-group trial. Its stated purpose was to evaluate low-dose vaginal estrogens for atrophic vaginitis. The three listed groups were estriol, estradiol valerate, and Vanicream Lite placebo. The active preparations were compounded into the cream base, and all three regimens used application to the vaginal introitus rather than insertion into the vagina. The record describes daily application for two weeks followed by twice-weekly application for 10 weeks.
Enrollment is listed as 63. The study start is recorded as 2008-10 and primary completion as 2011-09. The trial status is TERMINATED. The record does not explain the reason for termination, so it is not possible to infer whether the reason was related to recruitment, operations, safety, or the observed outcomes. A planned sample size, an enrollment target, and any explanation of how enrollment compared with plans are not reported in the registry record.
Random allocation is stated, but details of sequence generation, allocation concealment, and implementation are not reported in the registry record. Quadruple masking is listed, but the record does not specify which participant, clinician, investigator, or assessor roles were masked, or whether masking was tested. The parallel model indicates that participants were assigned to a group rather than described as crossing between treatments; further information about follow-up and analysis by assigned group is not reported.
The primary endpoint was change in VVAQ score from baseline to week 12. The secondary outcomes concerned changes in serum estrone and serum estradiol between baseline, 2 weeks, and 12 weeks. Although these outcomes are identified, numerical outcome findings are not reported in the registry record. The record also does not provide a complete analysis plan, a reason for choosing the particular follow-up schedule, or detail about treatment discontinuation and adherence.
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 | Estriol | Estradiol | Placebo |
|---|---|---|---|
| STARTED | 20 | 21 | 22 |
| COMPLETED | 18 | 19 | 19 |
| NOT COMPLETED | 2 | 2 | 3 |
Reasons for not completing this period:
| Reason | Estriol | Estradiol | Placebo |
|---|---|---|---|
| Adverse Event | 1 | 1 | 1 |
| Withdrawal by Subject | 1 | 1 | 1 |
| Lost to Follow-up | 0 | 0 | 1 |
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 | Estriol | Estradiol | Placebo | Total |
|---|---|---|---|---|---|
| Participants analysed | 18 | 19 | 19 | 56 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 18 | 19 | 19 | 56 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 0 | 0 |
| Sex: Female, Male: Female | Participants | 18 | 19 | 19 | 56 |
| Sex: Female, Male: Male | Participants | 0 | 0 | 0 | 0 |
| Region of Enrollment: United States | participants | 18 | 19 | 19 | 56 |
6. Primary Endpoint
The registry lists the primary outcome as Change in Vulvovaginal Atrophy Questionnaire (VVAQ) Scores From Baseline to Week 12, measured over baseline, 12 weeks.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Standard Deviation |
| Unit | units on a scale |
| Endpoint classification | Continuous Endpoint |
The primary endpoint was change in Vulvovaginal Atrophy Questionnaire scores from baseline to week 12. The VVAQ asks participants to rate the severity and bothersomeness of dryness, itching, and burning. Each symptom is graded from 0 through 10. A higher score indicates that the symptom is less severe or bothersome; 0 means very severe or bothersome, while 10 means least severe or bothersome. This direction matters when interpreting change: an increase in score corresponds to a more favorable rating on the questionnaire, not a worsening score.
A symptom questionnaire is used to capture how participants experience the condition, rather than relying only on a laboratory measurement. The endpoint therefore addresses patient-reported symptom severity and bothersomeness. In general, repeated measurement allows investigators to describe how scores change over the follow-up period and compare those changes among randomized groups. The registry specifies the baseline-to-week-12 change as the primary outcome, but does not report the group means, standard deviations, or between-group estimates for that endpoint.
The record describes the VVAQ as three symptom questions and identifies its scale interpretation, but does not report how the three ratings were combined into a total or summary score. It also does not state how incomplete questionnaires were handled. Consequently, the exact scoring and analysis details beyond the stated change in VVAQ scores are not reported in the registry record. Without the numerical results and those details, the endpoint’s estimated treatment contrasts and precision cannot be evaluated from the registry entry.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies a clinically focused primary outcome and a randomized comparison among two low-dose estrogen creams and a cream-only placebo. It does not, however, report the numerical primary-outcome results. In particular, the posted results do not give group-level VVAQ changes, standard deviations, treatment contrasts, confidence intervals, or a primary-outcome significance test. The record notes that the primary outcome has several categories or time points and was not reduced to one comparison. There is therefore no single reported primary estimate from which to describe the size, direction, or precision of an effect.
This absence is important for statistical interpretation. The trial’s stated research question concerns whether the active creams affect symptoms compared with placebo, but a design and an endpoint do not establish what the observed result was. Without reported estimates, it is not possible to determine whether scores tended to increase or decrease in any group, how groups compared, or how compatible the observed data were with different possible effects. No conclusion about efficacy follows from the fact that the trial was randomized or that a primary outcome was registered.
The record lists 63 enrolled participants and gives group-specific adverse-event denominators of 18, 19, and 19. These entries do not supply primary endpoint sample sizes or explain whether every enrolled participant contributed a week-12 questionnaire. It would be inappropriate to infer the analysis population or missing outcome counts from the adverse-event reporting. Reasons for missing outcome data and the methods used to address them are not reported in the registry record.
The registry describes secondary outcomes for serum estrone and serum estradiol, measured at baseline, 2 weeks, and 12 weeks. Their numerical findings are not reported in the registry record. Thus, the record does not permit an assessment of changes in these laboratory measures or their relationship to the symptom endpoint. The trial’s stated intention to evaluate estrogen levels does not itself demonstrate whether blood levels changed.
Adverse-event entries show no serious adverse events reported in any of the three groups. Other adverse events were recorded as 3 for estriol, 0 for estradiol, and 1 for placebo. These are descriptive counts, not a complete comparative safety analysis. The registry does not identify the types, timing, severity, or relatedness of the other events. Small group-level counts and missing event detail limit how much can be inferred from them.
In general, a confidence interval would communicate the range of effects reasonably compatible with an estimate and its sampling uncertainty. No such interval for the primary outcome is reported in the registry record. Likewise, a p-value without an effect estimate would not convey the size or clinical meaning of a difference, and no primary-outcome p-value is reported. The registry’s statistical record is therefore insufficient for a quantitative interpretation of the primary comparison.
The study status is TERMINATED, but the record does not state why. Termination alone does not establish whether the trial stopped early for a specific statistical or clinical reason. A stopping rationale, interim analyses, or any effect of termination on planned analyses is not reported in the registry record. Interpretation should remain bounded by the information actually recorded: the trial design, stated outcome definitions, and descriptive adverse-event counts, without assuming unreported outcomes or decisions.
9. Statistical Methods Explained
Statistical interpretation depends on both the outcome definition and the design used to compare groups. This trial is recorded as randomized, quadruple-masked, and parallel-group. In general, random allocation aims to make treatment groups comparable with respect to measured and unmeasured characteristics at assignment. Masking can reduce the influence of expectations on care, reporting, and outcome assessment. These design features can support a fair comparison, but they do not guarantee balance in every characteristic or remove the need to report how allocation and masking were implemented. Those implementation details are not reported in the registry record.
What does a change score represent?
The primary outcome is change in VVAQ score from baseline to week 12. A change score represents the difference between a participant’s follow-up score and baseline score, according to the analysis definition. The registry identifies the outcome as a mean of a continuous measure and says that dispersion is represented by a standard deviation. It does not report the group means or standard deviations, nor does it make clear how the symptom ratings were assembled for analysis. The scoring direction is explicitly stated: higher values indicate symptoms that are less severe or bothersome.
In general, analysis of change can be presented as the mean change within each group, a contrast between group mean changes, or an adjusted comparison accounting for baseline values. These approaches do not necessarily yield identical estimates. The registry record does not report which comparative model was used, whether baseline scores were included as covariates, or whether the posted primary analysis was adjusted. No model assumptions or diagnostics are reported in the registry record.
Why does dispersion matter?
A mean describes the central value of a continuous outcome, while a standard deviation describes how spread out individual observations are around that mean. In general, the spread helps readers judge how variable participants’ responses were and how precisely a group mean or between-group contrast might be estimated. A standard deviation is not the same as a confidence interval: the former describes variation among observations, while the latter describes uncertainty around an estimated quantity. Neither the primary outcome means nor their standard deviations are reported in the registry record, so precision cannot be reconstructed from the endpoint description alone.
In general, a confidence interval places an estimate in the context of sampling uncertainty. A narrow interval indicates greater precision than a wide interval, while an interval that includes values representing little or no difference can leave substantial uncertainty about the direction or size of an effect. This general interpretation depends on the estimate and the interval being reported. The registry entry does not provide a primary endpoint confidence interval, so it cannot support that assessment.
What do the planning assumptions mean?
The registry describes sample-size calculations as planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It further says that the effect to detect is a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power. They describe how a hypothetical study might be sized under specified assumptions; they do not measure the probability that this completed trial detected an effect, and they are not a substitute for its confidence interval or outcome results.
The record’s planning description refers to an observed effect, but the numerical primary endpoint effect is not reported in the registry record. The numerical planning illustrations are therefore not available for interpretation in the information recorded. The registry does not report the original design assumptions or sample-size justification, so the planning illustration should not be taken as evidence about what was planned before enrollment.
In general, a two-sided significance level sets a threshold for assessing data against a null hypothesis in either direction. It is an assumption used in a testing framework, not a measure of the importance or precision of an estimated difference. Equal allocation describes an assumed design balance for the illustration. A normal approximation is a mathematical approximation used in a calculation; the registry does not describe checks of its suitability for the trial’s primary data.
Why can over-dispersion matter?
General statistical explanation: over-dispersion occurs when variability in data is greater than assumed by a particular statistical model. If a model underestimates variability, its standard errors can be too small, making confidence intervals too narrow and tests appear more decisive than warranted. The registry identifies the primary endpoint as continuous and reports standard deviation as the dispersion measure, but does not report the fitted model or any evidence of over-dispersion. It would therefore be inappropriate to claim that over-dispersion did or did not affect this analysis.
What can the reported analysis count establish?
The record lists 12 analyses and states that the primary outcome has several categories or time points and was not reduced to one comparison. A count of analyses does not reveal which contrasts were prespecified, which were exploratory, or how the analyses were selected for reporting. The registry does not give the analysis specifications or identify a single primary contrast among the categories or time points. Accordingly, no individual comparison can be treated as the definitive primary estimate based on the information recorded.
10. Multiplicity, Missing Data and Analysis Populations
The registry identifies the VVAQ change from baseline to week 12 as the primary outcome and lists secondary outcomes for serum estrone and serum estradiol changes between baseline, 2 weeks, and 12 weeks. It also reports 12 analyses and notes that the primary outcome has several categories or time points and was not reduced to one comparison. These details raise questions about how multiple outcomes, time points, and contrasts were handled, but do not establish that a particular adjustment was or was not used.
Multiplicity arises when several hypotheses are tested. In general, testing more comparisons can increase the chance of a nominally positive result occurring by chance if no adjustment or other prespecified strategy is used. Statistical approaches may control error rates, prioritize a sequence of tests, or treat additional analyses as exploratory. The registry does not report a multiplicity strategy, the hierarchy among comparisons, or which analyses were prespecified. It is therefore not possible to determine how multiplicity was addressed.
Missing-data handling is also not described. The record does not state the number of participants with observed baseline and week-12 VVAQ scores, reasons for missing assessments, or the method used to include participants with incomplete data. It does not report whether analyses followed assigned groups or another analysis population. These details matter because an analysis restricted to complete observations may differ from one using a model or imputation strategy, especially if missingness is related to symptoms or treatment experience.
The registry record also does not describe sensitivity analyses for missing outcomes, protocol deviations, or treatment adherence. No assumptions about missingness or imputation method should be inferred. Without these details and the numerical outcome data, readers cannot assess the robustness of the primary finding to missing information or multiple comparisons.
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 |
|---|---|---|---|
| Estriol | 0 | 18 | 0.0% |
| Estradiol | 0 | 19 | 0.0% |
| Placebo | 0 | 19 | 0.0% |
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 |
|---|---|
| Estriol | 3 of 18 |
| Estradiol | 0 of 19 |
| Placebo | 1 of 19 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Estriol | Estradiol | Placebo |
|---|---|---|---|---|
| Vaginal Spotting | Reproductive system and breast disorders | 1 of 18 | 0 of 19 | 1 of 19 |
| Red Bumpy Rash | Skin and subcutaneous tissue disorders | 1 of 18 | 0 of 19 | 0 of 19 |
| Breast tenderness | Reproductive system and breast disorders | 1 of 18 | 0 of 19 | 0 of 19 |
The registry lists serious adverse events separately from other adverse events for the estriol, estradiol, and placebo groups. Serious adverse events were recorded as 0 for estriol, 0 for estradiol, and 0 for placebo. The corresponding group-specific numbers listed as at risk were 18, 19, and 19. These entries describe what was reported in the registry; zero recorded serious events is not proof that no event could occur, nor does it establish comparative safety.
Other adverse events were recorded as 3 for estriol, 0 for estradiol, and 1 for placebo. The record does not provide event descriptions, severity, timing, duration, or an assessment of whether events were considered related to treatment. It also does not explain whether these entries count participants, event episodes, or another reporting unit. Rates or comparative estimates should not be inferred from the counts without clarity about that unit and complete follow-up information.
Deaths are listed as null for each group, so death information is not reported in the registry record. The serious adverse event terms list is empty. An empty list does not identify specific events or provide further detail about ascertainment. These safety data are descriptive registry entries, not a complete account of all possible harms or a formal statistical comparison.
12. What the Result Does, and Does Not, Mean
The record establishes that investigators registered a randomized comparison of low-dose estriol and estradiol valerate creams with Vanicream Lite for atrophic vaginitis, using change in VVAQ score from baseline to week 12 as the primary endpoint. It also records the intended application site and schedule, and identifies serum estrone and estradiol as secondary outcomes. These registry entries describe the clinical question and trial structure; they do not show what the trial found on symptoms or hormone levels.
The primary outcome’s scale is interpretable: higher VVAQ scores mean less severe or bothersome symptoms. But the posted results do not report group scores, changes, comparative estimates, confidence intervals, or a primary significance test. The numerical direction and size of any difference are therefore unknown from the registry record. It is not possible to say whether the active groups differed from placebo, whether the groups had similar outcomes, or how precise a comparison might be.
The record reports no serious adverse events in the listed groups, and it records other adverse-event counts of 3, 0, and 1 for estriol, estradiol, and placebo, respectively. These counts are limited descriptive information. Without event types, follow-up completeness, definitions, and a comparative analysis, they do not provide a broad conclusion about safety.
The trial status is TERMINATED, but the reason is not reported in the registry record. Termination is not, by itself, evidence that a treatment was ineffective, harmful, or beneficial. The registry also does not give enough information to assess adherence, missing primary outcome data, analysis populations, or multiplicity procedures. Such omissions make the available statistical record incomplete.
In general, a trial result is best interpreted using an effect estimate, its uncertainty, the outcome’s clinical meaning, and the analysis context. Here, the endpoint definition and design are available, but the primary numerical result is not. The evidence recorded cannot support a quantitative claim about symptom effects or serum hormone changes. It also cannot establish that there was no effect: lack of reported results is not equivalent to a finding of no difference.
13. Why This Trial Matters Statistically
This trial is statistically notable because its primary endpoint is a participant-reported symptom measure while its secondary outcomes are laboratory measures of serum estrone and estradiol. These outcomes address different aspects of the research question. In general, a symptom score reflects participants’ reported experience, whereas a serum concentration reflects a biological measurement. Their results would need to be interpreted separately; the registry record does not report numerical findings for either type of outcome.
The three-group design also creates a need to define the comparisons of interest. The trial includes estriol, estradiol valerate, and a cream-only placebo, but the registry does not state which pairwise or overall comparison was the prespecified primary contrast. It notes that the primary outcome has several categories or time points and was not reduced to one comparison. This makes the analysis specification especially important: an endpoint name alone does not show which contrast should anchor interpretation.
The stated scale direction is another useful statistical detail. Since higher VVAQ values correspond to less severe or bothersome symptoms, a change must be interpreted using that direction rather than assuming that higher scores are worse. Clear scale interpretation prevents sign errors when reading estimates, though the registry does not provide the estimates needed to apply it to observed results.
Finally, the entry illustrates the distinction between a trial’s design record and its results record. Randomization and masking describe intended safeguards against bias, but they do not substitute for reporting effect estimates and uncertainty. The absence of numerical primary outcomes limits evaluation of both magnitude and precision. The record’s adverse-event counts offer some descriptive safety information, but do not resolve these limitations or establish a comparative safety profile.
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 principal limitation for interpreting this trial from the registry record is that numerical results for the primary endpoint are not reported. There are no group-level VVAQ changes, standard deviations, comparative estimates, confidence intervals, or primary-outcome p-values. Secondary serum estrone and estradiol results are also not reported. Consequently, the stated research question cannot be answered quantitatively from the posted record.
The primary outcome is described as VVAQ score change, but details of score construction are not reported. The record explains the three symptom questions and the score direction but does not state how responses were combined for analysis. It also does not describe the statistical model, adjustment for baseline values, or the exact contrast among the three groups. The registry notes that several categories or time points were not reduced to one comparison, leaving the primary analysis specification unclear.
The record does not report eligibility criteria in detail or describe participant characteristics at baseline. It also does not give a complete participant flow, the number contributing data to each outcome, reasons for missing assessments, adherence, withdrawals, or analysis populations. These omissions prevent assessment of how complete or representative the endpoint data were.
Although the study is recorded as randomized and quadruple-masked, sequence generation, allocation concealment, masking roles, and checks on masking are not described. The trial is marked TERMINATED, but the reason is not reported in the registry record. The record also does not explain whether termination affected planned recruitment or analysis.
Safety reporting is limited to group counts. Event descriptions, severity, timing, relatedness, definitions, and ascertainment methods are not reported. Death entries are null. These limitations mean the adverse-event counts should be treated as a narrow registry summary rather than a comprehensive safety assessment.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Trial to Evaluate the Efficacy of Low Dose Vaginal Estrogens in the Treatment of Atrophic Vaginitis — NCT00816556.
- Registry record last updated 2017-11-13; status last verified 2017-10.
- Results first posted 2014-03-28.
- 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
This Phase 3 trial is recorded as randomized, quadruple-masked, and parallel-group, with enrollment of 63 and status TERMINATED. It compared estriol and estradiol valerate creams with Vanicream Lite placebo for atrophic vaginitis. Each regimen was applied to the vaginal introitus daily for two weeks and then twice weekly for 10 weeks.
The primary endpoint was change in VVAQ scores from baseline to week 12. Higher scores indicate less severe or bothersome symptoms. Secondary outcomes concerned changes in serum estrone and estradiol between baseline, 2 weeks, and 12 weeks. Numerical results for these outcomes are not reported in the registry record.
Serious adverse events were recorded as 0 in each group. Other adverse events were recorded as 3 for estriol, 0 for estradiol, and 1 for placebo. Event details and the reason for trial termination are not reported in the registry record.