Estradiol Transdermal Spray in the Treatment of Vasomotor Symptoms: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Estradiol Transdermal Spray in the Treatment of Vasomotor Symptoms (NCT01389102), a randomized phase 3 study. The primary outcome is Mean Change in the Number of Moderate to Severe Vasomotor Symptoms Per Day.

2. Clinical Question

The clinical question is about a continuous symptom count summarized as a mean change, rather than whether a participant met a binary response threshold. The registry defines moderate symptoms as heat with sweating while the participant can continue activity; severe symptoms involve heat with sweating that causes the participant to stop activity. Mild symptoms are a sensation of heat without sweating, and are not part of the stated primary outcome of moderate-to-severe symptoms.

The posted results contain mean changes for each treatment arm and recalculated comparisons against the three-spray placebo group. Those comparisons are statistical contrasts in average change. They do not by themselves describe how many individual participants improved, how symptom changes varied day to day, or whether any particular participant experienced a benefit. Such participant-level details are not reported in the registry record.

3. Trial Design

The registry describes a randomized, double-blind, parallel-group, placebo-controlled phase 3 study. Its official title identifies it as a multicenter study evaluating the safety and efficacy of estradiol metered-dose transdermal spray for vasomotor symptoms in postmenopausal women. The listed enrollment is 454. The study status is completed, with a start date of 2004-12 and primary completion in 2006-11.

Estradiol was studied at three spray regimens: one 90 μL spray, two 90 μL sprays, and three 90 μL sprays. The placebo arms used matching one-, two-, and three-spray regimens. The arm descriptions say the product was applied daily to an inner forearm for 12 weeks using a blinded applicator. For the two-spray and three-spray regimens, the sprays were placed on adjacent, non-overlapping areas of one inner forearm.

Randomization and double masking are identified in the registry, but further operational details are not reported in the registry record. In particular, the method used to generate the random sequence, allocation concealment procedures, and the people covered by masking are not reported. The registry record also does not report the original sample-size justification, planned allocation ratios, or the trial’s detailed statistical analysis plan. These omissions limit what can be said about how the design decisions were made.

Arm-level endpoint summaries are available for each regimen. The posted primary measure is the mean change in moderate-to-severe vasomotor symptoms per day from baseline to week 12, with standard deviations as the measure of spread. The registry also lists sponsor analyses using ANCOVA for selected comparisons. Since the sponsor’s reported analyses and the unadjusted recalculations differ, the sponsor’s own analysis takes precedence for interpreting the trial’s inferential results.

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: Participants underwent a four week screening period to determine eligibility prior to assignment into the study.

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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Mean Change in the Number of Moderate to Severe Vasomotor Symptoms Per Day, measured over baseline to week 12.

The primary endpoint is mean change in the number of moderate-to-severe vasomotor symptoms per day from baseline to week 12. Participants recorded symptoms in a daily diary. The symptom definition combines hot flushes and sweating, with moderate symptoms characterized by sweating while activity continues and severe symptoms characterized by sweating that interrupts activity.

A daily count captures symptom frequency and allows the trial to compare average change across randomized groups. Summarizing the measure as a mean is a common approach for a continuous endpoint, particularly when the question concerns the average degree of change rather than a threshold-defined response. The standard deviation describes how dispersed participant results are around the arm mean; it is not the uncertainty interval for the mean itself.

The arm means are negative, which indicates a decrease relative to baseline in the recorded symptom count. The endpoint is specifically about change over the stated timeframe. It does not by itself establish how symptoms changed at intermediate visits, whether changes persisted after week 12, or how the mean change relates to an individual participant’s experience. Those details are not reported in the registry record.

The registry does not state a minimum change that would be considered important to participants, nor does it report a responder definition for this outcome. As a result, the numerical mean differences can be interpreted as average differences in change, but the record does not provide a threshold for judging their importance in everyday terms.

7. Results Posted in the Registry

• Placebo Transdermal Two 90 μL Sprays: mean -6.19 versus -5.32 on control; difference -0.87 (95% CI -2.80 to 1.06), standardized effect d = -0.14; z-test p = 0.376.
• Placebo Transdermal One 90 μL Spray: mean -4.76 versus -5.32 on control; difference 0.56 (95% CI -1.37 to 2.49), standardized effect d = 0.09; z-test p = 0.570.
• Estradiol Transdermal Three 90 μL Sprays: mean -8.44 versus -5.32 on control; difference -3.12 (95% CI -4.87 to -1.37), standardized effect d = -0.57; z-test p = <0.001.
• Estradiol Transdermal Two 90 μL Sprays: mean -8.66 versus -5.32 on control; difference -3.34 (95% CI -5.42 to -1.26), standardized effect d = -0.52; z-test p = 0.002.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary measure is a mean of a continuous symptom count. An arm mean is the average change in daily moderate-to-severe symptoms among participants represented in that arm’s posted summary. A negative change indicates that the average recorded count was lower at follow-up than at baseline. The standard deviation expresses how widely participant-level changes vary around that average. It is not interchangeable with a standard error or a confidence interval.

What does the unadjusted mean difference represent?

The recalculated comparisons subtract the placebo three-spray arm’s posted mean change from the other arm’s mean change. The resulting estimate expresses the difference between the two arm averages in the same units, vasomotor symptoms per day. A negative estimate means the comparison arm’s average change is more negative than the reference arm’s average change. A positive estimate means it is less negative. These calculations use posted summary statistics and are unadjusted; they do not reproduce the sponsor’s ANCOVA model.

The recalculations also use pooled standard deviations and standard errors derived from the posted arm summaries. A standard error describes the sampling uncertainty of an estimated mean or contrast under the assumptions of the calculation. It generally becomes smaller when estimates are based on more information, but its value also depends on variability. The standard deviation describes dispersion among observations, whereas the standard error describes uncertainty about an estimated quantity.

Why is an ANCOVA analysis different?

ANCOVA is a model-based method that can compare follow-up outcomes or changes between groups while accounting for one or more covariates. The registry identifies ANCOVA for the sponsor’s reported analyses, but the covariates, model specification, analysis population, handling of missing observations, and adjusted estimates are not reported in the registry record. Because those details are absent, the recalculated unadjusted differences should not be expected to match the sponsor’s adjusted results exactly. The sponsor’s own analysis takes precedence when the posted recalculations disagree with it.

For the estradiol three-spray and two-spray comparisons, the sponsor entries identify both the estradiol and placebo groups. The one-spray sponsor entry identifies only the estradiol group, so its comparator is not clear from the record. The sponsor entries give p-values and identify a 95% confidence level, but do not report numerical confidence interval bounds or adjusted effect estimates.

How should p-values be read?

A p-value describes how compatible the observed data are with a specified null model, under the assumptions of the analysis. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of a difference. The unadjusted p-values calculated from posted summaries are distinct from the sponsor’s ANCOVA p-values. The registry does not report whether the sponsor adjusted for multiple comparisons, so the p-values should not be interpreted as multiplicity-adjusted unless the record states that such adjustment was used.

A confidence interval expresses uncertainty around an estimated contrast under the method used to calculate it. An interval that includes zero is compatible with no difference under the corresponding statistical framework; an interval that lies entirely on one side of zero indicates that the estimate is not compatible with zero at the interval’s associated level. The recalculated comparison intervals are presented with their endpoint values, but the registry entries do not specify their confidence level. The sponsor’s reported analysis entries identify a 95% confidence level but do not include interval bounds.

Why can count outcomes be challenging?

Symptom counts may be skewed, may vary substantially among participants, and may show variability that exceeds the mean. Over-dispersion is a general statistical issue in count data: it means the observed variation is greater than a simple count model would expect. When that occurs, methods that account for the extra variation can produce more appropriate uncertainty estimates. This is a general consideration, not a claim that over-dispersion was assessed or found in this trial. The registry record does not describe diagnostic checks or alternative count models.

The posted primary outcome is summarized with a mean and standard deviation, and the sponsor analyses are identified as ANCOVA. The record does not explain whether alternative distributions, repeated-measures methods, or transformations were considered. The analysis method cannot be evaluated in detail without those specifications and the underlying participant-level data.

What information is missing for a full analysis review?

The record does not report the analysis population used for the primary outcome, the number of participants contributing endpoint data in each arm, or how missing daily diary entries and missing week-12 values were handled. It does not describe whether analyses followed intention-to-treat principles, whether participants were excluded after randomization, or whether sensitivity analyses were performed. The record also does not report the prespecified hierarchy of outcomes or a multiplicity strategy. These are important for judging how robust the inferential findings are, and their absence should be distinguished from evidence that a particular approach was or was not used.

10. Confidence Intervals and Precision

Precision concerns how much uncertainty surrounds an estimated contrast. The recalculated interval for estradiol three sprays versus placebo three sprays runs from -4.868 to -1.372 symptoms per day, around a mean difference of -3.12. For estradiol two sprays, the interval runs from -5.421 to -1.259 around -3.34. For estradiol one spray, it runs from -4.468 to -1.092 around -2.78. Each of these intervals lies below zero, meaning that the recalculated contrasts are on the negative side throughout the stated bounds.

The placebo two-spray comparison interval runs from -2.798 to 1.058 around -0.87, and the placebo one-spray interval runs from -1.372 to 2.492 around 0.56. Each includes zero, so the recalculated interval allows values on either side of no difference. The interval bounds should be considered alongside the point estimates rather than replaced by the p-values; they communicate a range of contrast values compatible with the calculation.

The registry entries do not specify the confidence level for these recalculated intervals. The sponsor’s analysis entries specify a 95% confidence level, but no adjusted interval endpoints are posted. This means precision for the sponsor’s adjusted effect estimates cannot be assessed from the numerical record presented.

Interval width reflects both variability and the amount of information contributing to the estimate. The posted standard deviations indicate variability in participant-level change, but endpoint-specific analysis counts and missing-data handling are not reported. Consequently, the posted intervals describe precision under the recalculation assumptions, not all sources of uncertainty about the study or its conduct.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm for 80% power and participants per arm for 90% power. They are not total events: the sample-size assumptions state that only time-to-event calculations use total event counts, while all other figures are participants per arm. The primary endpoint in this trial is continuous, so the listed planning values refer to participants per arm.

The planning illustration uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It calculates sample sizes for detecting the stated fraction of the observed effect. The rows for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect therefore represent different assumed target effect sizes. Smaller effects need more participants to detect with the same planned power, which is why the required figures increase as the assumed fraction decreases.

The 80% power column means the planning calculation targets an 80% chance of detecting the specified effect under the stated assumptions, if that effect is the true one and the assumptions hold. The 90% column uses a higher target chance of detecting the same effect and therefore generally requires more participants. These are prospective planning illustrations based on observed effects, not evidence about how likely the completed trial was to find a result.

This is not observed power. The trial’s original sample-size assumptions and justification are not reported in the registry record, and the planning illustration does not establish what design choices the trial actually used. It should be read as a way to understand how assumed effect size and target power relate to planning requirements, not as a retrospective rating of trial success.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -0.870; pooled standard deviation σ = 6.039.
2. n = 2 × (1.96 + 0.842)² × 6.039² / -0.870² = 756.4, rounded up to 757 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -0.87                      # observed difference in means
sigma <- 6.03903826958205                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(1389102)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 757 (80% power), 1,013 (90% power)
 75% of observed effect: n per arm = 1,345 (80% power), 1,801 (90% power)
 50% of observed effect: n per arm = 3,026 (80% power), 4,051 (90% power)
power.t.test: 757.3 
Simulated power at n = 757 per arm: 0.803 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Analyses Reported by the Sponsor

The registry reports sponsor analyses using ANCOVA for the estradiol three-spray versus placebo three-spray comparison and the estradiol two-spray versus placebo two-spray comparison. The respective p-values are < 0.001 and 0.010, with a 95% confidence level identified. For estradiol one spray, the sponsor entry reports p < 0.001 and a 95% confidence level, but lists only the estradiol group; the comparator is not clear from that entry. Numerical adjusted estimates and confidence interval bounds are not reported for these entries.

The recalculated comparisons use posted arm means and standard deviations and are unadjusted. Their p-values are <0.001 for estradiol three sprays, 0.002 for estradiol two sprays, and 0.001 for estradiol one spray against the three-spray placebo group. These do not replace the sponsor’s model-based results. The discrepancy flag indicates that the recalculations differ from the sponsor’s own analysis, so the sponsor’s analysis takes precedence.

The record does not provide enough detail to determine which model covariates or analysis-population decisions account for the difference. Nor does the sponsor entry for one spray establish a comparison with placebo on its own. The reported sponsor p-values should therefore be retained as recorded, while recognizing that the adjusted effect magnitude and its interval are unavailable in the registry record.

14. Multiplicity, Missing Data and Analysis Populations

The trial reports a primary endpoint and sponsor analyses across selected treatment comparisons, but the registry record does not describe a strategy for controlling multiplicity. Multiplicity arises when several statistical hypotheses are tested: even when each test uses a specified threshold, the chance of at least one apparently notable result across a family of tests can differ from the chance for a single prespecified test. Adjustment methods or a prespecified testing hierarchy can address this issue, but whether either was used in the trial is not reported in the registry record.

The sponsor’s ANCOVA entries report p-values for the three-spray and two-spray estradiol-placebo pairs and a separate one-spray entry. The one-spray entry does not identify its comparator. The record does not say whether these were the only planned comparisons, whether testing was sequential, or whether p-values were adjusted. The unadjusted recalculated p-values should not be read as if they were adjusted for multiple comparisons.

Missing-data handling is also not reported. The primary measure relies on daily diaries, but the registry record does not state how incomplete diary records were summarized, how missing baseline or week-12 values were handled, or whether participants with incomplete data were included in the reported analysis. The analysis population is not reported in sufficient detail to establish whether the outcome summaries represent all randomized participants or a subset.

The record does not report whether the sponsor’s ANCOVA analyses followed intention-to-treat principles, how post-randomization discontinuations were treated, or whether sensitivity analyses examined the effect of missing observations. These omissions matter because results from complete observations can differ from results under other missing-data assumptions. They do not show that the sponsor used an inappropriate method; they mean the registry record does not permit that aspect of the analysis to be assessed.

There are no secondary outcomes posted in the record. A detailed protocol, statistical analysis plan, and analysis-population definitions are not reported in the registry record, so the prespecification and handling of outcome testing cannot be established from the posted information.

15. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: spinal column stenosis (1.4%), uterine prolapse (1.3%), impaired gastric emptying (1.3%), chest pain (1.3%), chronic obstructive airways disease excerbated (1.3%).

The registry lists serious adverse event figures by arm as the number affected and the number at risk. The placebo three-spray group reports 0 affected among 75 at risk; placebo two sprays reports 0 among 76; placebo one spray reports 1 among 77. Estradiol three sprays reports 3 among 76; estradiol two sprays reports 1 among 74; and estradiol one spray reports 3 among 76.

These figures describe reported serious adverse event occurrence in the listed groups. They are counts, not estimates of comparative risk, and the registry record does not provide a statistical comparison or uncertainty interval for them. The listed terms with the highest reported frequencies include Spinal Column Stenosis at 1.4%, and Uterine Prolapse, Impaired Gastric Emptying, Chest Pain, Chronic Obstructive Airways Disease Excerbated, and Dyspnea, each at 1.3%. The record does not provide arm-specific attribution for these terms in the displayed summary.

Deaths are not reported in the registry record. The serious-event figures should be read separately from the primary symptom outcome; they do not establish an overall safety profile or explain causality. The record also lists other adverse-event counts, but these are not the serious adverse event counts.

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

The posted arm summaries show decreases from baseline in the average daily count of moderate-to-severe vasomotor symptoms in every group, including each placebo regimen. The estradiol arm means are more negative than the mean for the three-spray placebo arm, and the recalculated unadjusted contrasts are negative for each estradiol regimen. The placebo one-spray and two-spray recalculated contrasts against the three-spray placebo arm are closer to zero and have intervals that include zero.

These patterns describe group-average changes over baseline to week 12. They do not show that every participant experienced a decrease, quantify the likelihood of improvement for an individual, or establish how much change a participant would consider worthwhile. The registry record does not provide a threshold for a clinically important change or a responder analysis. It also does not report how outcomes evolved during the trial or after the 12-week treatment period.

The unadjusted recalculations and sponsor ANCOVA findings are different forms of analysis. The record identifies the sponsor’s analysis method and gives sponsor p-values for selected comparisons, but lacks adjusted effect estimates and interval bounds. Because the recalculations differ from the sponsor analyses, the sponsor’s own analysis takes precedence. The available information does not support substituting recalculated estimates for the sponsor’s model-based results.

Statistical evidence and clinical importance are related but not identical. A p-value does not measure effect size, and an interval does not define whether a difference matters to participants. The registry record does not report a prespecified clinically meaningful threshold, detailed missing-data methods, multiplicity handling, or a complete analysis plan. Those limits make it important to keep the interpretation close to the reported outcome and analyses.

These results are specific to the study population, regimens, endpoint, and timeframe described in the registry. The record alone does not establish longer-term outcomes, results in populations not described, or the balance of benefit and harm for an individual. It presents trial statistics, not individualized medical guidance.

17. Why This Trial Matters Statistically

This trial offers a useful statistical example of a multi-arm placebo-controlled design in which the same continuous endpoint is summarized across several dose regimens. The three placebo regimens provide context for interpreting the estradiol arms, while the posted recalculations use the three-spray placebo arm as the reference. That choice matters: a contrast is always defined relative to its comparator, and the comparison should be kept explicit when reading estimates.

The endpoint is a daily symptom count summarized as mean change, so interpretation depends on both average change and variability. The arm standard deviations are not identical, illustrating why uncertainty cannot be understood from mean differences alone. Intervals and standard errors add information about precision, though they do not address all potential sources of bias or uncertainty.

The trial also illustrates why posted summary-statistic calculations should be distinguished from sponsor analyses. Unadjusted recalculations can help readers understand the scale and direction of a contrast, but they may not match model-based estimates. Here, the registry identifies ANCOVA for sponsor analyses and flags a discrepancy, so the sponsor’s analysis takes precedence. The registry’s missing adjusted estimates and model details leave important aspects of that analysis opaque.

Finally, multiple treatment comparisons, unreported missing-data procedures, and unavailable original design assumptions are relevant statistical limitations. They do not invalidate the posted findings, but they constrain the strength and scope of conclusions that can be drawn from the registry record. Reading the mean changes, intervals, p-values, sponsor analyses, and safety counts as distinct pieces of evidence helps prevent any single statistic from carrying more meaning than it supports.

18. 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.

Several trial-specific details needed for a fuller evaluation are not reported in the registry record. The primary outcome population field is blank, and the record does not specify the analysis population, endpoint contribution counts, or missing-diary procedures. This is particularly relevant for a daily diary outcome, where incomplete recording could affect the calculation of a participant’s change. No sensitivity analyses addressing missing data are reported.

The sponsor reports ANCOVA, but the registry does not give the model covariates, exact specification, adjusted estimates, or confidence interval bounds. It is therefore not possible to verify how the model relates to the posted unadjusted summaries. The entry for the estradiol one-spray analysis lists only that arm, leaving its comparator unclear. Because recalculations differ from the sponsor’s analysis, the sponsor’s own analysis takes precedence, but its numerical effect estimates are not available in the record.

The registry does not state whether or how multiplicity was addressed across the treatment comparisons, or whether the reported tests followed a prespecified hierarchy. It does not report the trial’s original sample-size justification, its assumptions for power, or any interim analyses. These items are not inferable from the planning illustration, which is based on observed effects rather than the original design.

Randomized, double-blind, placebo-controlled design features are listed, but sequence generation, allocation concealment, and masking procedures are not detailed. The record does not report longer-term follow-up for the primary symptom outcome. For safety, deaths are not reported, and serious adverse event summaries do not provide comparative uncertainty estimates or establish causality. These limits restrict interpretation to the information recorded and do not establish that unreported procedures were absent.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Estradiol Transdermal Spray in the Treatment of Vasomotor Symptoms — NCT01389102.
• Registry record last updated 2012-06-11; status last verified 2012-06.
• Results first posted 2012-06-11.
• 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.

22. Record Summary

NCT01389102 is a completed randomized, double-blind, parallel-group, placebo-controlled phase 3 study of estradiol metered-dose transdermal spray for vasomotor symptoms in postmenopausal women. The registry lists enrollment of 454, a start date of 2004-12, and primary completion in 2006-11. Participants received one, two, or three 90 μL sprays of estradiol or matching placebo daily for 12 weeks.

The primary outcome was mean change in moderate-to-severe vasomotor symptoms per day from baseline to week 12, recorded in daily diaries. The registry posts arm means and standard deviations, sponsor ANCOVA p-values for selected analyses, and serious adverse event counts. It does not report numerical adjusted effect estimates, detailed analysis-population and missing-data methods, or multiplicity handling. Unadjusted recalculations are available for comparisons against the three-spray placebo arm, but the sponsor’s own analysis takes precedence where results differ.