Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension (NCT00323297), a randomized phase 4 study. The primary outcome is Change From Baseline in the Total Distance Walked During 6 Minute Walk Time (6MWT) at Week 12.

2. Clinical Question

The question concerns an add-on comparison: the trial was not described as comparing sildenafil alone with bosentan alone. Both groups received bosentan, with sildenafil or placebo as the added study treatment. The listed primary endpoint measures change in walking distance, rather than a direct measure of survival or a clinical-worsening event. The registry also lists secondary outcomes concerning functional class, clinical worsening, Borg Dyspnea Score, and one-year survival. Those listings identify additional topics of interest, but do not establish what was observed for them. In particular, results for the primary walking-distance comparison are not reported in the registry record, so the direction, size, and precision of any difference cannot be described from this record.

3. Trial Design

This was a randomized, parallel-group, phase 4 study. The official title describes a multinational, multicentre, double-blind trial of oral sildenafil 20mg Tid or placebo added to bosentan in people aged 18 years and above with PAH. The registry classifies masking as quadruple. It does not identify the four masked roles, so the exact masking arrangement is not reported in the registry record. The study status is completed, with enrollment of 105 participants. The recorded start is 2006-09, and primary completion is 2013-08.

The intended contrast is sildenafil added to background bosentan versus placebo added to background bosentan. Randomization supports a comparison between assigned groups by aiming to balance participant characteristics across treatment assignments. In general, masking is intended to reduce the influence of treatment knowledge on care, reporting, or assessment; the particular safeguards and roles used in this trial are not reported in the registry record. The record calls the model parallel, meaning participants were assigned to a group that received its allocated study treatment rather than being described as crossing between treatments.

The primary endpoint is change from baseline in total distance walked during the 6MWT at Week 12, measured in meters. The endpoint description says participants walked at a comfortable pace, could take as many breaks as needed, and had continuous pulse oximetry during the test for safety. The analysis population is described as the ITT Population (Full Analysis Set), consisting of participants randomly assigned to study drug who received at least one dose. Missing values were replaced using last observation carried forward (LOCF). Further eligibility criteria, treatment duration beyond the stated endpoint, allocation ratio, concealment procedures, and detailed analysis methods 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: Participants were on bosentan therapy for 3 months prior. Participants were randomized to sildenafil or placebo. Part A study was double-blind phase (12 weeks) and Part B was 12 months open-label phase. 53 and 51 participants were randomized to placebo and sildenafil arm respectively. One participant in sildenafil arm did not receive any treatment

Part A (Double Blind Randomized)

Reasons for not completing this period:

Part B (Open-label)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-Treat (ITT) Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward (LOCF) approach. Statistical analysis was carried out on LOCF values.

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 Time (6MWT) at Week 12, measured over Week 12.

The primary endpoint is change from baseline in the total distance walked during the 6 Minute Walk Test at Week 12, expressed in meters. The test records how far a participant can walk during a defined period. The registry description says participants were asked to walk at a pace comfortable to them and could take as many breaks as needed. Continuous pulse oximetry was conducted during the test for safety.

Walking distance is a continuous measure: it can take a range of numerical values rather than placing participants into only a few categories. Change from baseline focuses on how the measured distance at follow-up differs from a participant’s starting measurement. In general, a continuous endpoint can describe both the direction and magnitude of change, and an average can summarize the group’s measured changes. How meaningful an observed change is depends on its size, its uncertainty, and the clinical context; none of those can be assessed from an endpoint definition alone.

The record names the mean and standard deviation as the summary type, but arm-level endpoint values and a between-group estimate are not reported in the registry record. Therefore, the record does not establish whether the groups differed in average change, how precise an estimate was, or how much participants’ responses varied. The endpoint description explains what was measured; it is not itself a result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The trial is classified as randomized and parallel-group. In general, random assignment is used to reduce systematic differences between groups at the point of allocation. The registry does not report the randomization sequence method, allocation concealment procedure, or allocation ratio. Those details are therefore not reported in the registry record. The parallel model indicates that the study is organized around distinct assigned groups; the listed comparison is sildenafil or placebo added to bosentan.

What does the endpoint summary describe?

The primary endpoint is continuous: change from baseline in 6MWT distance at Week 12, measured in meters. The registry names the mean as the summary measure and the standard deviation as the dispersion measure. In general, the mean describes the central average of observed values, while the standard deviation describes how dispersed individual values are around that average. These are different quantities: a standard deviation reflects variability among observations and is not, by itself, the uncertainty around a treatment-effect estimate.

To interpret a randomized comparison, the group-level summaries are not enough unless the treatment contrast and its uncertainty are also available. In general, a contrast expresses the estimated difference between groups, while a confidence interval conveys uncertainty around that estimate under the analysis model. Neither the contrast nor its interval is reported for the primary endpoint in the registry record. No endpoint means or standard deviations are reported either, so the result cannot be reconstructed from the endpoint definition.

How should significance tests be understood?

In general, a significance test evaluates how compatible the observed data are with a stated null hypothesis under specified assumptions. A p-value is not the probability that the null hypothesis is true, and it does not quantify the magnitude or clinical importance of a difference. The registry record does not report a primary endpoint p-value or identify the test used. It also does not report whether the primary analysis was adjusted for baseline values or other factors. No particular test or adjustment should be inferred.

The record states that missing values were replaced using last observation carried forward (LOCF). In general, LOCF carries a participant’s last recorded value forward to a later assessment when the later value is missing. This approach makes assumptions about what the unobserved later value would have been. If participants’ measurements would have changed after their last observation, carrying the earlier value forward may not represent that unobserved outcome. The record does not give the amount or pattern of missing data, the reasons for missingness, sensitivity analyses, or further details of the imputation procedure. The effect of LOCF on the reported comparison therefore cannot be assessed.

The analysis population is called the ITT Population (Full Analysis Set), but its operational definition is participants who were randomized and received at least one dose of study medication. In general, an intention-to-treat analysis is understood to preserve randomized assignment in the comparison, while actual analysis populations can be defined differently across protocols. The registry definition and label should be read together; the record does not describe how participants who did not receive a dose were handled, or whether additional analysis populations were used.

What can be inferred about planning and power?

In general, a sample-size calculation depends on assumptions about the target effect, variability, significance level, power, and allocation. The record describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation; it specifies that the effect to detect is a stated fraction of the observed effect. Such illustrations are not the trial’s original design justification, and sample-size planning figures are not observed power. The original sample-size justification and the trial’s own planning assumptions are not reported in the registry record. Because the primary effect estimate is not reported in the registry record, the illustrations cannot be interpreted as a substitute for the trial’s results.

In general, over-dispersion means observed variation is greater than a model assumes. If present, it can make standard errors and tests based on a simpler variance assumption misleading. The registry record does not identify an over-dispersion issue or a model requiring that adjustment, so it is not appropriate to assert that one occurred. More broadly, the complete statistical analysis plan, model specifications, interim analyses, multiplicity procedure, and prespecified handling of protocol deviations are not reported in the registry record. These absent details limit appraisal of how the results were intended to be analyzed, but they do not justify guessing what methods were used.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists several secondary outcomes alongside the primary 6MWT endpoint. They include change in WHO Functional Class at Week 12, clinical worsening events, change in Borg Dyspnea Score at Week 12, and one-year survival measures. Considering multiple outcomes can create a multiplicity issue: in general, the more statistical tests performed, the greater the chance that at least one result appears noteworthy by chance if no adjustment or prespecified interpretation is used. The registry record does not report a multiplicity adjustment, a hierarchy among endpoints, or a complete statistical analysis plan. It is therefore not possible to determine how the trial controlled or interpreted multiple comparisons.

The record notes that the primary outcome has several categories or time points and was not reduced to one comparison. The specific categories or time points, and how they relate to the primary analysis, are not reported in the registry record. The primary endpoint is named, but there is no reported group estimate or single comparison from which to explain a result.

For missing data, the record states that missing values were replaced by LOCF. It does not report how many values were missing, when they were missing, why they were missing, or whether the amount differed between groups. It also does not describe sensitivity analyses that might test how conclusions depend on the missing-data approach. As a general principle, missing-data methods rely on assumptions about unobserved values; those assumptions can affect an estimate and its uncertainty.

The stated analysis population includes randomized participants who received at least one dose. The record does not describe exclusions after randomization, adherence to assigned treatment, or analyses using other populations. The detailed statistical plan and the handling of these issues are not reported in the registry record. Accordingly, neither multiplicity control nor the robustness of the missing-data and population choices can be evaluated from the available information.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pulmonary arterial hypertension (11.3%), right ventricular failure (6.0%), bronchopneumonia (4.0%), dyspnoea (4.0%), anaemia (3.8%).

The registry reports safety counts separately for serious adverse events and other adverse events. In the placebo group, 53 participants were at risk for each category; 23 were affected by serious adverse events and 38 by other adverse events. In the sildenafil group, 50 participants were at risk for each category; 22 were affected by serious adverse events and 33 by other adverse events. These are counts of affected participants, not event rates adjusted for time at risk. The registry record does not report exposure time or definitions that would support a more detailed rate comparison.

The listed leading serious adverse-event terms are pulmonary arterial hypertension (11.3%), right ventricular failure (6.0%), bronchopneumonia (4.0%), dyspnoea (4.0%), anaemia (3.8%), and abdominal pain (3.8%). The denominator and group attribution for these percentages are not reported in the registry record, so they should not be assigned to a particular treatment group or treated as group-specific rates.

The death counts are not reported in the registry record. The safety counts alone do not establish that a treatment caused an event or that groups differ in risk. Event timing, severity details, exposure-adjusted analyses, and a fuller account of adverse events are not reported in the registry record. These figures describe the posted safety information, not a complete safety comparison.

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

The record establishes the trial’s question and broad design: a randomized, parallel-group, phase 4 comparison of sildenafil or placebo added to bosentan in people with PAH. It specifies a primary endpoint of change in 6MWT distance at Week 12 and describes the analysis population and LOCF handling. It also reports selected safety counts and serious adverse-event terms. These registry entries describe what the study was intended to evaluate and some of the recorded safety information.

The record does not report the primary endpoint results or a treatment-effect estimate. It therefore does not show how the groups’ average walking-distance changes compared, how large any difference was, or how precisely it was estimated. No conclusion about statistical significance or clinical importance can be drawn from the endpoint title or study design. The secondary outcome names likewise do not establish their results.

In general, a trial’s interpretation depends not only on its design, but also on observed estimates, uncertainty, analysis choices, missing-data patterns, and outcome definitions. Here, important result details and analysis-plan details are not reported in the registry record. The listed safety counts can be read as counts of participants affected in the reported groups, but without event definitions, timing, exposure information, and attribution details they do not provide a complete comparative safety assessment.

These limitations do not imply that the trial found no difference or that an effect was absent. They mean that the posted record, as described, does not permit the primary comparison to be quantified or interpreted. The record also does not support a treatment recommendation. It supports a careful account of the study design, endpoint, analysis population, missing-value approach, and selected safety data, with substantial uncertainty about the unreported efficacy results and statistical methods.

13. Why This Trial Matters Statistically

This trial raises a familiar statistical question in add-on treatment studies: what is the contrast when both groups receive a background therapy and only the added study treatment differs? Here, the planned comparison is sildenafil added to bosentan versus placebo added to bosentan. Keeping that contrast clear matters because the study is not described as a comparison of sildenafil alone with bosentan alone. The registry’s arm descriptions are empty, so details beyond the named interventions are not reported in the registry record.

The primary endpoint also illustrates the distinction between a prespecified measurement and an interpretable result. A continuous outcome such as change in 6MWT distance can be summarized by group averages and variability, but a reader needs the between-group estimate and its uncertainty to understand the comparison. Those primary results are not reported in the registry record. Without them, a randomized design alone cannot answer whether the groups’ measured changes differed or how precise such an estimate was.

Missing-data handling is another important statistical feature. LOCF is stated as the approach, but the amount and pattern of missingness and any sensitivity analyses are not reported. In general, an imputation method can influence estimates when outcomes after dropout are not observed, so transparency about the missingness and assumptions is important.

Finally, the record lists several secondary outcomes but does not report the multiplicity strategy or their results. This leaves uncertainty about how outcomes were prioritized and interpreted. Statistically, the case underscores why registry entries about endpoint results, analysis plans, and missing data are needed alongside design information. The information recorded identifies what was asked, but does not provide enough to estimate the primary treatment contrast.

14. Limitations

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

The principal limitation is that the primary endpoint’s results are not reported in the registry record. The record names change from baseline in 6MWT distance at Week 12 and identifies mean and standard deviation summaries, but provides no group values, treatment contrast, confidence interval, or p-value. The direction, magnitude, and precision of the primary comparison therefore cannot be assessed.

Analysis reporting is incomplete. The description of the ITT Population ends after beginning to introduce the statistical analysis, and the detailed analysis method is not reported in the registry record. Randomization sequence generation, allocation concealment, allocation ratio, prespecified covariate adjustment, interim analyses, and the complete analysis plan are also not reported. The specific roles covered by quadruple masking are not stated.

Missing data were handled using LOCF, but the number of missing observations, reasons for missingness, distribution across groups, and sensitivity analyses are not reported. The registry’s operational analysis population includes randomized participants who received at least one dose; how participants outside that definition were handled is not reported. The record also says the primary outcome has several categories or time points and was not reduced to one comparison, without identifying those categories or explaining the analysis.

Safety reporting is limited to selected counts and listed serious adverse-event terms. Death counts, event timing, exposure duration, definitions, and denominator details for the serious-event percentages are not reported in the registry record. These limitations restrict both efficacy interpretation and comprehensive safety comparison.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension — NCT00323297.
• Registry record last updated 2021-02-01; status last verified 2021-01.
• Results first posted 2013-11-19.
• 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 record describes a completed, randomized, parallel-group phase 4 study enrolling 105 participants with PAH. The official title specifies oral sildenafil 20mg Tid or placebo added to bosentan in adults aged 18 years and above. The primary endpoint is change from baseline in 6MWT distance at Week 12. The stated analysis population includes randomized participants who received at least one dose, and missing values were handled using LOCF.

Primary endpoint estimates and detailed statistical methods are not reported in the registry record. Several secondary outcomes are listed without results in the registry entries. Safety information includes counts of participants affected by serious and other adverse events and leading serious-event terms; deaths are not reported in the registry record. The record supports description of the study design and selected safety data, but not a quantified conclusion about the primary treatment comparison.