Clinical Study to Assess the Long-term Safety and Tolerability of ACT 064992 in Patients With Symptomatic Pulmonary Arterial Hypertension: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Clinical Study to Assess the Long-term Safety and Tolerability of ACT 064992 in Patients With Symptomatic Pulmonary Arterial Hypertension (NCT00667823), a na phase 3 study. The primary outcome is Number of Participants With Treatment Emergent Adverse Events (TEAEs) up to 28 Days After Study Treatment Discontinuation.

2. Clinical Question

The study asked whether long-term use of ACT 064992, identified as macitentan, could be assessed for safety and tolerability among people with symptomatic pulmonary arterial hypertension who entered an extension after the SERAPHIN study. Its primary endpoint counted participants with treatment-emergent adverse events during treatment or related worsening of a pre-existing condition, through up to 28 days after treatment discontinuation.

This is a safety-and-tolerability question, not a randomized estimate of comparative treatment effect. The extension followed the SERAPHIN study, but the registry record does not report a concurrent control group or a comparison with participants who did not receive macitentan. It also does not report a primary-endpoint count or an effect estimate for that endpoint. The posted adverse-event summaries describe events in the treatment group; they cannot by themselves establish what would have occurred under another treatment or without treatment.

3. Trial Design

This was a Phase 3, single-group, open-label extension study sponsored by Actelion. Its official title describes it as an extension of the SERAPHIN study, intended to assess long-term safety and tolerability in people with symptomatic pulmonary arterial hypertension. The registry lists macitentan as the intervention and ACT-064992 as the arm. There was no masking, and allocation was not applicable.

The registry lists enrollment as 550 and the study status as completed. The recorded start date is 2008-10-17, and the primary completion date is 2020-12-07. These registry fields describe the study record; they do not establish that every enrolled participant received treatment or contributed data to every endpoint. The safety analysis set is defined as participants who received at least 1 dose of macitentan 10 milligrams.

The primary outcome was the number of participants with treatment-emergent adverse events up to 28 days after treatment discontinuation, with a timeframe described as up to 12 years. The registry defines a treatment-emergent event as an adverse event with onset during the treatment period, or an adverse event that is a consequence of a pre-existing condition that worsened since baseline.

Because the design had a single treatment group and no randomization, it does not support a like-for-like comparison of macitentan with another intervention. Open-label status means treatment was not masked. The registry record does not report additional design details such as a planned control group, an interim analysis plan, or a statistical analysis plan. Although the study followed SERAPHIN, the record does not establish that results from the earlier study are a suitable control for this extension.

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: Participant flow reported below is up to study closure.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).

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 Number of Participants With Treatment Emergent Adverse Events (TEAEs) up to 28 Days After Study Treatment Discontinuation, measured over Up to 28 days after study treatment discontinuation (Up to 12 years).

The primary endpoint is a participant count: the number of people in the safety analysis set who experienced at least one qualifying treatment-emergent adverse event. It is not a count of all event episodes. The registry defines adverse events broadly as untoward medical occurrences in someone who received study drug, without requiring a judged causal relationship to the drug. Treatment emergence refers to onset during treatment or worsening of a pre-existing condition since baseline.

The endpoint includes a follow-up window extending up to 28 days after study treatment discontinuation. The listed timeframe also says up to 12 years, indicating the long-term observation period described in the registry. Those phrases define the stated observation window; the record does not provide individual treatment durations or follow-up distributions.

A participant count is used to describe how many people in the safety set experienced the specified event outcome. In general, safety counts help characterize the observed burden of events during exposure and follow-up. They do not, by themselves, show that treatment caused an event. The registry's definition explicitly does not require a causal relationship, and this single-arm design offers no concurrent comparison to estimate how event occurrence might differ under another treatment.

The primary endpoint result itself is not reported in the registry record. Consequently, its observed count, the precision of that count, and any breakdown by event type cannot be described from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a single-group safety extension, rather than a randomized comparison. Its main statistical task is therefore descriptive: recording how many participants experienced defined safety outcomes during treatment and follow-up. The primary outcome is a participant count, not a continuous measurement or a time-to-event estimate. The registry record does not report a primary-endpoint result or a statistical analysis plan.

What does a participant count represent?

For a binary safety outcome, each participant can be classified as having or not having the defined outcome over the specified observation period. The resulting count describes participants with the event; it does not count repeated episodes as separate participants. In general, an event count and the number of affected participants are different quantities when a participant can experience more than one episode. The primary endpoint is explicitly framed as the number of participants with treatment-emergent adverse events.

The analysis population matters because an outcome can only be interpreted in relation to who was eligible for its calculation. The registry defines the safety analysis set as people who received at least 1 dose of macitentan 10 milligrams. It does not provide a primary-endpoint result or clarify from the posted record how missing follow-up information was handled. The enrollment field should not be treated as proof that every enrolled participant was included in every outcome calculation.

Why does the study design limit inference?

In general, randomization helps create comparable groups by allocating participants to treatment groups according to chance. This study had no randomized comparator group: it is listed as single-group, with allocation not applicable. Consequently, its event counts describe outcomes in the treated group but do not estimate a difference between treatment strategies. Events may occur because of the underlying condition, other factors, or treatment; the broad adverse-event definition does not establish causality.

Open-label status means treatment was not masked. In general, awareness of treatment can influence reporting, assessment, or follow-up, depending on the outcome and study procedures. The registry record does not describe procedures intended to reduce such influence, so their use cannot be assumed. The extension design also means entry followed the SERAPHIN study; this record does not report enough information to assess how continuation, eligibility, or follow-up may affect the observed group.

How should uncertainty be understood?

In general, an estimate is more informative when accompanied by a measure of uncertainty, such as a confidence interval. A confidence interval conveys the precision of an estimate under specified assumptions; it does not correct for a missing comparator or remove bias from study design. Since the primary endpoint count and its uncertainty are not reported in the registry record, its precision cannot be evaluated from the posted information.

For safety summaries, denominators and event definitions are essential. The registry reports participants at risk and participants affected for serious and other adverse-event summaries, alongside a list of serious-event terms with percentages. The denominator for those term percentages is not reported in the registry record. They should therefore be read as the listed percentages, without translating them into counts or assuming a denominator. In general, adverse-event terminology also requires care: a term may describe a medical condition, and its appearance in an event listing does not prove that treatment caused it.

What can sample-size planning show?

In general, a sample-size illustration estimates the number of participants that might be needed to detect a chosen effect under stated assumptions. It is a planning exercise, not an observed result and not evidence that a study had a particular probability of finding an effect. The registry record's planning description refers to a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with an effect defined as a fraction of an observed effect. It also distinguishes total events for time-to-event planning from participants per arm for other outcomes.

Those stated assumptions do not match the actual single-arm extension design as described in the registry, which has no two-arm randomized comparison. A planning illustration based on two arms cannot be treated as an analysis of this study. The record does not report a sample-size justification, and the specific assumptions or results of any such planning should not be attributed to the trial's own design. Any sample-size figures elsewhere are hypothetical planning quantities, not observed power or evidence of treatment effect.

The registry lists 0 analyses. It does not report the inferential method used for the primary endpoint, a model, covariate adjustment, or a plan for handling repeated events. No method should be inferred solely from the endpoint being a participant count. General statistical explanations describe possible concepts, not methods confirmed for this study.

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("Macitentan 10 mg")
n      <- c(550)
events <- c(527)
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  Macitentan 10 mg  550  527  95.8  93.8  97.3  93.8  97.2  93.8  97.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 6 outcome measures and 0 analyses. It does not report a multiplicity procedure, such as an adjustment for testing several outcomes, nor does it describe a hierarchy that would identify which outcomes were intended to support formal claims. Without a posted statistical plan, it is not possible to determine how multiple outcomes or comparisons, if any, were handled.

The primary endpoint is described as a count of participants with treatment-emergent adverse events. Its result is not reported in the registry record. The record also does not provide a missing-data method for that endpoint, the extent of missing outcome information, or a sensitivity analysis addressing missingness. It is therefore not possible to assess whether participants with incomplete follow-up were included, excluded, or treated under a particular assumption.

The safety analysis set is defined as all participants who received at least 1 dose of macitentan 10 milligrams. That definition identifies the intended safety population, but it does not by itself explain how each outcome was analyzed or how incomplete records were handled. Enrollment and the safety population should not be assumed to be interchangeable for every outcome.

In general, multiplicity matters because repeated statistical testing can increase the chance of a nominally notable finding arising by chance. Missing-data assumptions also matter because results may depend on how participants with unavailable outcomes are handled. Neither issue can be evaluated fully from this registry record. No interim analysis, statistical analysis plan, or sample-size justification is reported.

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 2% 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 (22.4%), right ventricular failure (13.1%), pneumonia (7.3%), anaemia (4.9%), syncope (3.6%).

The serious adverse-event summary lists 354 participants affected among 550 at risk in the Macitentan 10 mg group. The other adverse-event summary lists 476 participants affected among 550 at risk. A separate registry field lists 182 deaths. These are reported as separate entries; they should not be added together or treated as mutually exclusive categories. The record does not establish that they share identical observation windows or provide a causal assessment of the deaths.

The serious-event terms are listed with percentages: Pulmonary Arterial Hypertension, 22.4%; Right Ventricular Failure, 13.1%; Pneumonia, 7.3%; Anaemia, 4.9%; Syncope, 3.6%; and Dyspnoea, 2.9%. The denominator and reporting basis for these percentages are not reported in the registry record. They should be read as recorded, not converted into participant counts.

In general, a safety summary describes events recorded during the specified monitoring and reporting process. It does not, without an appropriate comparison and causal assessment, show that treatment caused an event. The primary endpoint result is not reported in the registry record, so these summaries should not be presented as that endpoint's result.

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

This study's registry record documents a long-term, open-label extension with a safety and tolerability objective. It reports serious and other adverse-event summaries for the macitentan group and lists serious-event terms and deaths. These figures describe what the registry recorded for the group; the primary treatment-emergent adverse-event count is not reported in the registry record.

The design does not include a concurrent randomized comparator. As a result, event summaries cannot determine how outcomes would have differed under another treatment or without treatment. The adverse-event definition does not require a causal relationship, so the presence of an event during treatment does not establish that macitentan caused it. The death entry likewise does not establish cause.

The record also does not report a confidence interval or other uncertainty measure for the primary endpoint, a detailed analysis plan, or how missing outcome information was handled. The serious-event term percentages have no stated denominator in the registry record. These omissions limit assessment of precision and interpretation of the reported categories.

In general, long-term safety observations can help describe events recorded during continued follow-up, but they cannot by themselves resolve comparative effectiveness or causal safety questions. The extension's findings should be interpreted in light of its single-arm, open-label design, the defined safety population, and the incompleteness of the posted endpoint results. They should not be read as proof that treatment is beneficial, harmful, or equivalent to another option.

14. Why This Trial Matters Statistically

This trial is statistically notable because its question concerns long-term safety, while its design is a single-arm extension. That combination makes descriptive reporting central: the study can record events during ongoing treatment and follow-up, but it has no concurrent randomized group for estimating a comparative difference. Distinguishing description from comparison is especially important when adverse events may also reflect the underlying condition or other factors.

The endpoint definition makes clear that treatment-emergent events are not necessarily treatment-caused events. It includes untoward medical occurrences without regard to a possible causal relationship, and also includes worsening of a pre-existing condition. Interpreting the event counts therefore requires attention to what was counted, who was included in the safety set, and the observation window.

The registry's missing primary-endpoint result and analysis details also matter. Without the endpoint count, uncertainty measure, or missing-data approach, readers cannot assess how precisely the primary safety outcome was estimated. The listed adverse-event summaries provide information, but they do not fill in those missing elements or create a comparator.

For clinical researchers, the record illustrates why long follow-up, population definitions, event definitions, and control-group structure need to be considered together. It also shows why safety listings should not be interpreted as causal claims. The registry entry supports a description of the study's purpose, design, and reported adverse-event summaries; it does not support a randomized treatment comparison or a complete inferential account of the primary endpoint.

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 principal limitation is the single-arm, open-label design. Without a concurrent comparison group, observed events cannot be separated statistically from the background experience of participants with pulmonary arterial hypertension or from other influences. The extension's relationship to the SERAPHIN study does not supply a control group within this record.

The primary endpoint result is not reported in the registry record. The record also does not report a confidence interval, analysis method, statistical analysis plan, interim analysis plan, or sample-size justification. It does not state how missing endpoint data were handled or describe completeness of follow-up. These gaps prevent assessment of the primary estimate's precision and robustness.

The safety population is defined by receipt of at least 1 dose of macitentan 10 milligrams, while enrollment is listed separately. The record does not provide outcome-specific denominators beyond those in the adverse-event summaries. It also does not report the denominator or basis for the percentages attached to serious-event terms. These details limit interpretation of the event listings and comparisons across categories.

The adverse-event definition does not require a causal link, and the record does not provide causal adjudication for the listed terms or deaths. The reported timeframe is up to 28 days after treatment discontinuation, with the overall timeframe described as up to 12 years; individual exposure and follow-up durations are not reported. The registry's completion status does not resolve these reporting limitations.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Clinical Study to Assess the Long-term Safety and Tolerability of ACT 064992 in Patients With Symptomatic Pulmonary Arterial Hypertension — NCT00667823.
• Registry record last updated 2025-03-30; status last verified 2025-03.
• Results first posted 2022-02-10.
• 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

NCT00667823 is a completed Phase 3, open-label, single-arm extension study sponsored by Actelion. It followed the SERAPHIN study and aimed to assess long-term safety and tolerability of ACT 064992, listed as macitentan, in people with symptomatic pulmonary arterial hypertension. The registry lists enrollment as 550, a start date of 2008-10-17, and primary completion on 2020-12-07.

The primary endpoint was the number of participants with treatment-emergent adverse events through up to 28 days after treatment discontinuation, with a timeframe described as up to 12 years. The safety analysis set included participants who received at least 1 dose of macitentan 10 milligrams. The primary endpoint result is not reported in the registry record.

Adverse-event summaries list 354 participants affected by serious events and 476 affected by other events, each with 550 at risk; the record also lists 182 deaths. Because the study had no randomized comparator and the event definition does not establish causation, these figures are descriptive rather than comparative or causal estimates.