The Efficacy and Safety of Sildenafil Citrate Used in Combination With Intravenous Epoprostenol in PAH: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Efficacy and Safety of Sildenafil Citrate Used in Combination With Intravenous Epoprostenol in PAH (NCT00159861), a randomized phase 3 study. The primary outcome is Categorized Change From Baseline in 6-Minute Walking Distance.

2. Clinical Question

3. Trial Design

This was a Phase 3, randomized, double-blind, parallel-group study described as multinational, multicenter, and placebo-controlled. It evaluated sildenafil citrate used in combination with intravenous epoprostenol for pulmonary arterial hypertension. The registry status is completed, and the recorded enrollment is 267. The study start is listed as 2003-07.

The official title describes subject-optimized sildenafil dosing at 20, 40, or 80 mg three times daily, based on toleration. The posted intervention entry names sildenafil citrate. The registry safety groups include placebo/sildenafil, sildenafil/sildenafil, and placebo/discontinued. Those labels indicate treatment sequences in the safety data, but do not by themselves establish the full treatment history, the timing of any transition, or the analysis population for each outcome.

The primary outcome was categorized change from baseline in 6-minute walking distance. Its timeframe is listed as 1 Year, 2 Year, and 3 Year. The description says walking distance was assessed at a comfortable pace, with breaks permitted as needed, and as close to trough sildenafil levels as possible. The primary outcome population is described as the full analysis set, with the number of participants based on evaluable core-study baseline data. The outcome description also notes that treatment groups are shown according to core-study randomization and that participants who continued into an extension study are included.

Secondary outcomes included survival status, functional capacity and therapeutic class, health-related quality-of-life measures, and BORG dyspnea score. The registry lists 9 outcome measures and 5 analyses, but it does not report the detailed analysis methods or results for these outcomes. Allocation concealment details, the sample-size justification, the planned analysis population definitions beyond the primary outcome description, and any interim analyses are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Subjects were entered into the open-label extension study portion upon completion of the preceding 16-week, placebo controlled core study portion or, for subjects who required a change in epoprostenol dose due to clinical deterioration, after at least 4 weeks in the core study portion.

Core Study - 16 Weeks

Reasons for not completing this period:

Extension Study - up to 3 Years

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: FAS. m = meters. N=number of subjects with evaluable data at core study Baseline. Treatment groups shown by core study randomization; includes subjects who were only treated in the core study and those who continued into the extension 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 Categorized Change From Baseline in 6-Minute Walking Distance, measured over 1 Year, 2 Year, 3 Year.

The primary endpoint counts participants according to categorized change from baseline in 6-minute walking distance. The walking test measures the distance a participant can cover in 6 minutes at a comfortable pace, with as many breaks as needed. The registry describes testing as close to trough sildenafil levels as possible, just before dosing and at least 4 hours after the previous study-drug dose.

Walking distance is a functional measure: it summarizes performance during a standardized period of walking rather than relying only on symptoms or a laboratory measurement. Categorizing change can make the outcome easier to present as counts in groups of change. However, categories discard some detail in the original distance measurements, and interpretation depends on the category boundaries and labels. Those definitions are not reported in the registry record.

The outcome is listed at 1 Year, 2 Year, and 3 Year. The description states that missing-visit categories were imputed as the worse score of non-missing neighboring visits; if a visit was missing with no subsequent score, it was coded as missing. This is a particular handling rule for some missing measurements, not a complete account of all missing-data procedures. The registry does not report category counts by randomized group, the treatment contrast, or its precision. Therefore, the endpoint definition can be described, but the comparative result cannot be reconstructed from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry gives the design label and endpoint description, but does not report the statistical analysis plan in enough detail to identify the method used for the primary comparison. In particular, it does not state whether the categories were analyzed using a model, a contingency-table test, or another approach. The registry lists 5 analyses, but does not specify the corresponding model terms, test procedures, or multiplicity adjustments. The following concepts are general statistical explanations, not claims about methods used in this trial.

What does a categorized outcome retain?

General: categorizing a continuous measurement converts individual values into ordered or named groups. This can simplify communication and may focus attention on meaningful levels of change. It also removes information about how far apart measurements are within a category. For example, two participants in the same category can have different underlying changes. The category boundaries matter because they determine which participants are counted together. The registry names the endpoint as categorized change but does not report the category definitions or labels.

For an outcome with several categories, an analysis can compare the full distribution across treatment groups or focus on a prespecified contrast. These choices answer different questions. A distributional comparison asks whether the pattern of category counts differs overall; a contrast focused on one category or a threshold asks a narrower question. The registry record does not state which interpretation was primary in the statistical analysis. Nor does it report the category counts needed to examine the distribution directly.

Why do the time points matter?

General: measurements repeated over time are related because observations from the same participant are not usually independent. Analyses of repeated outcomes can account for that relationship, or can analyze time points separately, but the choice affects the estimand and uncertainty. Separate testing at multiple times also raises a multiplicity issue: the more comparisons considered, the greater the chance of at least one apparently unusual result under a null model if no adjustment or prespecified strategy is used. This is a general consideration, not evidence that any particular analysis was or was not adjusted in this trial.

The primary endpoint timeframe lists 1 Year, 2 Year, and 3 Year. The registry does not identify a single primary time point, say whether all times were co-primary, or describe how conclusions across times were to be combined. It also does not report whether the 5 listed analyses relate to these time points, other outcomes, or another analysis structure. Without those details, the multiplicity implications cannot be resolved.

What does a confidence interval contribute?

General: a confidence interval presents uncertainty around an estimate using a procedure with specified coverage properties under its assumptions. Its width reflects the information and variability relevant to that analysis. A narrow interval indicates greater precision than a wide interval for the same kind of estimate; neither width nor statistical significance alone determines clinical importance. The registry record does not report a primary treatment-effect estimate or confidence interval, so precision cannot be assessed for the main outcome.

General: a p-value is calculated relative to a null hypothesis and an analysis model. It is not the probability that the null hypothesis is true, and it does not indicate the magnitude of an effect. A p-value without an effect estimate and uncertainty interval gives an incomplete account of the data. No primary-outcome p-value is reported in the registry record.

How should planning calculations be read?

The stated sample-size assumptions describe a planning illustration computed from the observed effect, rather than the trial's own design: a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation, with the effect to detect defined as a stated fraction of the observed effect. For time-to-event tables, the assumption describes the total number of events; for other outcomes, it describes participants per arm. Such calculations are planning illustrations, not observed power and not evidence that the study was designed around those assumptions. The registry does not report the trial's sample-size justification. The primary endpoint is categorized and repeated across time points, so a planning calculation also depends on the chosen contrast and analysis assumptions; those details are not reported in the registry record.

General: over-dispersion occurs when variability in count data exceeds what a chosen model assumes. If ignored, standard errors and uncertainty estimates can be inaccurate. This is relevant as a general concern for some count outcomes, but the primary endpoint is described as counts of participants within change categories, and the record does not identify a count model. It would be inappropriate to claim that over-dispersion was present or that a particular adjustment was used.

10. Multiplicity, Missing Data and Analysis Populations

The primary endpoint is reported across 1 Year, 2 Year, and 3 Year, and it includes multiple categories of change. This creates potential multiplicity because several comparisons may be possible. The registry does not identify the primary contrast, specify whether the time points were tested separately, or report a procedure for controlling the family-wise error rate or another multiplicity strategy. Although 5 analyses are listed, the record does not explain their relationship to the primary outcome or to each other. The presence or absence of an adjustment cannot be inferred.

The endpoint description does report a rule for some missing visits: a missing visit was assigned the worse score of its non-missing neighbors; if there was no subsequent score, the score was coded as missing. This tells readers how certain missing measurements were categorized, but does not establish how all missing data were handled in the analyses. The registry does not report missingness by group or time point, the number of participants included in each analysis, or any sensitivity analysis assessing the consequences of missing data.

The primary population is described as the full analysis set, with the number of participants based on evaluable core-study baseline data. Treatment groups are shown by core-study randomization, and the description includes participants who continued into an extension study. The exact analysis population definitions, exclusions, and denominators at each time point are not reported in the registry record. As a result, readers cannot establish from the record whether the primary analysis included all randomized participants or how participants with incomplete follow-up contributed.

11. 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.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pulmonary hypertension (16.4%), right ventricular failure (13.9%), catheter related infection (13.0%), catheter related complication (12.2%), dyspnoea (10.4%).

The safety record separates serious-event affected counts from other-event affected counts for three treatment-sequence groups. For placebo/sildenafil, the serious-event count is 93 among 115 at risk, and the other-event count is 115 among 115 at risk. For sildenafil/sildenafil, the serious-event count is 104 among 134 at risk, and the other-event count is 134 among 134 at risk. For placebo/discontinued, the serious-event count is 7 among 16 at risk, and the other-event count is 15 among 16 at risk. These are the posted counts; they should not be treated as a randomized comparison of treatment effects.

The record lists pulmonary hypertension at 16.4%, right ventricular failure at 13.9%, catheter related infection at 13.0%, catheter related complication at 12.2%, dyspnoea at 10.4%, and central line infection at 9.7% among the top serious-event terms. The record does not provide the denominators or group-specific breakdown for these percentages, so they cannot be used to compare risks between groups. Death counts are not reported for the listed groups. General: safety counts describe observed events in the recorded groups; interpretation of comparative risk also depends on follow-up, event definitions, and the analysis population.

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

The record establishes that a randomized, double-blind, parallel-group study assessed sildenafil citrate in combination with intravenous epoprostenol in pulmonary arterial hypertension. It identifies categorized change in 6-minute walking distance as the primary outcome and gives the measurement timeframe and some assessment and missing-visit details. It also lists secondary outcomes and descriptive safety counts. These registry entries describe the study question and data structure, not the comparative outcome.

The registry record does not report the primary category counts by treatment group, a treatment-effect estimate, a confidence interval, or a p-value. It therefore does not show whether the groups differed, in which direction any difference lay, how large it was, or how precisely it was estimated. An objective to assess efficacy and safety is not itself evidence of a favorable or unfavorable result. No treatment recommendation or conclusion about benefit or harm can be drawn from the outcome description alone.

The safety counts and serious-event terms are likewise descriptive. Without complete denominators, follow-up information, group-specific event details for the listed terms, and a defined comparative analysis, they do not establish that one treatment sequence had greater or lesser risk. The registry's completed status indicates that the study is recorded as completed; it does not supply the missing outcome results.

General: statistical evidence is strongest when the outcome definition, analysis population, estimate, and uncertainty are considered together. A count without its analysis context can be difficult to compare, while a test result alone can hide the size and precision of an effect. The information in the registry is sufficient to identify the central endpoint and several important design features, but not sufficient to determine the trial's primary comparative finding.

13. Why This Trial Matters Statistically

This study raises several important statistical issues common to clinical trials. Its primary outcome is a categorized change in a functional measure, reported at multiple time points. Interpretation requires knowing how the categories were defined, which time point or contrast was primary, and how repeated measurements and multiple comparisons were handled. The registry identifies the outcome and timeframes but does not provide those analysis details or results.

The outcome description also makes the analysis population and follow-up structure important. It refers to evaluable baseline data in the core study and includes participants who continued into an extension, while treatment groups are classified by core-study randomization. These choices can affect what a reported count represents. The stated handling rule for certain missing visits is informative, but readers still need group- and time-specific missingness and the complete analysis strategy to assess the robustness of conclusions.

Finally, the safety record illustrates why descriptive event counts are not automatically comparative evidence. Counts need clear denominators and a defined analysis context, and serious-event terms may not be directly comparable without group-level information and follow-up details. The registry gives selected safety counts and percentages, but not enough detail for a comparative risk analysis.

These issues matter because statistical interpretation depends on more than the study design label or the outcome name. Estimates, uncertainty, prespecified contrasts, population definitions, and missing-data handling all contribute to an accountable reading of trial evidence. The record documents meaningful design and measurement features, while leaving the central efficacy comparison and several key statistical decisions not reported.

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 main limitation for interpreting this trial from the registry record is the absence of primary-outcome results. No category counts by randomized group, treatment-effect estimate, confidence interval, or p-value are reported. The category definitions and labels are also absent, limiting the ability to understand what each outcome count would represent.

The endpoint is listed at 1 Year, 2 Year, and 3 Year, but the registry does not say whether a particular time point was primary, how repeated observations were analyzed, or how multiplicity was addressed. It lists 5 analyses without describing the methods. The statistical analysis plan, sample-size justification, and interim-analysis information are not reported in the registry record.

The primary population description refers to evaluable core-study baseline data and includes participants who continued into an extension, but the record does not provide analysis denominators at each time point or a complete account of exclusions. The stated missing-visit rule addresses some situations, but the extent and pattern of missing data and any sensitivity analyses are not reported.

Safety interpretation is limited by missing details about follow-up and by the absence of group-specific denominators for the listed serious-event terms. Death counts are not reported. The listed safety groups include a discontinued-treatment group, but the record does not fully explain how treatment exposure and follow-up were defined for each safety analysis. These limitations do not establish that the analyses were flawed; they mean the registry entry alone does not contain enough information to assess them.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: The Efficacy and Safety of Sildenafil Citrate Used in Combination With Intravenous Epoprostenol in PAH — NCT00159861.
• Registry record last updated 2021-02-01; status last verified 2021-01.
• Results first posted 2011-01-12.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The registry describes a completed Phase 3 randomized, double-blind, parallel-group study of sildenafil citrate used with intravenous epoprostenol for pulmonary arterial hypertension. Enrollment is recorded as 267, and the study start is listed as 2003-07. The primary outcome is categorized change from baseline in 6-minute walking distance at 1 Year, 2 Year, and 3 Year.

The outcome description specifies walking-test conditions, the full analysis set, core-study randomization groups, extension participants, and a rule for some missing visits. Secondary outcomes include survival, functional capacity and therapeutic class, quality of life, and dyspnea. The safety information gives affected counts for three treatment-sequence groups and percentages for selected serious-event terms.

The primary comparative results, analysis methods, category definitions, uncertainty estimates, and detailed multiplicity and missing-data procedures are not reported in the registry record. Accordingly, the record describes the trial and its outcome framework but does not establish the primary treatment comparison.