Safely Change From Bosentan to Ambrisentan in Pulmonary Hypertension: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safely Change From Bosentan to Ambrisentan in Pulmonary Hypertension (NCT01330108), a na phase 4 study. The primary outcome is Number of Subjects Not Able to Tolerate Ambrisentan.

2. Clinical Question

The study’s stated objective was to assess the safety and tolerance of changing patients from bosentan to ambrisentan. The primary outcome defines inability to tolerate ambrisentan by an adverse event or side effect that the subject found unacceptable. Under that definition, inability to tolerate treatment led to withdrawal of ambrisentan and a return to bosentan within the first 12 weeks.

This is a question about tolerability during a treatment change, not a randomized comparison of ambrisentan with bosentan. The study is listed as single-group, with allocation recorded as not applicable and no masking. As a result, the record does not describe a concurrent group against which to compare the frequency of intolerance or other outcomes.

The registry lists a secondary outcome of mean change in distance for a six-minute walk at 12 weeks after starting ambrisentan. The result for that outcome is not reported in the registry record. The primary outcome’s count of subjects unable to tolerate ambrisentan is also not reported in the registry record. The safety counts that are reported offer related information, but they do not substitute for the primary outcome’s subject-defined intolerance measure.

3. Trial Design

This was a Phase 4, completed, single-group study sponsored by the University of Alabama at Birmingham. The registry lists enrollment of 32 and describes patients currently on bosentan changing to ambrisentan for pulmonary arterial hypertension. The study started in 2011-05, and primary completion was recorded as 2012-06.

The record lists no masking and records allocation as not applicable. It does not describe a randomized assignment or a separate control group. The design therefore provides a description of outcomes in the treated group, rather than a direct randomized estimate of how outcomes would differ under another treatment strategy. Any changes recorded during follow-up cannot, by this design alone, be separated from other influences over time.

The primary outcome was the number of subjects unable to tolerate ambrisentan, with a timeframe from baseline to 12 weeks. The record’s definition links an unacceptable adverse event or side effect to stopping ambrisentan and returning to bosentan within that period. A secondary outcome was mean change in six-minute walk distance at 12 weeks after starting ambrisentan.

Safety results list 32 at risk for serious adverse events and 32 at risk for other adverse events. The corresponding counts affected were 0 and 14. These safety counts are not the same as the primary outcome: an adverse event may be recorded without meeting the subject-defined criterion for unacceptable intolerance, and the primary outcome count is not reported in the registry record. The record does not report details of the statistical analysis plan, analysis populations, or handling of missing observations.

4. Participant Flow and Accounting

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

Overall Study

Reasons for not completing this period:

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: Subjects described in baseline are those that completed the study

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects Not Able to Tolerate Ambrisentan, measured over baseline to 12 weeks.

The primary endpoint is a count: the number of subjects who were not able to tolerate ambrisentan from baseline to 12 weeks. Its stated definition is based on an adverse event or side effect that was unacceptable to the subject. If that criterion was met, ambrisentan was to be withdrawn and the subject returned to bosentan within the first 12 weeks.

This endpoint is used to capture treatment tolerability in the context of switching therapy. It is clinically interpretable as a count of subjects meeting the stated stopping criterion, rather than as a measure of the severity of every event or of a treatment effect relative to a control group. The definition includes the subject’s judgment about whether an event or side effect was acceptable, so the endpoint combines an experience reported by the subject with a treatment action specified in the record.

The registry record does not report the observed count for this primary endpoint. The safety results report 14 subjects with other adverse events and 0 with serious adverse events, but those categories are not identified as equivalent to the primary endpoint. The registry also lists mean change in six-minute walk distance at 12 weeks as a secondary outcome, without reporting its result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of outcome is the primary endpoint?

The primary endpoint is a binary event summarized as a count of participants: whether a subject met the definition of not being able to tolerate ambrisentan during the stated timeframe. A count can be useful because it directly records how many subjects experienced an event meeting the study’s criterion. To interpret that count fully, readers also need the relevant denominator, a clear event definition, and information about missing outcome data. The registry gives the definition and timeframe, but the primary endpoint count is not reported in the registry record.

A count is not itself an estimate of a comparative treatment effect. In a study with a suitable comparison group, analysts might estimate a difference or ratio between groups, with uncertainty measures. Here, the design is listed as single-group and does not describe a concurrent comparator. The record therefore does not support a direct between-group treatment contrast.

How should the event definition be understood?

The endpoint combines an adverse event or side effect with the subject’s judgment that it was unacceptable. The record also describes a related treatment consequence: withdrawal of ambrisentan and return to bosentan within the first 12 weeks. This makes the outcome a measure of tolerability under the stated rule, not simply a count of all adverse events. A subject may have an event without finding it unacceptable, and the record does not say that every event in the safety categories resulted in treatment withdrawal.

For that reason, the separate safety counts should remain distinct from the primary endpoint. The record reports 0 subjects affected by serious adverse events and 14 affected by other adverse events, each among 32 at risk. It does not report how many of those subjects met the primary intolerance definition. The distinction matters because broad event recording and a subject-defined treatment-stopping criterion answer different questions.

What does a single-group design allow?

A single-group study can describe outcomes recorded among people receiving the intervention. It does not, without a suitable comparison, show what would have happened to similar subjects under another treatment strategy. General statistical reasoning therefore cautions against treating changes over time or event counts as evidence of a causal difference between treatments. Other influences, including the course of the condition and events unrelated to treatment, cannot be separated from the intervention using a concurrent comparison that the registry does not describe.

The registry records allocation as not applicable and masking as none. It does not report an analysis plan explaining how outcomes were summarized, whether any adjustment was planned, or how estimates of uncertainty were to be obtained. There are no analysis records listed. A particular test, model, or inferential procedure should not be inferred from those omissions.

Why do uncertainty estimates matter?

General statistical interpretation considers both the observed count and the uncertainty around it. A confidence interval is one common way to express that uncertainty. It does not guarantee that the true value lies within the interval, but it shows a range generated by a specified method and the observed data. The registry record does not report confidence intervals for the safety outcomes or the primary endpoint.

When event counts are small, estimates can be imprecise even if the observed count is low. A zero count does not establish that the underlying event risk is zero; it means no events in that category were recorded in the reported group. This general principle is relevant to reading the serious adverse event count, while the registry record’s lack of an interval prevents a more specific assessment of precision.

What can planning illustrations say?

Sample-size illustrations based on an observed effect are planning exercises, not evidence about the trial’s observed precision or about the probability that a result is true. The stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Those assumptions describe the illustration, not the registered single-group design. The registry record does not report a sample-size justification for the study, and no planning illustration can replace the missing primary endpoint result or an analysis of uncertainty.

More generally, sample-size planning depends on the outcome, the effect a future study aims to detect, the chosen error threshold, and the design assumptions. Planning for a fraction of an observed effect is hypothetical: it explores what a future comparison might require under stated assumptions. Such planning does not show that the present study had a particular power, and it does not turn a single-group description into a comparative trial.

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(28)
events <- c(4)
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  28  4  14.3  4.0  32.7  5.7  31.5  5.8  31.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary tolerability outcome and a secondary outcome for mean change in six-minute walk distance at 12 weeks. It does not report a multiplicity plan, such as whether interpretation of multiple outcomes would follow a prespecified hierarchy or use an adjustment for multiple testing. Without such information, the approach to controlling the chance of a false-positive finding across outcome analyses is not reported in the registry record.

The record lists 0 analysis records. This means the registry record does not give analysis-level results or methods for the listed outcomes. It does not establish whether analyses were conducted outside the registry or whether a detailed plan existed elsewhere. The statistical analysis plan, including any interim analyses or model choices, is not reported in the registry record.

Missing-data handling and analysis populations are also not reported in the registry record. The record does not state how subjects with incomplete follow-up were handled, whether all enrolled subjects were included in each endpoint analysis, or how missing outcomes were distinguished from no event. These omissions matter because an outcome count can be interpreted only in relation to who was assessed and how incomplete observations were treated.

The safety results do provide risk denominators of 32 for serious and other adverse events. Those denominators should not automatically be taken as the analysis population for the primary endpoint, whose count is not reported. The registry record does not explain whether follow-up was complete for the primary endpoint or whether any subjects were excluded from its assessment.

12. 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 1% reporting threshold.

Most frequent non-serious adverse event terms

The safety record lists 0 serious adverse events among 32 at risk and 14 other adverse events among 32 at risk in the ambrisentan group. These are counts, not comparative estimates. The serious-event count means no serious adverse events were recorded in that category in the posted results; it does not establish that such events are impossible or that the underlying risk is zero.

The count of other adverse events is a separate category from serious adverse events. The record does not provide further event terms for serious events, and no serious-event terms are listed. It also does not state whether the other adverse events were judged related to treatment, whether they were acceptable to subjects, or whether they led to stopping ambrisentan. Those details should not be inferred from the counts.

The primary tolerability outcome uses a subject-defined criterion and a treatment consequence, while the safety counts record events by category. The count of subjects meeting the primary definition is not reported in the registry record. Deaths are also not reported in the registry record, so the death field does not support a conclusion about whether deaths occurred.

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

The registry record describes a completed study of changing from bosentan to ambrisentan in patients with pulmonary arterial hypertension. Its primary question concerns the number of subjects unable to tolerate ambrisentan during the first 12 weeks, using a definition based on an event or side effect the subject found unacceptable. That primary count is not reported in the registry record.

The reported safety counts provide a limited descriptive account: 0 serious adverse events and 14 other adverse events among 32 at risk in the ambrisentan group. They do not establish a treatment effect. In particular, the absence of a concurrent comparator means the record does not directly compare changing treatment with continuing bosentan or another strategy. The reported counts also do not reveal whether events were attributed to ambrisentan or whether they led subjects to meet the primary intolerance definition.

The registry lists mean change in six-minute walk distance at 12 weeks as a secondary outcome, but its result is not reported in the registry record. No confidence intervals, analysis records, or methods for handling missing data are reported. Those gaps limit assessment of the precision and completeness of the reported findings.

General statistical interpretation separates a descriptive observation from a causal conclusion. The counts describe what was recorded in the study group; they do not show what would have happened to the same subjects under a different treatment strategy. The record therefore supports a cautious account of observed safety categories, but not a conclusion about comparative safety, effectiveness, or the frequency of the primary intolerance outcome.

14. Why This Trial Matters Statistically

This study raises a useful statistical distinction between a treatment-tolerability endpoint and a broad adverse-event count. The primary endpoint depends on whether an event or side effect was unacceptable to the subject and was linked to withdrawal of ambrisentan and return to bosentan. The safety record separately reports serious and other adverse events. Keeping those outcomes distinct prevents a safety count from being mistaken for the study’s primary result.

The single-group design also illustrates why design determines the kind of inference available. A treated group can provide descriptive information about events observed during follow-up. Without a concurrent comparison group, it cannot directly estimate how those outcomes would differ under another strategy. This remains true even when the treatment change and the follow-up period are clearly described.

The registry’s reporting gaps matter as much as the observed counts. The primary endpoint result, the secondary six-minute walk result, confidence intervals, analysis methods, missing-data handling, and analysis populations are not reported in the registry record. Without those details, readers cannot assess the primary tolerability result or the precision and completeness of the outcome analyses.

Finally, a zero count is not equivalent to proof of no risk. It is a description of what was recorded in the study group. Clear event definitions, denominators, uncertainty estimates, and an appropriate comparison design would be needed to support stronger interpretations. This record is a reminder that an outcome’s meaning depends on both how it is defined and how the study was designed to evaluate it.

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 central limitation for interpreting the primary question is that the registry record does not report the number of subjects unable to tolerate ambrisentan. Although the outcome definition and timeframe are described, the posted safety counts cannot fill this gap because the record does not equate other adverse events with unacceptable intolerance or with withdrawal of ambrisentan.

The study is listed as single-group, with no concurrent comparator described. The safety counts therefore do not directly estimate differences between changing to ambrisentan and another treatment strategy. The record also lists no masking. It does not report whether outcome assessment used any additional safeguards against awareness of treatment or whether the primary criterion was assessed consistently across subjects.

The record does not report the result for the secondary six-minute walk outcome. It also does not provide confidence intervals or other uncertainty estimates, details of event types beyond the listed categories, treatment-relatedness assessments, or the number of subjects completing follow-up. Missing-data handling and analysis populations are not reported in the registry record, so completeness of outcome assessment cannot be evaluated.

The registry lists 0 analysis records and does not report a statistical analysis plan or multiplicity approach. Consequently, the analysis methods and the way multiple outcomes were interpreted are unclear from the registry record. The safety data are useful as counts with stated denominators, but the available reporting does not support a full assessment of the primary endpoint, comparative effects, or the precision of outcome estimates.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safely Change From Bosentan to Ambrisentan in Pulmonary Hypertension — NCT01330108.
• Registry record last updated 2014-08-11; status last verified 2014-06.
• Results first posted 2014-08-11.
• 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

The registry describes a completed Phase 4, single-group study sponsored by the University of Alabama at Birmingham. It enrolled 32 and evaluated changing patients with pulmonary arterial hypertension from bosentan to ambrisentan. The study started in 2011-05, with primary completion in 2012-06.

The primary outcome was the number of subjects unable to tolerate ambrisentan from baseline to 12 weeks, defined by an unacceptable adverse event or side effect. That outcome count is not reported in the registry record. The listed safety results are 0 serious adverse events and 14 other adverse events among 32 at risk. Mean change in six-minute walk distance at 12 weeks was listed as a secondary outcome, but its result is not reported. The record lists no analysis records and does not report methods for missing data, analysis populations, or multiplicity.