To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension. (NCT00430716), a randomized phase 4 study. The primary outcome is Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 12.

2. Clinical Question

The primary outcome is a continuous measure of walking distance in meters. Participants were asked to walk at a comfortable pace and could take breaks as needed. The endpoint therefore concerns change in a functional test over the treatment period, not a direct measure of survival or a clinical event. The registry record lists secondary outcomes involving pulmonary arterial pressure, clinical worsening, PAH functional capacity and therapeutic class, biomarkers, TAPSE, and dyspnoea. Numerical results for those secondary outcomes are not reported in the registry record in the registry record for these results.

3. Trial Design

This was a phase 4, randomized, parallel-group study of oral sildenafil in participants with PAH. The official title describes a multinational, multicentre, randomized, parallel-group, double-blind study; the registry labels masking as triple. Which people or roles were masked is not reported in the registry record. The study compared sildenafil doses of 1 mg, 5 mg, and 20 mg taken three times daily. An open-label phase from week 12 to week 24 is also described, but the arm descriptions do not give further details of that phase.

The record lists enrollment of 130. It gives a start date of 2008-04-08 and a primary completion date of 2010-05-25, and the status is terminated. The reason for termination, whether recruitment ended as planned, and whether the primary completion date reflects completion of all study activity are not reported in the registry record. The record does not provide a sample-size justification or explain whether the stated enrollment was a target or the final number enrolled beyond labeling it as enrollment.

The primary outcome was change from baseline in total distance walked during the six-minute walk test at week 12. The registry identifies the analysis population as intention to treat (ITT), defined for this endpoint as randomized participants who received at least 1 dose of study medication. Missing values at any visit were imputed using last observation carried forward (LOCF). Details about other analysis populations, exclusions, protocol deviations, or sensitivity analyses are not reported in the registry record.

The record lists eight outcome measures and 14 analyses. It names seven secondary outcomes, including change in mean pulmonary arterial pressure, clinical worsening, changes in PAH criteria for functional capacity and therapeutic class, biomarkers, TAPSE, and BORG dyspnoea score. The listed outcome names and counts do not establish which outcomes were tested in a prespecified hierarchy or how the analyses were organized. That information is 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.

Double Blind Phase

Reasons for not completing this period:

Open Label Phase

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intention to Treat (ITT population) included all participants who were randomized to study treatment and received at least 1 dose of study medication. If participant had missing value at any visit, last observation carried forward (LOCF) method of imputation was used.

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 Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 12, measured over Baseline and Week 12.

The primary endpoint is the change from baseline in total distance walked during the six-minute walk test (6MWT) at week 12, measured in meters. A participant was asked to walk for six minutes at a comfortable pace and could take as many breaks as needed. Continuous pulse oximetry was conducted during the test for safety. The registry reports the mean change for each dose group and gives a 95% confidence interval for each group estimate.

As a continuous measure, walking distance retains more information about the size of an individual’s change than an endpoint that classifies participants only as improved or not improved. In general, a walking test can provide a standardized way to assess exercise-related functional capacity. Its interpretation depends on how the test is conducted, the population assessed, and how missing measurements are handled. The record does not describe further test procedures or report the distribution of individual changes.

The endpoint is change from baseline, rather than the week-12 distance alone. This focuses the outcome on the difference between the baseline and follow-up measurements for participants included in the analysis. The registry’s ITT description includes randomized participants who received at least 1 dose, and missing values were handled using LOCF. That method carries a prior observation forward when a later value is missing; it does not recover an unobserved week-12 measurement. The registry record does not report additional sensitivity analyses addressing missing data.

The endpoint is a functional measure, not itself a measure of clinical worsening, hospitalization, or death. Those are different kinds of outcomes. The registry lists clinical worsening among the secondary outcomes, but its numerical result is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a continuous measurement, and the registry reports group means for change from baseline. A mean describes the average value in a group, but by itself does not show how widely individual observations vary. The outcome record supplies confidence intervals for the group means rather than a standard deviation or another measure of individual-level spread. Therefore, the posted figures describe uncertainty around estimated means, not the full distribution of participants’ changes.

What does a confidence interval communicate?

In general, a confidence interval is a range produced by a statistical procedure to express uncertainty in an estimate. A 95% confidence interval for a group mean is not a range of likely values for every participant. Under repeated use of the same method and its assumptions, intervals constructed in this way would cover the underlying quantity at the stated rate. The registry reports 95% confidence intervals for the three group means. For the sponsor’s pairwise analyses, it reports 97.5% confidence intervals but only the lower bound for each comparison. The unreported upper bounds prevent full assessment of the reported intervals.

How should the ANOVA comparisons be read?

The registry identifies analysis of variance (ANOVA) as the method for the two reported comparisons. In general, ANOVA is a model-based method for comparing mean outcomes. The reported comparisons are the 1 mg and 20 mg groups and the 5 mg and 20 mg groups. The record calls the estimate a mean difference (net), but does not explain the subtraction order or provide further model details. The posted group means give context, while the reported net difference, confidence interval bound, and p-value belong to the sponsor’s specified analysis. The method’s assumptions and any covariate adjustments are not reported in the registry record.

The sponsor reports p = 0.011 for the 1 mg versus 20 mg comparison and p = 0.545 for the 5 mg versus 20 mg comparison. In general, a p-value measures compatibility between observed data and a null model, conditional on the analysis assumptions. It is not an effect-size measure and does not establish clinical importance. It also does not show the probability that a finding is due to chance. The absence of a reported adjustment for multiple testing matters when interpreting a set of analyses: testing more than one hypothesis can increase the chance that at least one result appears statistically notable under null effects. Whether and how that issue was addressed is not reported in the registry record.

What does the analysis population include?

The primary endpoint population is described as ITT and includes all randomized participants who received at least 1 dose of study medication. This definition differs from an analysis that includes everyone randomized regardless of treatment received. The registry’s wording should therefore be retained when describing the analysis. It does not report the count excluded from this population or the reasons for any exclusions. The analysis population used for the safety figures is given separately through group-specific numbers at risk.

How does LOCF affect interpretation?

The registry says that if a participant had a missing value at any visit, LOCF was used. In general, LOCF replaces a missing later measurement with the participant’s last observed measurement. It creates an analysis value but does not make the missing measurement observed. This approach can be problematic when the outcome changes over time, because the carried-forward value may not represent the participant’s condition at the intended assessment. Whether the method materially affected these estimates cannot be determined from the posted information. Reasons for missing measurements, the amount of missingness by group, and sensitivity analyses using other methods are not reported in the registry record.

What is the role of planning illustrations?

Any sample-size illustrations based on the observed effect are planning exercises, not results about the trial’s achieved power. The stated assumptions for those illustrations are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. Such scenarios can help illustrate how a future study’s planning requirements might vary with the target effect. They do not show that this trial was designed with those assumptions, and the record’s own sample-size justification is not reported in the registry record. No inference about observed power follows from a planning calculation.

The registry entries include 14 analyses and eight outcome measures, but do not identify a prespecified hierarchy, correction strategy, interim analyses, or complete statistical analysis plan. General statistical interpretation should therefore distinguish the displayed estimates from claims about the full analysis process. The registry record also does not report model diagnostics or details of the ANOVA implementation. These omissions limit independent evaluation of assumptions and multiplicity handling.

10. Analyses Reported by the Sponsor

The posted group means for change in six-minute walk distance are 14.21 meters for 1 mg, 40.75 meters for 5 mg, and 38.36 meters for 20 mg. The sponsor’s own ANOVA analysis reports the comparison of 1 mg with 20 mg as a mean difference (net) of 24.15, with a reported 97.5% confidence interval lower bound of 3.37 and p = 0.011. For 5 mg versus 20 mg, it reports a mean difference (net) of -1.17, a lower bound of -21.48, and p = 0.545. In both cases, the upper confidence bound is not reported in the registry record.

The net-difference direction is not explained in the available record, so these estimates should be described using the registry’s own labels rather than assigning a subtraction order. A separate recalculation from posted summary statistics is not listed among the available results. The registry does not flag a discrepancy between a recalculation and the sponsor’s analysis. The sponsor’s reported analyses therefore remain the available inferential results; the group means and their confidence intervals are descriptive estimates, not substitutes for the sponsor’s pairwise model.

The record does not report further details of the ANOVA model, such as covariate adjustments or diagnostic checks. Nor does it state whether the reported p-values were adjusted for the other analyses. These limits matter when assessing how precisely and in what inferential framework the sponsor’s comparisons were made.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists eight outcome measures and 14 analyses. It identifies the primary outcome as change from baseline in six-minute walk distance at week 12 and names seven secondary outcomes. The named secondary outcomes include mean pulmonary arterial pressure, clinical worsening, PAH functional capacity and therapeutic class, B-type natriuretic peptide, pro-BNP, TAPSE, and BORG dyspnoea score. The numerical results for these secondary outcomes are not reported in the registry record in the registry record for these results.

When several outcomes, comparisons, or analyses are examined, the chance of obtaining at least one apparently notable result can increase if each is assessed without accounting for the others. In general, multiplicity procedures can control or otherwise address that issue, while a prespecified testing hierarchy can define which conclusions are confirmatory. The record does not report a multiplicity adjustment, testing hierarchy, or a full statistical analysis plan. It is therefore not possible to tell from the listed p-values whether they were adjusted or how they relate to the full set of analyses. This does not establish that no adjustment was used; the details are not reported in the registry record.

The missing-data approach is specified for the primary endpoint: LOCF was used when a participant had a missing value at any visit. The record does not give the amount or pattern of missingness by group, reasons for missing data, or sensitivity analyses. In general, imputation replaces an unobserved value with an analysis value based on assumptions; it does not eliminate uncertainty about what the missing measurement would have been. The appropriateness of LOCF for these data cannot be assessed fully without details about missingness and the outcome’s course over time.

The primary analysis population is described as randomized participants who received at least 1 dose. This is the registry’s stated ITT definition for the endpoint. The record does not report how many randomized participants were not included in that analysis or why, and it does not give a separate per-protocol or other efficacy population. The exact masking roles, interim analyses, and procedures for handling protocol deviations are also not reported in the registry record.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: right ventricular failure (4.4%), atrial flutter (2.4%), cor pulmonale (2.4%), hepatitis (2.4%), lower respiratory tract infection (2.4%).

The safety figures list group-specific numbers at risk and counts of participants with serious adverse events, other adverse events, and deaths. For serious adverse events, the record lists 6 among 41 at risk in the 1 mg group, 3 among 43 at risk in the 5 mg group, and 5 among 45 at risk in the 20 mg group. For other adverse events, the corresponding counts are 21 among 41, 22 among 43, and 22 among 45. Deaths are listed as 1, 1, and 0, respectively. These figures should be read with their own group-specific denominators; they are not the same as the primary efficacy analysis counts.

The record lists right ventricular failure at 4.4% among the top serious adverse event terms, and atrial flutter, cor pulmonale, hepatitis, lower respiratory tract infection, and pneumonia at 2.4% each. The registry information does not provide enough detail to determine the relationship of each event to study treatment, its timing, or whether a participant experienced more than one event. The event counts do not by themselves establish causation or allow a complete comparison of safety across doses.

In general, adverse-event summaries describe events observed during a study; they do not automatically identify events caused by the study drug. Differences in group denominators and the limited event detail constrain interpretation. The reason for termination and further safety-monitoring details are not reported in the registry record.

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

The results describe a randomized comparison of three sildenafil doses for a continuous functional endpoint. The group mean changes in six-minute walk distance were 14.21 meters for 1 mg, 40.75 meters for 5 mg, and 38.36 meters for 20 mg. The sponsor’s reported comparisons show p = 0.011 for 1 mg versus 20 mg and p = 0.545 for 5 mg versus 20 mg. The latter p-value does not establish that the two doses have equivalent effects; equivalence requires a specific design and analysis framework that is not reported in the registry record.

These values do not, by themselves, determine whether observed differences are clinically important. The record does not supply a threshold for a meaningful change in walking distance, nor does it report enough detail about the upper bounds of the pairwise confidence intervals to characterize their full precision. The group-mean confidence intervals describe uncertainty around average change, not the range of individual responses. A mean can also obscure variation among participants.

The findings concern the endpoint, population, and analysis described in the registry. The endpoint population included randomized participants who received at least 1 dose, and missing values were handled using LOCF. This means interpretation depends in part on the stated population and imputation approach. The record does not report missingness by group or sensitivity analyses to show how alternative missing-data assumptions might affect estimates.

The registry’s stated objective was to demonstrate a dose response, but the posted comparisons alone do not fully establish the shape of a dose-response relationship. The record reports two pairwise sponsor analyses, not a detailed dose-response model or its assumptions. It does not report numerical results for the listed secondary outcomes in the registry record for these results. No conclusion about those outcomes follows from the primary endpoint estimates.

These results are not a complete account of the benefit-risk profile. The safety record gives event counts, but the available information does not establish causality or provide detailed timing and attribution. The trial is marked terminated, and the reason is not reported in the registry record. The available findings should therefore be read as estimates from a specific trial record, not as advice about treatment or a claim about what an individual should expect.

14. Why This Trial Matters Statistically

This trial illustrates why a multi-arm dose comparison requires more than reading a single p-value. The posted data include mean changes and confidence intervals for three doses, while the sponsor’s reported inferential analyses cover two pairwise comparisons. The distinction between group estimates and model-based comparisons is important: the former describe each group’s observed mean change, while the latter address specified contrasts under an analysis model.

The outcome is continuous, so the results retain information about the magnitude of change in walking distance. At the same time, the mean does not show the spread of individual outcomes, and the record gives confidence intervals for group means rather than an individual-level distribution. The incomplete confidence interval reporting for the pairwise comparisons further limits assessment of precision. This makes clear why point estimates, uncertainty intervals, and the analysis method all matter together.

The record also provides a concrete example of the interpretation issues raised by multiple outcomes and comparisons. It lists 14 analyses and eight outcome measures, but does not report a multiplicity strategy or testing hierarchy. That omission does not prove that none was used, but it prevents readers from identifying how the reported p-values fit into the full analysis plan. Similarly, LOCF is specified for missing primary endpoint values, while the extent and pattern of missing data and sensitivity analyses are not reported.

Finally, the study’s terminated status, open-label extension, and group-specific safety denominators are relevant context, but the record does not explain the termination or provide a complete account of later-phase conduct. Reading the efficacy and safety findings with these reporting limits in view helps separate what the registry reports from questions it leaves unanswered.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record leaves several trial-specific details unclear. It marks the study as terminated but does not state why, whether termination affected enrollment or follow-up, or whether the planned analyses were completed as intended. The record lists an open-label extension from week 12 to week 24, but gives little detail about participation or outcomes during that phase. Its results therefore do not provide a basis for describing the extension’s findings.

The primary endpoint analysis uses LOCF for missing values, but the amount, timing, and reasons for missingness are not reported. No sensitivity analyses are listed to show whether conclusions depend on that imputation choice. The analysis population is defined as randomized participants who received at least 1 dose, but the record does not describe exclusions from that population or provide other efficacy populations.

For the sponsor’s pairwise comparisons, only a lower confidence bound is reported, not the full interval. The net-difference direction is not explained in the available description, and details of the ANOVA model are not reported. The record also does not report whether p-values were adjusted for multiple analyses, whether there was a prespecified testing hierarchy, or whether interim analyses occurred. The sample-size justification and full statistical analysis plan are not reported in the registry record.

The safety data provide counts and group-specific numbers at risk but limited information about event timing, treatment attribution, recurrence, or overlap among event terms. The record does not explain why the denominators differ between the efficacy and safety summaries. These limitations do not invalidate the reported figures, but they restrict how far they can be generalized or used to draw conclusions beyond the specific outcomes and analyses recorded.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension. — NCT00430716.
• Registry record last updated 2020-12-22; status last verified 2020-12.
• Results first posted 2011-05-17.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

This phase 4 randomized, parallel-group trial assessed oral sildenafil at 1 mg, 5 mg, and 20 mg three times daily in adults with PAH. The registry lists enrollment of 130, a start date of 2008-04-08, a primary completion date of 2010-05-25, and terminated status. The primary endpoint was change from baseline in six-minute walk distance at week 12.

Reported mean changes were 14.21 meters, 40.75 meters, and 38.36 meters for the 1 mg, 5 mg, and 20 mg groups, respectively. Sponsor analyses report comparisons of 1 mg with 20 mg and 5 mg with 20 mg, with incomplete confidence interval bounds. The primary analysis used an ITT population defined as randomized participants who received at least 1 dose, with LOCF for missing values.

The record lists secondary outcomes and safety counts but does not report numerical secondary outcome results in the registry record for these results. The reason for termination, multiplicity strategy, sample-size justification, full analysis plan, and further details of missing data are not reported in the registry record.