Viagra in the Treatment of Primary Dysmenorrhea: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Viagra in the Treatment of Primary Dysmenorrhea (NCT00123162), a randomized phase 1, phase 2 study. The primary outcome is The Primary Outcome Was Total Pain Relief Over 4 Hours (TOPAR4), Comparing a Single Dose of Sildenafil 100 mg to a Single Dose of Placebo..

2. Clinical Question

The primary outcome combines pain-relief ratings recorded each hour after study drug administration for four hours. Each hourly rating uses a scale from 0, meaning no relief, to 4, meaning complete relief. The four ratings are summed to make a TOPAR4 score ranging from 0 to 16. This makes the comparison about the average accumulated pain-relief score across the observation period, rather than a binary count of participants who did or did not improve.

The registry lists a secondary outcome of improvement in pain severity determined by a visual analog scale. Numerical results for that secondary outcome are not reported in the registry record. The primary comparison therefore concerns the posted TOPAR4 group means and the reported between-group analysis, not a VAS result.

3. Trial Design

This was a randomized, single-masked, parallel-group trial in Phase 1 and Phase 2. The registry lists an enrollment of 25. The posted outcome summaries include 13 participants in the sildenafil citrate group and 12 in the placebo group. These are the group counts attached to the outcome results; the registry record does not describe the analysis population or explain whether any enrolled participants were excluded from an analysis.

The intervention was one vaginal dose of sildenafil citrate 100 mg. The comparison group received one vaginal dose of placebo. The registry identifies the trial as completed, with a start date of 2007-05 and primary completion in 2011-06. Who was masked is not reported in the registry record, so the single-masking designation does not identify whether participants, investigators, outcome assessors, or another group were masked.

The primary outcome was the mean Total Pain Relief over 4 Hours score, based on pain-relief ratings taken in Hours 1, 2, 3 and 4. The four hourly ratings were summed, and higher totals indicate greater pain relief over time. Missing TOPAR scores after the first hour were imputed using last observation carried forward. The record lists a visual analog scale measure of pain severity as a secondary outcome, but numerical results for it are not reported in the registry record.

The record does not report the original sample-size justification, planned allocation ratio, or detailed protocol for the statistical analysis. The outcome group counts are close in size, but they do not establish the trial's planned allocation method. The sample-size planning illustration is a separate calculation based on the observed result, not a description of the trial's design.

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

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 The Primary Outcome Was Total Pain Relief Over 4 Hours (TOPAR4), Comparing a Single Dose of Sildenafil 100 mg to a Single Dose of Placebo., measured over Hours 1, 2, 3 and 4..

The primary endpoint is Total Pain Relief over 4 Hours, or TOPAR4. It summarizes pain relief ratings recorded at the end of each of the first four hours after administration of the study drug. Each rating is on a scale from 0, no relief, to 4, complete relief. Adding the four ratings produces a score from 0 to 16; a higher score represents greater pain relief accumulated over the four-hour period.

A summed score offers a way to represent both the level and persistence of relief during the observation window. A single rating would describe only one time point, while TOPAR4 incorporates the sequence of hourly ratings into one continuous measure. The posted results report the mean and standard deviation for each group, which permits a comparison of average scores.

The record states that missing TOPAR scores after the first hour were imputed using last observation carried forward. Under that approach, the last available score is carried forward for later missing scores. The record does not report how many scores were missing or how many participants were affected. The endpoint is the posted primary measure; it should not be confused with the registry summary's stated hypothesis about an improvement rate, which describes a different kind of outcome.

7. Results Posted in the Registry

• Sildenafil Citrate: mean 11.90 versus 6.40 on control; difference 5.50 (95% CI 3.39 to 7.61), standardized effect d = 2.01; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a continuous measure, and the registry reports its group means and standard deviations. The central comparison is the difference in average TOPAR4 scores between the sildenafil citrate and placebo groups. A mean difference retains the units of the outcome, so it is expressed in units on the TOPAR4 scale. A positive estimate means the average score is higher in the sildenafil citrate group, given the direction of the comparison used in the record.

What does ANCOVA contribute?

The registry identifies its reported primary analysis as ANCOVA and describes the result as a net mean difference. ANCOVA is a general statistical method for comparing group means while accounting for one or more other variables in the model. Which covariates were included, how they were measured, and the full model specification are not reported in the registry record. The term ANCOVA alone therefore does not establish which adjustments were made or how much they influenced the result.

The recalculated comparison is different in scope. It uses only the posted group summary statistics to obtain a simple unadjusted comparison. It does not reproduce an ANCOVA model because the covariate data and model details are not reported. The recalculated estimate is useful as a summary-statistic cross-check, but it is not a replacement for the registry's own analysis.

What does the confidence interval describe?

A confidence interval gives a range of estimates compatible with the observed data under the analysis assumptions and method. The reported 95% confidence interval for the ANCOVA mean difference extends from 2.9 to 7.6. Its position relative to zero indicates that the reported estimate is positive across that interval. The width also conveys uncertainty: a wider interval indicates less precision than a narrower interval, all else equal. The interval does not capture uncertainty arising from every possible source, such as unreported design choices or limitations in missing-data handling.

The recalculated unadjusted interval is based on the posted group means, standard deviations, and group counts. It is not an interval from the ANCOVA model. The fact that the two estimates are similar does not make their methods interchangeable; the model-based result and the summary-statistic result answer closely related but distinct questions.

How should the p-value be read?

The reported p-value is p < 0.001. In general, a p-value is a measure of how inconsistent the observed data are with a specified null hypothesis, assuming the statistical model and test assumptions hold. It is not the probability that the null hypothesis is correct, and it is not a measure of the probability that a result occurred by chance. Nor does it measure the magnitude or clinical importance of an effect. The registry also reports p < 0.001 for its ANCOVA result, while the recalculation has the same displayed threshold.

Why do outcome distributions matter?

The mean is a useful summary for a continuous endpoint, but it does not show the full distribution of participant scores. The standard deviation describes the spread around the mean, yet neither the mean nor the standard deviation indicates whether scores were symmetric, clustered, or affected by extreme observations. Distributional plots and individual-level data would be needed to examine those features, and those details are not reported in the registry record.

TOPAR4 is bounded from 0 to 16 because it sums four ratings, each bounded from 0 to 4. That finite range is part of the endpoint's definition. The registry reports an ANCOVA analysis, but does not report diagnostics or modeling details that would allow assessment of how well the model assumptions fit this outcome. No additional model assumption should be inferred from the analysis label alone.

What does last observation carried forward imply?

The registry states that missing TOPAR scores after the first hour were imputed using last observation carried forward. In general, this method substitutes the most recent available score for a later missing score. It can preserve a complete series of hourly values for the sum, but it assumes that the carried-forward value is an acceptable stand-in for the missing later measurement. That assumption may not reflect actual changes over time. The number and timing of missing scores, and any sensitivity analyses using alternative methods, are not reported in the registry record.

The main result should therefore be understood as the registry's ANCOVA comparison of the posted primary endpoint, alongside a separate unadjusted recalculation. Statistical significance, the estimated size of the contrast, uncertainty, the outcome's construction, and missing-data assumptions are related but distinct parts of interpreting the result.

10. Confidence Intervals and Precision

The registry's reported ANCOVA estimate is a mean difference of 5.3 TOPAR4 units, with a 95% confidence interval from 2.9 to 7.6. The interval gives a range of values compatible with the observed data under the model and its assumptions. It is entirely on the positive side of zero, which aligns with the reported direction of a higher mean score in the sildenafil citrate group.

The interval is important because the point estimate alone does not show how uncertain the comparison is. Its endpoints indicate that the data are compatible with differences smaller or larger than the central estimate. They do not mean there is a 95% probability that this particular interval contains the true effect; the usual confidence-interval interpretation concerns the long-run behavior of the method under repeated sampling and its assumptions.

The unadjusted recalculation gives a mean difference of 5.5 and a 95% confidence interval from 3.393 to 7.607. This interval is based on the posted arm summaries, not on the ANCOVA model. It should be read as a separate estimate rather than combined with the registry's interval. The reported and recalculated estimates are similar, but the registry's adjusted analysis remains the registry's stated result.

Both intervals describe uncertainty in a group-level mean contrast, not the range of individual participants' scores or responses. The group standard deviations—3.2 in the sildenafil citrate arm and 2.1 in the placebo arm—describe observed score variability, which is a different quantity from the confidence interval for the difference. With 13 and 12 participants in the outcome groups, the limited group counts are relevant context when considering precision and how well the estimate may apply beyond the trial. The confidence intervals do not account for unreported features such as the full analysis model, missing-data pattern, or the clinical importance threshold for TOPAR4.

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 sample-size table and curve are planning illustrations based on the observed treatment contrast, not the trial's original design calculation. The figures are participants per arm for the continuous outcome; they are not total event counts. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each row considers an effect to detect set to the stated fraction of the observed effect: 100%, 75%, or 50%.

For planning for 100% of the observed effect, the illustration gives 4 participants per arm for 80% power and 6 participants per arm for 90% power. For planning for 75% of the observed effect, it gives 7 participants per arm for 80% power and 10 participants per arm for 90% power. For planning for 50% of the observed effect, it gives 16 participants per arm for 80% power and 21 participants per arm for 90% power.

The 80% power column describes the planned number per arm for a future study to have an 80% chance of detecting the specified effect under the stated assumptions, if that effect and the model assumptions are correct. The 90% column describes the corresponding planning target for a 90% chance. These are design calculations for hypothetical future studies, not guarantees of detection. As the effect being targeted becomes smaller, more participants are needed under the same assumptions. This is not observed power.

The illustration is computed from the observed result and should not be read as evidence that the original trial was designed around these assumptions. The original sample-size justification and design assumptions are not reported in the registry record. The displayed planning figures also depend on the observed effect, which is uncertain, so they are not a substitute for a prospective design calculation based on a justified target effect.

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 = 5.500; pooled standard deviation σ = 2.730.
2. n = 2 × (1.96 + 0.842)² × 2.730² / 5.500² = 3.9, rounded up to 4 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 <- 5.5                      # observed difference in means
sigma <- 2.72978737824666                     # 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(123162)
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 = 4 (80% power), 6 (90% power)
 75% of observed effect: n per arm = 7 (80% power), 10 (90% power)
 50% of observed effect: n per arm = 16 (80% power), 21 (90% power)
power.t.test: 5 
Simulated power at n = 4 per arm: 0.663 (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 the trial's own primary analysis as an ANCOVA mean difference (net) of 5.3, with a 95% confidence interval from 2.9 to 7.6 and p < 0.001. This is the analysis to cite as the posted trial result. The record does not provide the full ANCOVA model specification or identify its covariates.

The recalculation from the posted group summary statistics is unadjusted: it compares the means of 11.9 and 6.4 and yields a mean difference of 5.5, with a 95% confidence interval from 3.393 to 7.607 and p < 0.001. Because it is based on aggregate means and standard deviations rather than the trial's model, it cannot reproduce the ANCOVA estimate exactly. It is a complementary check on the direction and approximate size of the contrast, not an alternative sponsor analysis.

The registry record does not flag a discrepancy between the reported and recalculated results. The two estimates are close, and both are positive, but they remain methodologically distinct. Interpretation should preserve that distinction rather than presenting the recalculation as if it were the adjusted result reported by the trial.

14. Multiplicity, Missing Data and Analysis Populations

The record lists two outcome measures and two analyses. It identifies TOPAR4 as the primary outcome and lists improvement in pain severity determined by visual analog scale as a secondary outcome. Numerical results for that secondary outcome are not reported in the registry record. The record does not report a multiplicity-adjustment plan, a hierarchy for interpreting multiple outcomes, or whether any outcomes were designated as exploratory.

Multiplicity is a general statistical concern when several outcomes or hypotheses are tested. Each additional test can create another opportunity for a statistically significant result, so a prespecified plan may define how evidence across outcomes will be interpreted. Without a reported plan, it is not possible to determine whether the p-value for the primary outcome was adjusted for other analyses, or what inferential status should be assigned to the secondary outcome.

The registry names ANCOVA for the primary comparison but does not report the full statistical analysis plan, analysis population, or details such as covariates and model diagnostics. It is therefore not possible to determine whether the analysis followed an intention-to-treat approach, a per-protocol approach, or another population definition. The outcome group counts alone do not resolve that question.

Missing TOPAR scores after the first hour were handled using last observation carried forward, as stated in the record. The number of missing scores and participants affected is not reported in the registry record. The record also does not report sensitivity analyses that would show how the result changes under other missing-data assumptions. In general, imputation methods rely on assumptions about unobserved values; without missingness details and alternative analyses, the sensitivity of the result to those assumptions cannot be evaluated.

The registry summary's hypothesis refers to a higher improvement rate, whereas the posted primary endpoint is a continuous mean TOPAR4 score. The record does not explain how the summary hypothesis relates to the outcome analysis or whether a separate binary improvement analysis was conducted. The posted mean comparison should therefore be described according to the registered primary outcome as reported, without treating it as a reported improvement-rate analysis.

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 0% reporting threshold.

The adverse-event results list 13 participants at risk in the sildenafil citrate group and 12 in the placebo group. The record reports 0 serious adverse events in each group and 0 other adverse events in each group. These are the posted event counts for the categories shown; they are not a comparison of event rates adjusted for follow-up time.

These zero counts should be interpreted as the registry's reported figures, not as proof that no adverse events occurred in any broader sense. The registry record does not provide further event descriptions, timing, severity breakdowns, or information about how events were collected. The deaths field is not populated with a count, so deaths are not reported in the registry record.

The safety figures also come from a trial with 13 participants in one group and 12 in the other. Counts from groups of this size provide limited information about uncommon events. They describe what is posted in the record and do not establish the absence of risks beyond the observed and reported events.

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

The posted results show higher average TOPAR4 scores in the sildenafil citrate group than in the placebo group during the four-hour observation period. The registry's ANCOVA estimate is a mean difference of 5.3, with a 95% confidence interval from 2.9 to 7.6 and p < 0.001. The group means, 11.9 and 6.4, provide the descriptive context for that comparison. The endpoint ranges from 0 to 16, with higher values representing greater pain relief over time.

This finding is specific to the outcome, dose, route, comparator, and observation window described in the registry. The trial evaluated a single vaginal dose of sildenafil citrate 100 mg against a single vaginal dose of placebo. It does not, from the posted primary comparison alone, answer questions about other doses, routes, repeated use, longer-term outcomes, or other populations. Participant eligibility details beyond the registry's description of moderate to severe primary dysmenorrhea are not reported in the registry record.

The statistical result does not by itself establish the practical or clinical importance of the score difference. The record does not report a threshold for a clinically meaningful TOPAR4 change. A small p-value does not measure the benefit an individual might experience, and the group mean difference does not predict any one participant's response.

The secondary VAS outcome is listed, but its numerical result is not reported in the registry record. The posted record therefore does not permit a parallel assessment of the secondary pain-severity measure. Missing scores were handled with last observation carried forward after the first hour, and the amount of missing data is not reported, so the robustness of the result to that choice cannot be assessed from the record.

Overall, the reported analysis supports a positive difference in mean TOPAR4 scores under the trial's analysis, while leaving uncertainties about precision, missing-data assumptions, model specification, clinical interpretation, and applicability. The findings should be read as results from this completed trial rather than as a universal prediction about outcomes in other settings.

17. Why This Trial Matters Statistically

This trial illustrates why a clinical result should be read through the endpoint definition as well as the headline comparison. TOPAR4 is not a direct count of participants who improved; it is a sum of four hourly pain-relief ratings. Understanding its 0-to-16 range and the meaning of higher scores is necessary to interpret the direction of the reported mean difference.

It also demonstrates the distinction between a registry-reported model-based result and a recalculation from summary statistics. The registry's ANCOVA estimate is 5.3, whereas the unadjusted recalculation is 5.5. Both summarize the contrast, but the model-based result and the recalculation are not interchangeable. This distinction matters whenever the model specification is only partly described.

The record also makes missing-data handling relevant to interpretation: later missing hourly scores were imputed by carrying the last observation forward. That method affects how the four-hour sum is formed when values are missing, yet the extent of missingness is not reported. Naming an imputation method is useful, but assessing its influence requires information about missingness and, ideally, sensitivity analyses.

Finally, the planning illustration shows how sample-size calculations depend on the effect a future study aims to detect. Smaller targeted effects require more participants under the stated assumptions. Because the illustration starts from the observed result, it is a planning aid rather than evidence of the original trial's design rationale or observed power. Together, these features show how endpoint construction, analysis choices, precision, and planning assumptions each contribute to statistical interpretation.

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 assessment are not reported in the registry record. The participant eligibility criteria beyond the stated dysmenorrhea context, the identities of the people masked, and the planned allocation ratio are not given. Although the record identifies randomization and single masking, those labels do not supply further procedural details.

The ANCOVA result is reported, but the model covariates, diagnostics, and full analysis plan are not reported in the registry record. The analysis population is also not specified. Consequently, the extent to which the model adjusted for baseline information or included all randomized participants cannot be established from the posted information.

The registry states that last observation carried forward was used for missing TOPAR scores after the first hour, but the number of missing values and affected participants is not reported. Sensitivity analyses using other assumptions are not reported in the registry record. The result's dependence on the imputation choice therefore cannot be assessed.

The record lists a secondary VAS outcome but does not report its numerical result. It also does not report a multiplicity plan or explain how the summary's hypothesis about an improvement rate relates to the continuous primary endpoint. A threshold for a clinically meaningful TOPAR4 difference is not reported, limiting interpretation of the practical importance of the estimated contrast.

The sample-size illustration is based on the observed effect and does not describe the original design justification, which is not reported in the registry record. Finally, the posted outcome groups contain 13 and 12 participants. This small total limits the amount of information available about variability and uncommon adverse events. The record reports zero serious and other adverse events in both groups, but the deaths count and fuller safety details are not reported.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Viagra in the Treatment of Primary Dysmenorrhea — NCT00123162.
• Registry record last updated 2015-12-23; status last verified 2015-11.
• Results first posted 2015-12-23.
• 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

The registry identifies a completed randomized, single-masked, parallel-group Phase 1 and Phase 2 trial of sildenafil citrate versus placebo for primary dysmenorrhea. Enrollment was 25. Participants received a single vaginal dose of sildenafil citrate 100 mg or a single vaginal dose of placebo.

The primary outcome was mean TOPAR4, the sum of hourly pain-relief ratings over four hours, with higher scores indicating greater relief. The reported ANCOVA mean difference (net) was 5.3, with a 95% confidence interval from 2.9 to 7.6 and p < 0.001. The secondary VAS outcome is listed, but its numerical result is not reported in the registry record.

The record states that missing TOPAR scores after the first hour were imputed using last observation carried forward. It reports 0 serious and 0 other adverse events in each group. Further details of the analysis model, missing-data extent, analysis population, and original sample-size justification are not reported in the registry record.