This page separates reported trial results from statistical interpretation. The numerical results on this page are restricted to the ClinicalTrials.gov trial data posted on ClinicalTrials.gov for SERAPHIN. Where the ClinicalTrials.gov record does not provide a result or design detail, it is not inferred.
Trial at a Glance
SERAPHIN was a randomized, parallel-group, quadruple-masked phase 3 trial evaluating macitentan in patients with symptomatic pulmonary arterial hypertension. The registry reports a total enrollment of 742 participants across three arms, with a primary time-to-event endpoint assessing the time to first confirmed morbidity or mortality event up to the end of treatment.
| Feature | SERAPHIN |
|---|---|
| Phase | Phase 3 |
| Condition | Pulmonary Arterial Hypertension |
| Population | Patients with symptomatic pulmonary arterial hypertension |
| Design | Randomized, parallel-group, quadruple-masked, treatment-purpose study |
| Allocation | Randomized |
| Arms | Macitentan 3 mg, macitentan 10 mg, and placebo |
| Enrollment | 742 |
| Primary endpoint | Time to first confirmed morbidity or mortality event up to the end of treatment |
| Primary endpoint type | Time-to-event |
| Primary analysis method | Log-rank test |
| Primary effect measure | Hazard ratio |
| Hypothesis type | Superiority |
| Study start | 2008-05 |
| Primary completion | 2012-03 |
| Lead sponsor | Actelion |
| Sponsor type | Industry |
Clinical Question
The central statistical question was whether macitentan reduced the time to a first confirmed morbidity or mortality event compared with placebo in patients with symptomatic pulmonary arterial hypertension.
Population
Patients with symptomatic pulmonary arterial hypertension enrolled in a phase 3 randomized study.
Intervention
Macitentan at the reported study dose levels of 3 mg and 10 mg.
Comparator
Placebo.
Primary question
Does macitentan change the time to a first confirmed morbidity or mortality event relative to placebo?
Trial Design
ACT-064992 3 mg
- Macitentan (ACT-064992)
- Randomized treatment arm
- Primary comparison reported against placebo
- Secondary time-to-event comparisons also reported
ACT-064992 10 mg
- Macitentan (ACT-064992)
- Randomized treatment arm
- Primary comparison reported against placebo
- Secondary time-to-event comparisons also reported
Placebo
- Placebo drug
- Randomized control arm
- Reference group for the reported hazard ratios
Parallel, quadruple-masked study
- Randomized allocation
- Parallel design model
- Quadruple masking
- Primary purpose: treatment
The ClinicalTrials.gov record does not report a crossover procedure, factorial structure, non-inferiority margin, Bayesian analysis, or a formal missing-data/imputation method. Those features are therefore not incorporated into the statistical interpretation of this page.
Endpoints
| Endpoint role | Registered endpoint | Time frame | Type |
|---|---|---|---|
| Primary | Time to First Confirmed Morbidity or Mortality Event up to the End of Treatment (Kaplan-Meier Estimate of Patients Without a Morbidity or Mortality Event) | Up to end of treatment (data presented up to month 36) | Time-to-event |
| Secondary | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Up to end of treatment (data presented up to month 36) | Time-to-event |
| Secondary | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Up to end of treatment (data presented up to month 36) | Time-to-event |
| Secondary | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Up to end of study (data presented up to month 36) | Time-to-event |
What counted as a morbidity or mortality event?
The registry definition states that morbidity or mortality events included death, atrial septostomy, lung transplantation, initiation of intravenous or subcutaneous prostanoids, or other worsening of pulmonary arterial hypertension.
The registry further defines other worsening of pulmonary arterial hypertension using a combined set of clinical criteria, beginning with at least a 15% decrease in the 6 minute walk distance from baseline. The registry-reported trial extract ends during that definition, so this page does not reconstruct additional criteria that are not present in the ClinicalTrials.gov record.
Statistical Methodology
Kaplan-Meier estimation
The registry describes the primary endpoint as a Kaplan-Meier estimate of patients without a morbidity or mortality event. Kaplan-Meier estimation is appropriate for time-to-event outcomes because participants may have different lengths of observed follow-up and may be censored before experiencing the event.
The Kaplan-Meier curve estimates the probability of remaining free of the event over time while accounting for right-censored observations.
Log-rank test
The registry reports the log-rank test for the primary and secondary time-to-event comparisons. The log-rank test evaluates whether the observed event-time distributions differ between randomized groups over follow-up.
Hazard ratio
The reported effect measure is the hazard ratio. A hazard ratio compares the estimated instantaneous event rates between treatment groups within the time-to-event analysis.
The hazard ratio is a relative time-to-event measure. It is not the same as an absolute reduction in event probability, a difference in Kaplan-Meier percentages, or a statement that a particular proportion of participants benefited.
Analysis population
The statistical analyses posted on ClinicalTrials.gov specify all randomized patients as the analysis population for the reported primary and secondary efficacy comparisons. This is important because treatment assignment, rather than subsequent treatment behavior, anchors the randomized comparison.
Superiority framework
The registered hypothesis type for the reported analyses is superiority. The reported comparisons therefore assess whether the time-to-event outcome differs between macitentan and placebo, rather than whether macitentan remains within a prespecified non-inferiority margin.
Results: Primary Endpoint
The registry reports two formal primary-endpoint analyses, both comparing a macitentan dose with placebo. Both use the log-rank test, report hazard ratios, use all randomized patients, and specify superiority as the hypothesis type.
Macitentan 3 mg vs placebo
Time to first confirmed morbidity or mortality event
97.5% CI: 0.516–0.960 · P = 0.0108
Log-rank analysis; all randomized patients; data presented up to month 36.
The hazard ratio of 0.704 means that the estimated instantaneous rate of experiencing the first confirmed morbidity or mortality event was lower in the ACT-064992 3 mg group than in the placebo group within the reported time-to-event analysis. Expressed as a simple relative interpretation, the estimate corresponds to an approximately 29.6% lower estimated hazard relative to placebo.
The estimate does not mean that 29.6% of participants avoided an event, that each participant had exactly the same reduction in risk, or that the absolute event probability was reduced by that amount.
The 97.5% confidence interval of 0.516–0.960 describes statistical uncertainty around the estimated hazard ratio. Because the interval remains below the null value for a hazard ratio, the reported interval is consistent with a lower estimated event hazard for ACT-064992 3 mg than placebo under the stated analysis.
The P-value of 0.0108 addresses the evidence against the null hypothesis in the reported statistical test. It does not measure the magnitude or clinical importance of the treatment effect. Interpretation also depends on the time-to-event analysis, censoring, and the assumptions underlying a hazard-ratio summary.
Macitentan 10 mg vs placebo
Time to first confirmed morbidity or mortality event
97.5% CI: 0.392–0.762 · P < 0.0001
Log-rank analysis; all randomized patients; data presented up to month 36.
The hazard ratio of 0.547 indicates a lower estimated instantaneous rate of the first confirmed morbidity or mortality event in the ACT-064992 10 mg group relative to placebo under the reported analysis. As a direct mathematical interpretation of the reported estimate, this corresponds to an approximately 45.3% lower estimated hazard.
The hazard ratio does not mean that 45.3% of participants were protected from an event, nor does it describe an absolute difference in the probability of an event by a particular time.
The 97.5% confidence interval of 0.392–0.762 indicates the statistical precision of the reported hazard-ratio estimate. The interval lies below the null value, so the reported confidence interval is consistent with a lower estimated event hazard for ACT-064992 10 mg than placebo.
The P-value of <0.0001 describes the strength of evidence against the null hypothesis under the reported test. It should not be interpreted as a probability that the treatment works, a measure of effect size, or a measure of clinical importance.
| Primary comparison | Analysis population | Method | Hazard ratio | 97.5% CI | P-value |
|---|---|---|---|---|---|
| Placebo vs ACT-064992 3 mg | All randomized patients | Log-rank | 0.704 | 0.516–0.960 | 0.0108 |
| Placebo vs ACT-064992 10 mg | All randomized patients | Log-rank | 0.547 | 0.392–0.762 | <0.0001 |
Results: Secondary Endpoints
Time to death due to PAH or hospitalisation for PAH
| Comparison | Hazard ratio | 97.5% CI | P-value | Method |
|---|---|---|---|---|
| Placebo vs ACT-064992 3 mg | 0.669 | 0.462–0.970 | 0.0146 | Log-rank |
| Placebo vs ACT-064992 10 mg | 0.500 | 0.335–0.747 | <0.0001 | Log-rank |
These analyses use all randomized patients and assess time to death due to pulmonary arterial hypertension or hospitalisation for pulmonary arterial hypertension up to the end of treatment, with data presented up to month 36.
The ACT-064992 3 mg hazard ratio of 0.669 corresponds to an approximately 33.1% lower estimated hazard relative to placebo. The ACT-064992 10 mg hazard ratio of 0.500 corresponds to an approximately 50.0% lower estimated hazard relative to placebo. These are relative hazard interpretations, not absolute reductions in the probability of death or hospitalisation.
Time to death due to any cause up to the end of treatment
| Comparison | Hazard ratio | 97.5% CI | P-value | Method |
|---|---|---|---|---|
| Placebo vs ACT-064992 3 mg | 0.971 | 0.477–1.976 | 0.9249 | Log-rank |
| Placebo vs ACT-064992 10 mg | 0.638 | 0.287–1.418 | 0.2037 | Log-rank |
The reported hazard ratio for ACT-064992 3 mg versus placebo is 0.971, with a 97.5% confidence interval of 0.477–1.976 and P = 0.9249. The corresponding ACT-064992 10 mg comparison has a hazard ratio of 0.638, a 97.5% confidence interval of 0.287–1.418, and P = 0.2037.
For both comparisons, the confidence intervals include the null value. The statistical interpretation is therefore different from the primary composite endpoint: the ClinicalTrials.gov record does not provide evidence from these reported tests that the time to death from any cause up to the end of treatment differed between either macitentan dose and placebo.
Time to death due to any cause up to the end of study
| Comparison | Hazard ratio | 97.5% CI | P-value | Method |
|---|---|---|---|---|
| Placebo vs ACT-064992 3 mg | 1.046 | 0.653–1.673 | 0.8312 | Log-rank |
| Placebo vs ACT-064992 10 mg | 0.771 | 0.464–1.282 | 0.2509 | Log-rank |
The reported ACT-064992 3 mg hazard ratio is 1.046, with a 97.5% confidence interval of 0.653–1.673 and P = 0.8312. The ACT-064992 10 mg hazard ratio is 0.771, with a 97.5% confidence interval of 0.464–1.282 and P = 0.2509.
Both confidence intervals include the null value. These estimates therefore do not establish a statistically detectable difference in time to death due to any cause up to the end of study under the reported analyses.
Safety Results
The ClinicalTrials.gov record reports serious adverse events by randomized arm as the number of affected participants divided by the number at risk.
| Arm | Serious adverse events affected / at risk |
|---|---|
| Placebo | 137 / 249 |
| ACT-064992 3 mg | 130 / 250 |
| ACT-064992 10 mg | 109 / 242 |
These counts should be kept separate from the efficacy analyses. The primary efficacy analysis was based on all randomized patients, whereas serious adverse events are presented here as affected participants divided by participants at risk in each arm.
The ClinicalTrials.gov record does not provide a formal statistical comparison, confidence interval, or P-value for serious adverse events. Accordingly, the affected/at-risk counts are descriptive and are not converted into an inferential treatment comparison on this page.
Statistical Methods Explained
Why was a time-to-event endpoint appropriate for SERAPHIN?
The primary outcome is defined by the time until the first confirmed morbidity or mortality event. Time-to-event analysis preserves information about when events occur and can accommodate participants who have not yet experienced an event by the end of their observed follow-up.
What does the hazard ratio represent in this trial?
A hazard ratio summarizes the relative instantaneous event rate between a macitentan group and placebo during the analyzed follow-up. A value below the null value indicates a lower estimated event hazard in the macitentan group under the model used to summarize the time-to-event data.
Why is the hazard ratio not the same as a risk reduction?
The hazard ratio is a relative rate measure over time. It is not an absolute probability difference. For example, the primary hazard ratio of 0.547 should not be read as saying that the absolute probability of a morbidity or mortality event was reduced by 45.3%. The correct interpretation is that the estimated instantaneous event rate was lower by that relative amount under the reported hazard-ratio framework.
What does the confidence interval add?
The confidence interval communicates uncertainty around the estimated hazard ratio. A narrow interval indicates greater statistical precision than a wide interval, while the location of the interval relative to the null value helps describe the evidence from the corresponding statistical test.
Why use a log-rank test?
The log-rank test is designed for comparing time-to-event distributions between groups. It uses information from event times throughout follow-up rather than reducing the outcome to whether each participant eventually experienced an event.
What does the P-value tell us?
The P-value measures the degree of compatibility between the observed data and the null hypothesis under the specified statistical test. It does not measure effect size, clinical importance, or the probability that the treatment hypothesis is true.
Why does the analysis population matter?
The registry specifies all randomized patients for the reported primary and secondary analyses. Maintaining the randomized treatment assignment in the efficacy analysis helps preserve the balance created by randomization and avoids redefining the comparison according to treatment received after randomization.
Understanding the Primary Endpoint More Deeply
The primary endpoint combines several clinically important events into a single time-to-first-event outcome. This has an important statistical consequence: the hazard ratio describes the first qualifying event, regardless of which component of the composite occurs first.
Composite endpoint
The event definition includes death and several forms of clinical worsening, including atrial septostomy, lung transplantation, initiation of specified prostanoids, and other worsening of pulmonary arterial hypertension.
Time-to-first-event
Only the first qualifying morbidity or mortality event contributes as the primary event for an individual participant.
Kaplan-Meier perspective
The analysis estimates the probability of remaining free from the composite event as follow-up progresses.
Hazard-ratio perspective
The hazard ratio summarizes the relative instantaneous event rate between randomized treatment groups.
Interpreting the Pattern of Reported Results
The analyses posted on ClinicalTrials.gov show a consistent pattern for the primary composite endpoint: both macitentan comparisons have hazard ratios below the null value, with the reported confidence intervals remaining below the null value and the reported P-values indicating evidence against the corresponding null hypotheses.
The secondary endpoint results illustrate why a trial should not be summarized by one statistic alone. For time to death due to pulmonary arterial hypertension or hospitalisation for pulmonary arterial hypertension, the reported hazard ratios are also below the null value. For time to death due to any cause, however, the reported confidence intervals include the null value for both dose comparisons in the end-of-treatment analysis and in the end-of-study analysis.
The primary endpoint and the secondary endpoints are related but not interchangeable. A treatment effect on a composite morbidity-or-mortality endpoint does not automatically imply that every individual component, including death from any cause, will show the same estimated effect.
The ClinicalTrials.gov record reports hazard ratios and confidence intervals rather than the underlying Kaplan-Meier event-free percentages at specific time points. Consequently, this page does not manufacture absolute risk differences from the reported hazard ratios.
The P-values for the primary comparisons provide evidence from the specified statistical tests, but they do not quantify the size of the treatment effect. The hazard ratio and its confidence interval are the appropriate reported quantities for describing the relative magnitude and statistical precision of the primary treatment comparisons.
Assumptions and Cautions in Time-to-Event Analysis
Hazard ratios are useful summaries of time-to-event treatment effects, but their interpretation depends on the structure of the survival data and the model used to obtain the estimate. A hazard ratio is not a direct statement about cumulative risk at a particular time point.
- Censoring: Kaplan-Meier methods require appropriate handling of participants whose event status is not observed for the entire follow-up period.
- Event timing: time-to-event methods retain information about when events occur rather than treating all events as occurring at the same time.
- Composite endpoints: the primary outcome combines several clinically distinct events, so its hazard ratio summarizes the first occurrence of any qualifying component.
- Hazard-ratio interpretation: a single hazard ratio is a model-based relative measure and should not automatically be translated into an absolute risk difference.
- Proportional-hazards considerations: when a hazard ratio is used to summarize treatment effects, the extent to which the relative hazard remains reasonably represented by a single value over follow-up is an important interpretive consideration.
- Multiple comparisons: the registry supplies multiple primary and secondary statistical analyses, but the ClinicalTrials.gov record does not describe an alpha-allocation or multiplicity-adjustment procedure. This page therefore does not infer a multiplicity strategy that is not reported in the ClinicalTrials.gov record.
- Missing-data methodology: the registry extract does not specify a formal imputation strategy for the time-to-event analyses, so none is attributed to the trial here.
Design Features That Affect Statistical Interpretation
The ClinicalTrials.gov record does not report stratification factors, interim-analysis boundaries, a non-inferiority margin, crossover rules, a factorial structure, Bayesian methods, or a prespecified missing-data method. Those topics are therefore not presented as trial features.
Limitations
- Registry-data scope: this analysis is restricted to the numerical results and design information from ClinicalTrials.gov. It does not import additional numerical findings from publications.
- No baseline table: baseline demographic and clinical characteristics are not included in the ClinicalTrials.gov record.
- No median event times: median time-to-event estimates are not included in the statistical analyses posted on ClinicalTrials.gov.
- No Kaplan-Meier coordinates: the ClinicalTrials.gov record does not provide sufficient information to reconstruct the Kaplan-Meier curves or calculate time-specific event-free percentages.
- No subgroup analyses: the statistical analyses posted on ClinicalTrials.gov do not report subgroup-specific hazard ratios or interaction tests.
- No formal safety comparison: serious adverse events are reported descriptively by arm, without an inferential comparison in the ClinicalTrials.gov record.
- No documented multiplicity strategy in the registry-reported extract: multiple reported analyses are present, but an alpha hierarchy or multiplicity adjustment is not provided in the ClinicalTrials.gov record.
- Model assumptions: hazard ratios require appropriate interpretation in the context of the underlying time-to-event model and censoring structure.
Why This Trial Matters Statistically
SERAPHIN is a useful statistical teaching case because the trial combines randomized treatment allocation with a clinically meaningful composite time-to-event endpoint and several layers of survival analysis. The registry results allow the treatment comparison to be examined through the hazard ratio, confidence interval, log-rank test, and analysis population rather than through a single P-value.
| Statistical concept | How it appears in SERAPHIN |
|---|---|
| Randomization | Randomized parallel-group phase 3 design |
| Masking | Quadruple-masked study |
| Kaplan-Meier estimation | Primary and secondary endpoints reported as Kaplan-Meier time-to-event measures |
| Hazard ratio | Primary and secondary treatment effects reported as hazard ratios |
| Confidence interval | 97.5% confidence intervals reported for the formal statistical analyses |
| Log-rank test | Reported method for the primary and secondary time-to-event comparisons |
| Composite endpoint | Primary endpoint combines morbidity and mortality events |
| Superiority testing | Reported hypothesis type for the statistical analyses |
| Analysis population | All randomized patients for the reported efficacy analyses |
| Safety analysis | Serious adverse events reported descriptively by randomized arm |
Clinical Biostats Interpretation of the Evidence
What the primary analysis shows
The reported primary hazard ratios are below the null value for both macitentan dose comparisons, and both corresponding 97.5% confidence intervals remain below the null value.
What the secondary analyses show
The reported hazard ratios for death due to pulmonary arterial hypertension or hospitalisation for pulmonary arterial hypertension are below the null value for both dose comparisons. The reported all-cause mortality analyses have wider uncertainty and confidence intervals that include the null value.
What cannot be concluded from the ClinicalTrials.gov record
The registry extract does not support conclusions about subgroup heterogeneity, median survival, absolute event probabilities, or a formal multiplicity strategy.
Why the confidence intervals matter
The intervals show that statistical precision differs across endpoints. The all-cause mortality estimates have substantially wider intervals than the primary composite estimates.
Related Tutorials
Learn more about the methods used in this trial:
Related Calculators
Sources
- ClinicalTrials.gov: NCT00660179 — SERAPHIN.
- PubMed: PMID 23984728.
- PubMed: PMID 35917059.
- PubMed: PMID 35819570.
- PubMed: PMID 31109190.
- PubMed: PMID 29501590.
Continue through the Clinical Biostats statistical pathway
Connect the trial's time-to-event endpoints to deeper statistical tutorials and practical analysis tools.
Record Summary
SERAPHIN provides a clear example of how a randomized clinical trial can evaluate a composite morbidity-or-mortality endpoint using time-to-event methods. The registry analyses use all randomized patients, Kaplan-Meier estimation, log-rank testing, hazard ratios, and 97.5% confidence intervals. The primary comparisons report hazard ratios of 0.704 for ACT-064992 3 mg versus placebo and 0.547 for ACT-064992 10 mg versus placebo, while the reported all-cause mortality analyses show wider uncertainty. The statistical story is therefore best understood through the combination of the endpoint definition, analysis population, hazard-ratio estimates, confidence intervals, P-values, and the distinction between the composite primary endpoint and the secondary mortality endpoints.