Open Label Extension Study in Patients With Idiopathic Pulmonary Fibrosis Who Completed Protocol AC-052-321/ BUILD 3 / NCT00391443: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Open Label Extension Study in Patients With Idiopathic Pulmonary Fibrosis Who Completed Protocol AC-052-321/ BUILD 3 / NCT00391443 (NCT00631475), a non-randomized phase 3 study. The primary outcome is Extent of Exposure to Bosentan in Patients With Idiopathic Pulmonary Fibrosis (IPF).

2. Clinical Question

The study was designed to assess long-term safety and tolerability in patients with idiopathic pulmonary fibrosis who had completed the preceding protocol. It was not a randomized comparison of bosentan against placebo within the extension. The registry record does not report a numerical primary-outcome result, so it cannot establish the average exposure duration from the posted results.

3. Trial Design

This was a phase 3, open-label, non-randomized, single-group extension study sponsored by Actelion. It enrolled 128 patients with idiopathic pulmonary fibrosis who had completed protocol AC-052-321 / BUILD 3 (NCT00391443). The record lists the study start as 2008-04, primary completion as 2010-04, and status as completed.

All patients in the extension received bosentan. Dosing depended on treatment during BUILD 3: patients previously given bosentan continued the same dose, while those previously given placebo started at 62.5 mg for 4 weeks and then took a maintenance dose of 125 mg. Because treatment was open-label and there was no concurrent randomized control group, differences between those with different prior treatment histories cannot be read as randomized treatment effects.

The primary outcome was mean extent of bosentan exposure, measured in months from study start to study end, with a stated timeframe of up to 21 months. Secondary outcomes included patients exposed over time, adverse events leading to study-drug discontinuation, treatment-emergent serious adverse events, and abnormalities in alanine aminotransferase and aspartate aminotransferase. The registry record does not report the protocol’s detailed statistical plan, the method used to select the enrolled population, or a sample-size justification.

The extension’s purpose was continued observation of exposure and safety after the preceding study. The record does not describe a treatment-effect comparison against placebo within this study. Its single-group design can describe recorded outcomes during bosentan exposure, but cannot separate those outcomes from the course of the underlying condition, earlier treatment history, or other influences.

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: In total, 128 of the 615 patients who received randomized treatment in BUILD 3 (NCT00391443) rolled over into the BUILD 3 OL extension.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: For two patients, the exact treatment stop date was missing and the duration could not be calculated, but these patients received at least 345 and 127 days of open label (OL) treatment.

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 Extent of Exposure to Bosentan in Patients With Idiopathic Pulmonary Fibrosis (IPF), measured over Start of study to end of study, up to 21 months.

The primary endpoint was the mean extent of exposure to bosentan, measured in months. The recorded timeframe ran from study start to study end, up to 21 months. A mean describes the average of individual exposure durations, while the standard deviation describes how dispersed those durations are around the mean. Together, these statistics can characterize both typical exposure and variation across patients.

Exposure duration is useful in an extension study focused on long-term safety and tolerability because it describes how long patients remained on study treatment. It is not itself a measure of clinical benefit or a direct measure of safety. Interpreting exposure alongside adverse events can help readers understand the time during which treatment was observed, but exposure duration alone cannot establish why treatment ended or whether treatment changed the disease course.

The registry record identifies the endpoint as a mean with standard deviation, but does not report the numerical mean or standard deviation. It also notes that exact treatment stop dates were missing for two patients, preventing calculation of their durations. Those patients received at least 345 and 127 days of open-label treatment, respectively. The record does not report how these incomplete durations were handled in the primary endpoint analysis.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean and standard deviation describe?

General statistical explanation: for a continuous outcome such as treatment duration, the mean is the arithmetic average across the observations included in an analysis. The standard deviation describes how much individual observations vary around that average. A mean can be easy to interpret, but it can be affected by unusually short or long durations. The standard deviation provides information about spread, not the uncertainty in the estimated mean.

The registry specifies mean and standard deviation for the primary exposure endpoint. It does not report their numerical values. It also does not report a confidence interval for the mean. In general, a confidence interval expresses uncertainty around an estimate under a stated statistical method; it is not a range containing a guaranteed share of individual exposure durations. Without an estimate, interval, or analysis details, precision cannot be evaluated.

What can a single-group design show?

General statistical explanation: a single-group study can describe what was observed among people receiving the study treatment. It cannot, by itself, show what would have happened to those same people under a different treatment. A randomized concurrent comparator can help support such a comparison by balancing factors that might otherwise differ between groups. This extension was non-randomized, open-label, and single-group, so its results are descriptive rather than a randomized estimate of treatment effect.

The registry describes different dosing histories based on treatment in BUILD 3. Previously treated patients continued the same bosentan dose; those who had received placebo started bosentan at 62.5 mg for 4 weeks and then received 125 mg as maintenance. These histories do not form a randomized comparison within the extension. Prior treatment, study completion, and other differences between patients may be related to subsequent exposure and safety observations.

What is the role of the exposure endpoint?

General statistical explanation: an exposure-duration endpoint describes time receiving treatment, not necessarily time until a particular clinical event. A simple mean duration does not distinguish why treatment ended, whether patients had different opportunities for follow-up, or whether duration was affected by discontinuation. Those questions require definitions and analysis methods that are not reported in the registry record. Exposure can provide context for safety observations, but it is not a substitute for a clinical outcome or a controlled safety comparison.

For two patients, the exact treatment stop date was missing, so duration could not be calculated. The registry states that they received at least 345 and 127 days of open-label treatment. In general, incomplete duration data can affect an average if the missing values are excluded, imputed, or otherwise handled; the choice and its consequences depend on the analysis. The registry record does not report how these cases were included in the primary endpoint analysis, so the effect of the missing dates on the reported mean cannot be assessed.

How should the safety counts be understood?

General statistical explanation: safety summaries depend on the event definitions, observation period, and whether the reported measure counts affected patients, event episodes, or both. A count of affected patients is not the same as a count of all event occurrences. The registry summary reports 51 affected in the serious adverse-event category and 5 in the other adverse-event category, with 128 at risk in each. The record does not provide enough detail in these figures to interpret event recurrence or compare risks against a control group.

The serious-event terms are listed with percentages, including idiopathic pulmonary fibrosis at 18.0%, respiratory failure at 3.1%, lower respiratory tract infection at 3.1%, pneumonia at 3.1%, dyspnoea at 2.3%, and lung transplant at 2.3%. These descriptions identify reported terms; they do not show whether events were judged treatment-related, how event severity was classified, or whether the terms overlap within patients. Such interpretation requires definitions and results not reported in the registry record.

What analysis and planning details are available?

The registry lists no analyses. A detailed statistical analysis plan, including treatment of missing observations, methods for uncertainty estimation, and prespecified subgroup analyses, is not reported in the registry record. It is therefore not possible to assess whether the posted endpoint definition was accompanied by additional analysis decisions or how deviations, if any, were addressed.

General statistical explanation: sample-size calculations are planning exercises based on assumptions about an effect, variability, significance level, allocation, and analysis method. A planning illustration is not observed power, and it does not establish what the study was designed to detect unless it reflects the trial’s actual design assumptions. The registry record does not report the study’s sample-size justification. It also does not report interim-analysis procedures or a multiplicity strategy. Any planning illustration should be understood as hypothetical rather than as evidence of the study’s achieved precision or power.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Bosentan Treatment")
n   <- c(126)
m   <- c(6.4)
sp  <- c(4.6)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Bosentan Treatment  126  6.400  4.600  5.589  7.211

11. Multiplicity, Missing Data and Analysis Populations

The registry lists several secondary safety outcomes alongside the primary exposure endpoint. It does not report a multiplicity adjustment or describe how conclusions across multiple outcomes were to be controlled. General statistical explanation: when many outcomes or comparisons are examined, the chance of at least one apparently unusual result can increase. Whether adjustment is appropriate depends on the purpose of the analyses and the prespecified statistical plan; that plan is not reported in the registry record.

The record lists no analyses and does not provide a numerical result for the primary endpoint. It also does not report numerical results for several listed secondary outcomes. A statistical analysis plan, including analysis populations, handling of missing data, and methods for estimating uncertainty, is not reported in the registry record. The record therefore does not establish whether analyses used all enrolled patients, patients who received treatment, or another defined population.

For two patients, the exact treatment stop date was missing, preventing calculation of exposure duration. The registry reports minimum open-label treatment durations of 345 and 127 days for these patients, but does not state how those observations were handled in the endpoint analysis. General statistical explanation: excluding incomplete observations, assigning a value under an imputation method, or using a method designed for incomplete follow-up can lead to different estimates. The appropriate approach depends on why data are missing and on the analysis question; neither the reasons nor the analysis approach is reported in the registry record.

Consequently, the potential influence of missing duration data, the consistency of the analysis with a prespecified plan, and the handling of multiple outcomes cannot be evaluated from the registry information.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: idiopathic pulmonary fibrosis (18.0%), respiratory failure (3.1%), lower respiratory tract infection (3.1%), pneumonia (3.1%), dyspnoea (2.3%).

The safety summary lists 128 at risk in the bosentan-treatment group. It reports 51 affected in the serious adverse-event category and 5 affected in the other adverse-event category. These are descriptive counts from an open-label, single-group extension, not a comparison with a concurrent control group. They do not establish that bosentan caused an event or indicate what event frequency would have occurred without treatment.

The serious-event terms and reported percentages are idiopathic pulmonary fibrosis at 18.0%, respiratory failure at 3.1%, lower respiratory tract infection at 3.1%, pneumonia at 3.1%, dyspnoea at 2.3%, and lung transplant at 2.3%. These terms describe events recorded in the registry summary. The record does not report whether the terms were judged related to treatment, whether a patient could contribute to more than one term, or the event-specific observation periods.

The listed secondary outcomes also include adverse events leading to study-drug discontinuation and liver-function-test abnormalities. Numerical results for those outcomes are not reported in the registry record. The figures should therefore be interpreted as limited descriptive safety information, not as a complete account of all safety outcomes or a controlled estimate of risk.

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

This study addresses continued bosentan exposure and safety observation among patients with idiopathic pulmonary fibrosis who completed AC-052-321 / BUILD 3. Its primary endpoint is a measure of treatment duration, and its listed secondary outcomes concern adverse events and liver-function-test abnormalities. The design and outcome choices make the record relevant to describing treatment exposure and recorded safety events in this extension cohort.

The registry does not report the numerical mean exposure duration or its standard deviation. It also does not report many of the listed secondary outcome results. As a result, the posted results do not permit a numerical summary of the primary endpoint, nor do they provide a complete account of the specified safety outcomes. Missing stop dates for two patients further limit assessment of the endpoint, because the record does not describe how their durations were treated in the analysis.

The study does not establish whether bosentan caused the recorded events or how safety would compare with another treatment. Its open-label, non-randomized, single-group design lacks a concurrent control. Prior treatment histories differed, and all participants entered after completing the preceding protocol. These features limit causal interpretation and generalization beyond the described extension population.

General statistical explanation: descriptive results can be informative about what was recorded in a defined study group, while causal comparisons require a credible basis for comparing outcomes under alternative treatments. This extension contributes descriptive exposure and safety information, but its design and incomplete numerical reporting leave substantial uncertainty about treatment effects and the precision of outcomes.

Nothing in the listed results establishes clinical benefit or lack of benefit. The registry record is not a basis for medical advice. It documents a study intended to assess long-term safety and tolerability, while the numerical primary endpoint result and several other details needed for fuller statistical interpretation are not reported in the registry record.

14. Why This Trial Matters Statistically

Extension studies address a different question from randomized treatment comparisons. They can continue observation after a preceding trial and describe treatment exposure and safety events among people who enter the extension. This record makes that distinction especially important: it follows patients who completed AC-052-321 / BUILD 3 and uses an open-label, non-randomized, single-group design.

The primary endpoint, mean exposure duration, is a useful descriptive measure for understanding how long treatment was observed. Its interpretation depends on complete duration information and on how treatment discontinuation and incomplete dates are handled. The registry notes missing exact stop dates for two patients, but does not report the analysis method or numerical endpoint result. This illustrates why an endpoint definition alone is not enough to assess an estimate’s precision or robustness.

The safety summary also shows why event counts require design context. Serious and other adverse events are reported for the bosentan-treatment group, but no concurrent randomized control is available to support a comparative risk estimate. Event percentages describe recorded terms rather than proving causation. The open-label design and prior treatment histories also matter when interpreting these observations.

More broadly, the record illustrates the limits of registry summaries for statistical appraisal. It identifies outcomes and some safety figures but does not report the primary endpoint estimate, analysis details, multiplicity handling, or a sample-size justification. Readers can identify the intended questions and design, but cannot evaluate the mean exposure result or many analysis choices. Distinguishing descriptive evidence from comparative evidence is essential to a cautious reading.

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 main limitation for interpreting the primary outcome is that the registry record identifies mean exposure in months but does not report the mean or standard deviation. No confidence interval or other uncertainty estimate is reported. The numerical primary result and its precision therefore cannot be assessed.

The record states that exact treatment stop dates were missing for two patients and that their exposure durations could not be calculated. It gives minimum open-label treatment durations of 345 and 127 days, but does not explain how these observations were handled in the primary analysis. The impact of these incomplete dates on the endpoint estimate is therefore unknown.

The study was open-label, non-randomized, and single-group, with no concurrent like-for-like control. The participants had completed the preceding protocol, and dosing histories differed according to prior treatment. These design features limit causal interpretation and make the observed safety experience unsuitable as a direct randomized comparison.

The registry lists several secondary outcomes, but numerical results for many of them are not reported in the registry record. It does not report the statistical analysis plan, analysis populations, multiplicity strategy, interim-analysis methods, or sample-size justification. The absence of these details limits evaluation of endpoint handling, uncertainty, and the completeness of reported analyses.

The safety summary lists affected counts and selected serious-event terms, but does not report details such as treatment-relatedness judgments, recurrence, or event-specific observation periods. These omissions constrain interpretation of the event profile. The record’s completed status does not fill in the missing results or analysis information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Open Label Extension Study in Patients With Idiopathic Pulmonary Fibrosis Who Completed Protocol AC-052-321/ BUILD 3 / NCT00391443 — NCT00631475.
• Registry record last updated 2025-02-04; status last verified 2025-01.
• Results first posted 2012-08-03.
• 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

NCT00631475 was a completed, phase 3, open-label extension study sponsored by Actelion. It enrolled 128 patients with idiopathic pulmonary fibrosis who completed protocol AC-052-321 / BUILD 3 (NCT00391443). The study start was 2008-04 and primary completion was 2010-04.

The single-group, non-randomized study assessed bosentan exposure and safety. Patients who had received bosentan in BUILD 3 continued the same dose; patients who had received placebo began 62.5 mg for 4 weeks and then received a 125 mg maintenance dose. The primary endpoint was mean bosentan exposure in months, from study start to study end, up to 21 months.

The registry record does not report the numerical primary endpoint result or a detailed statistical analysis plan. It reports 51 affected in the serious adverse-event category and 5 affected in the other adverse-event category among 128 at risk. Exact stop dates were missing for two patients. The non-randomized, uncontrolled design supports descriptive interpretation, not a causal treatment comparison.