Study of Ambrisentan in Participants With Pulmonary Hypertension: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Ambrisentan in Participants With Pulmonary Hypertension (NCT00777920), a na phase 3 study. The primary outcome is Percentage of Participants With Adverse Events (AEs) Associated With Long-Term Exposure to Ambrisentan.

2. Clinical Question

In practical terms, this study describes adverse events observed during ambrisentan exposure in its enrolled population. Because it was open-label and single-group, the study can characterize events recorded during treatment but cannot, by design, isolate the effect of ambrisentan from the underlying condition, background therapies, or other factors. The registry record reports serious adverse-event counts and selected serious-event terms, but it does not establish that every event was caused by ambrisentan.

3. Trial Design

This was a phase 3, long-term, open-label, multicenter safety study sponsored by Gilead Sciences. The registry lists the study as completed, with a start date of 2008-11-17 and primary completion on 2019-09-11. Enrollment was 140. The design is identified as single-group; allocation is listed as NA, and masking as none. There is no randomized or masked comparator in the record.

Participants received ambrisentan orally once daily at 2.5 mg, 5 mg, or 10 mg. Investigators could adjust the dose as clinically indicated, observing a minimum interval of 4 weeks between dose adjustments. Participants receiving other pulmonary hypertension therapies could enroll and continue those therapies if they were not contraindicated for concomitant use with ambrisentan. Thus, the study describes safety in a setting that could include ongoing background treatment, rather than a comparison of ambrisentan alone against another assigned regimen.

Treatment was intended to continue until the participant or investigator chose to stop ambrisentan, ambrisentan became commercially available, or the sponsor stopped the study. The primary outcome timeframe runs from the first dose through the last dose plus 30 days, with a maximum duration described as approximately 550 weeks. This is a follow-up window, not a statement that every participant received treatment or follow-up for that entire period. Individual exposure and follow-up durations are not reported in the registry record.

The safety analysis set included enrolled participants who received at least one dose of study drug. The record gives adverse-event summaries for the ambrisentan group, including participants with serious and other adverse events and selected serious-event terms. It does not report a formal inferential analysis, an adjusted estimate, or a between-group treatment effect. The registry record also does not describe the rationale for the enrollment target or a detailed statistical analysis plan.

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: 140 participants were screened.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Safety Analysis Set included participants who were enrolled into the study and received at least one dose of study drug.

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.

Population: The Safety Analysis Set included participants who were enrolled into the study and received at least one dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Adverse Events (AEs) Associated With Long-Term Exposure to Ambrisentan, measured over First dose date of study drug up to the date of last dose plus 30 days (Maximum: approximately 550 weeks).

The primary endpoint is the percentage of participants with adverse events associated with long-term exposure to ambrisentan. The observation window begins on the first dose date and extends through the date of the last dose plus 30 days; the maximum timeframe is approximately 550 weeks. The safety analysis set comprises enrolled participants who received at least one dose.

A participant-level percentage is a way to describe how many people in the defined safety population experienced an event during the specified observation window. It differs from an event count: one participant could experience more than one event, while a participant-level measure generally classifies whether each person experienced an event. The registry record identifies the outcome as a percentage of participants, but it does not provide a numerical value for the primary endpoint. It therefore does not support a precise estimate of that primary percentage from the record alone.

Safety endpoints are used to characterize events that occur during treatment and follow-up. Such monitoring is particularly relevant in a long-term study because exposure can continue for variable periods. However, an event observed after treatment begins is not automatically caused by the study drug. The endpoint title refers to events associated with exposure, but the record does not give the criteria used to determine association or report a drug-attribution breakdown for the primary outcome.

The endpoint also does not, by itself, quantify event timing, recurrence, severity beyond any separately specified classifications, or risk relative to an untreated or alternative-treatment group. Those questions require additional definitions and analyses, which are not reported in the registry record. The posted counts and selected serious-event terms should therefore be read as descriptive safety information, not as a comparative estimate of treatment effect.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation starts with the study design and the question the endpoint can answer. This study is listed as single-group, open-label, and unmasked. Its safety summaries describe participants who received ambrisentan, rather than comparing randomized groups. General statistical principle: a comparison requires a suitable reference group and an analysis designed to account for how participants entered each group. Without that framework, the observed event frequency is descriptive and cannot identify the treatment’s causal contribution.

What does a participant percentage represent?

The primary outcome is expressed as a percentage of participants with adverse events over a defined exposure-related timeframe. In general, a participant-level percentage counts people who meet an event definition, rather than counting every occurrence of the event. This distinction matters if a person experiences recurrent events: the participant-level summary and the total number of events answer different questions. The registry record does not provide the primary percentage or explain the event-association criteria, so the primary measure cannot be independently interpreted as a numerical estimate from this record.

The listed safety summaries report 80 participants with serious adverse events and 112 with other adverse events, with 140 at risk for each listing. Those are counts, not an adjusted risk estimate or a rate per unit of exposure. The record also reports 39 deaths. These values should not be combined or treated as mutually exclusive categories: the record does not state that the categories are mutually exclusive, and participants may have different event experiences. No additional totals should be inferred from them.

Why does the observation window matter?

The endpoint timeframe begins with the first dose and ends at the last dose plus 30 days, with a maximum of approximately 550 weeks. General statistical principle: a longer observation window creates more opportunity to detect events, while differences in observation time between participants can affect simple counts and percentages. Time-to-event methods or rates using person-time can address some questions about unequal follow-up, but the registry record does not report such analyses. It also does not provide individual exposure durations, event dates, or censoring details. Therefore, the listed counts cannot be interpreted as rates that account for how long each participant was followed.

The 30-day period after the last dose is part of the stated endpoint window. It sets the boundary for which events are included in the endpoint definition; it does not itself establish that an event was caused by treatment. The registry record does not report how events outside that interval were handled or whether additional safety follow-up was conducted.

What can confidence intervals and tests add?

General statistical explanation: a confidence interval conveys the uncertainty of an estimate under a specified statistical model. A narrower interval generally indicates greater precision, while a wider interval indicates less precision. A hypothesis test addresses compatibility between observed data and a stated null hypothesis under its assumptions. Neither measure establishes causality, and statistical significance is not a measure of clinical importance. The registry record reports no confidence interval, hypothesis test, or numerical primary endpoint estimate, so no such inference can be made from the reported summary.

In a single-group safety study, a confidence interval around an event percentage could describe sampling uncertainty in that group, if the estimate and method were reported. It would not provide a treatment-versus-control contrast. A causal comparison would require a suitable comparator and assumptions about comparability, as well as an analysis of the contrast. The study design listed in the registry does not supply that comparison.

How should the serious-event terms be read?

The record lists selected serious adverse-event terms with percentages: right ventricular failure (9.3%), pneumonia (8.6%), pulmonary hypertension (8.6%), atrial fibrillation (4.3%), chronic obstructive pulmonary disease (4.3%), and cardiac failure congestive (3.6%). In general, term-level summaries depend on how events are coded and whether a participant can appear under multiple terms. The registry record does not state those details in the information available. The percentages should therefore be read as term-specific descriptive figures, not added together or treated as a single overall rate.

General statistical principle: over-dispersion occurs when variation in event counts exceeds what a simple model assumes. It can arise, for example, when events cluster in some participants or when risk varies across the population. Models that account for over-dispersion may be useful for some count outcomes, but no count model, dispersion estimate, or related analysis is reported in the registry record. It would be inappropriate to imply that such a method was used.

What does the planning illustration mean?

The planning assumptions describe illustrations based on an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The target effect is framed as a stated fraction of the observed effect. General explanation: a planning calculation estimates the sample size that a hypothetical design might require under its assumptions. It is not a measure of power observed after a study is completed, and it does not establish that the actual study was designed with those assumptions. Here, the actual registry design is single-group, and the registry record does not report its sample-size justification or the detailed statistical plan.

Because the study has no control arm, a hypothetical two-arm planning illustration does not describe the study’s observed design. No calculated planning values are included in the registry record, so no sample-size figures or implied power can be stated. The record also reports no formal analyses, with the number of analyses listed as zero. This means that the registry record does not present inferential analysis results to support an estimate of comparative efficacy or safety.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Ambrisentan")
n      <- c(140)
events <- c(127)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Ambrisentan  140  127  90.7  84.6  95.0  84.8  94.5  84.7  94.5

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists one outcome measure and zero analyses. It does not report a multiplicity strategy, such as a hierarchy for multiple outcomes or an adjustment for repeated testing. With no formal analyses reported, there is no basis to describe how multiple statistical comparisons were controlled. The selected serious-event terms are descriptive listings; the record does not report inferential tests for them.

Missing-data methods are not reported in the registry record. The safety analysis set is defined as enrolled participants who received at least one dose of study drug, but the record does not state how incomplete follow-up, missing event information, withdrawal, or loss to follow-up was handled. It also does not describe imputation, sensitivity analyses, or the handling of participants with differing lengths of exposure. These omissions limit assessment of whether the reported summaries represent complete safety follow-up for all eligible participants.

The stated safety analysis population is based on receiving at least one dose. The registry does not report a separate analysis population, exclusions after enrollment, or a detailed accounting of who contributed to each endpoint summary. The displayed at-risk counts are 140 for serious adverse events and 140 for other adverse events, but the record does not provide further detail about missing observations or endpoint-specific denominators.

These are reporting limitations, not evidence that missing data or multiplicity necessarily changed the results. Without the methods, analysis details, and primary endpoint value, readers cannot assess the extent to which these issues affected the estimates. The record also does not report interim analyses or stopping rules; their presence or absence should not be inferred.

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 5% 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 (9.3%), pneumonia (8.6%), pulmonary hypertension (8.6%), atrial fibrillation (4.3%), chronic obstructive pulmonary disease (4.3%).

The adverse-event summary records 80 participants with serious adverse events among 140 at risk, and 112 participants with other adverse events among 140 at risk. It also lists 39 deaths. These are descriptive counts in the ambrisentan study group. The registry record does not provide a control group, a comparative risk estimate, or enough detail to determine whether each event was considered related to ambrisentan. The counts should not be interpreted as treatment-attributable effects.

The listed serious-event terms and percentages are right ventricular failure (9.3%), pneumonia (8.6%), pulmonary hypertension (8.6%), atrial fibrillation (4.3%), chronic obstructive pulmonary disease (4.3%), and cardiac failure congestive (3.6%). Each percentage describes a reported term; the record does not explain whether terms overlap within participants or provide full coding and attribution details. The percentages should not be added together to form an overall serious-event percentage.

Deaths are listed as a count, but the registry record does not report their causes or whether they were judged related to study treatment. Serious adverse events, other adverse events, and deaths are different summaries and should not be assumed to be exclusive categories. The available information supports a description of safety events recorded during the study, not a causal conclusion about ambrisentan.

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

The record establishes that a long-term, open-label, single-group safety study of ambrisentan was completed in adults with pulmonary hypertension. It describes an oral daily regimen at 2.5 mg, 5 mg, or 10 mg, with investigator-directed dose adjustment and the possibility of continuing permitted background therapies. It also reports serious and other adverse-event counts, deaths, and selected serious-event terms. These observations are useful as a record of events reported in this study population.

The data do not establish whether ambrisentan caused a particular event. An event occurring during exposure may relate to treatment, pulmonary hypertension, another therapy, or other factors. The registry record does not report the event-attribution criteria or a control group against which the observed event counts could be compared. A single-group description cannot show how the same participants would have fared under a different treatment or without ambrisentan.

The record also does not provide the numerical primary endpoint percentage, its uncertainty, or formal statistical analyses. The serious-event counts and term percentages are not substitutes for that missing endpoint result unless the record explicitly connects them, which it does not. No conclusion about comparative benefit, comparative risk, statistical significance, or the precision of a treatment effect can be drawn from the reported summaries.

The long stated maximum timeframe indicates that the study was designed to observe long-term exposure, but it does not mean every participant was followed for that length of time. Individual follow-up and exposure durations are not reported. Counts accumulated over differing periods of observation cannot answer questions about event rates over time without additional information and methods.

Accordingly, the most defensible reading is descriptive and limited to the reported study group. The posted results document adverse events during an open-label safety study, while leaving the primary percentage, event attribution, comparative risk, and uncertainty unreported. These limitations should remain central when interpreting the figures.

14. Why This Trial Matters Statistically

This study is statistically notable because its aim and design are focused on long-term safety rather than a randomized comparison. Long observation can capture events arising during extended exposure, but interpretation depends on knowing who was followed, for how long, and how events were classified. The record states the overall endpoint window and the safety analysis population, while leaving individual follow-up, event attribution rules, and the primary endpoint value unreported.

The single-group design defines the scope of inference. Counts and term-specific percentages can describe what was recorded among participants exposed to ambrisentan, but they do not provide a counterfactual comparison. In general, a control group helps distinguish treatment-associated differences from background event occurrence and other influences. Without that comparison, the results cannot quantify a treatment effect or establish causation.

The distinction between participant counts, event counts, and time-adjusted rates is also important. The registry reports counts of participants with serious and other adverse events and lists selected serious-event terms. It does not provide event timing or person-time analyses. Readers therefore cannot use these summaries to compare event rates across follow-up durations or characterize how hazards changed over time.

Finally, the record illustrates why complete endpoint reporting matters. The primary question is framed as a percentage of participants with adverse events associated with long-term exposure, yet the registry record does not provide that percentage or its precision. Without the estimate, analytical methods, and handling of missing data, the safety summaries remain informative but incomplete. Their value lies in documenting observed events, not in supporting a causal or comparative conclusion.

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 study has no concurrent control group and is open-label, so the reported event summaries are not randomized comparisons. The registry record does not report a numerical primary endpoint percentage, confidence interval, hypothesis test, or adjusted estimate. It also does not describe criteria for attributing events to ambrisentan. These limitations prevent estimation of a comparative treatment effect from the reported information.

Exposure could vary because treatment continued until a participant or investigator chose to stop, ambrisentan became commercially available, or the sponsor stopped the study. The timeframe permits follow-up through 30 days after the last dose, with a maximum of approximately 550 weeks, but individual exposure and follow-up durations are not reported. Without participant-level timing, the counts cannot be interpreted as time-adjusted rates or used to assess when events occurred.

The registry record does not report missing-data handling, event-coding details, or whether participants could appear under multiple serious-event terms. It also does not provide causes of death or a breakdown of treatment-related events. The reported terms and counts should therefore be interpreted as descriptive summaries, with uncertainty about classification and attribution.

The record lists one outcome measure and zero analyses, and does not report a detailed statistical plan, sample-size justification, interim analyses, or stopping rules. The planning assumptions describe hypothetical illustrations rather than the actual single-group design. These omissions limit assessment of the intended inferential framework and the robustness of any potential estimates. They do not establish that a particular bias occurred, but they constrain what can be concluded from the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Ambrisentan in Participants With Pulmonary Hypertension — NCT00777920.
• Registry record last updated 2020-09-30; status last verified 2020-09.
• Results first posted 2020-09-30.
• 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

NCT00777920 is a completed, phase 3, open-label, multicenter, single-group safety study of ambrisentan in participants with pulmonary hypertension. Enrollment was 140. The study began on 2008-11-17, and primary completion was 2019-09-11. Participants received oral ambrisentan at 2.5 mg, 5 mg, or 10 mg once daily, with dose adjustment permitted.

The primary outcome concerns the percentage of participants with adverse events associated with long-term exposure, through 30 days after the last dose, with a maximum timeframe of approximately 550 weeks. The numerical primary endpoint result and formal analyses are not reported in the registry record. The adverse-event summary lists 80 participants with serious adverse events, 112 with other adverse events, and 39 deaths, alongside selected serious-event terms and percentages. These are descriptive findings from a single-group study and do not establish causation or comparative risk.