Clinical Study of Macitentan in Patients With PAH to Psychometrically Validate PAH-SYMPACT Instrument: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Clinical Study of Macitentan in Patients With PAH to Psychometrically Validate PAH-SYMPACT Instrument (NCT01847014), a na phase 3 study. The primary outcome is Incident Rate of Adverse Events (AEs)..

2. Clinical Question

The study’s stated objective was to assess the long-term safety of macitentan in participants with pulmonary arterial hypertension beyond treatment in AC-055-401. Its title also describes the extension as part of a program to psychometrically validate the PAH-SYMPACT instrument, but the primary outcome listed in this record is an adverse-event count. This distinction matters: the posted primary result addresses safety-event reporting, not the psychometric performance of the instrument.

Because all four participants entered the extension after completing the preceding study, the question concerns a small, selected group continuing into follow-up. It is not a comparison of macitentan with placebo or another treatment, and it cannot estimate a between-group difference. The registry record does not report a separate control group or a randomized allocation.

3. Trial Design

This is a Phase 3b, open-label, single-arm extension study of macitentan in participants with pulmonary arterial hypertension. It is described as an extension of AC-055-401, a multicenter study. The intervention group received macitentan tablets at 10 mg once daily. Masking is listed as none, and allocation is not applicable because the study has one group rather than randomized treatment groups.

The registry lists an enrollment of four. The primary-outcome population is also described as four participants in the Extension Analysis Set, all of whom transitioned from completion of SYMPHONY AC-055-401 to this extension. The record gives a study start date of 2013-09-01, a primary completion date of 2015-10-01, and a status of terminated. It does not report why the study was terminated.

The primary outcome is the number of participants with incident adverse events. Its stated observation window runs from Visit 1 through the post-treatment safety follow-up visit, which was 30 days after discontinuation of study drug. The description says safety events were reported and documented as defined in the study protocol from baseline through the end of treatment, including the safety follow-up. Further detail about visit schedules, treatment duration, or the circumstances of discontinuation is not reported in the registry record.

A single-group extension can describe events observed among participants receiving the study drug, but it has no concurrent control group for separating treatment-related events from events that might have occurred for other reasons. The record also does not report a randomized comparison, an allocation procedure, or masking.

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: Subjects who completed the sixteen week treatment of macitentan on the SYMPHONY AC-055-401 clinical trial were eligible to enter this open-label extension study.

Baseline Extension Visit

Completion of Extension Study

Analysis population for the primary outcome, as defined in the registry: Four participants represent the Extension Analysis Set, who transitioned from completion of SYMPHONY AC-055-401 to this open-label extension clinical trial.

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: A total of four participants enrolled directly from the parent clinical trial, SYMPHONY AC-055-401 (NCT01841762). There was only one arm associated with the Extension study.

6. Primary Endpoint

The registry lists the primary outcome as Incident Rate of Adverse Events (AEs)., measured over From Visit 1 to Post-treatment safety follow-up visit (30 days after discontinuation of the study drug)..

The primary endpoint is titled “Incident Rate of Adverse Events (AEs),” but the unit and parameter identify it as a count of participants, not a person-time rate. It records how many participants experienced adverse events during the specified observation period. The record says events were documented according to the study protocol from baseline through the end of treatment, including safety follow-up.

Safety endpoints are used to describe the kinds of events observed and how many participants experienced them during study participation. In an extension, such monitoring is relevant to the stated goal of assessing safety beyond treatment in the preceding study. The outcome does not, by itself, establish that an event was caused by macitentan; attribution methods are not reported in the registry record.

The posted primary result is a participant count in a group of four. A count gives a direct description of this small study group, but it does not express the duration each participant was at risk or estimate an event rate over person-time. No confidence interval, formal comparative estimate, or analysis result is reported. The endpoint should therefore be read as a descriptive record of participants with events within the stated follow-up window, not as an estimate of comparative risk or a test of treatment effect.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count describe?

A participant count describes how many people in a defined analysis group experienced an event during a specified observation period. It is different from a count of event episodes: one participant may experience more than one event, and the record does not provide enough detail to determine how repeated events were handled. The primary outcome is explicitly characterized as a count of participants. Although its title uses “Incident Rate,” the record does not supply person-time, so it should not be interpreted as a person-time rate.

For a count to be interpretable, the population and observation window need to be clear. The registry identifies four participants in the Extension Analysis Set and defines the outcome window as Visit 1 through the post-treatment safety follow-up visit, 30 days after discontinuation. It does not provide participant-level follow-up durations, so the total time under observation cannot be derived from the posted information.

Why does an uncontrolled design limit interpretation?

In a single-group study, all participants receive the same listed intervention, and no concurrent control group is available for comparison. As a general statistical principle, a control group helps distinguish changes or events associated with the intervention from changes that might occur without it. Without that comparison, the observed event counts are descriptive. They do not estimate a difference between treatments or isolate the cause of an event.

Open-label means masking is listed as none. In general, knowledge of treatment assignment can affect reporting, observation, or classification of outcomes, particularly when outcome assessment involves judgment. The registry record does not describe event-adjudication procedures, so no conclusion about how events were classified beyond the stated protocol-based documentation can be made.

What would uncertainty measures add?

A confidence interval is a statistical range expressing uncertainty around an estimated quantity under the assumptions of the analysis. General statistical reasoning suggests that estimates based on very few participants are typically imprecise. However, no confidence interval or other uncertainty interval is reported for these event counts, and none can be added without an analysis and assumptions that are not in the record.

A p-value, when used, summarizes how compatible data are with a specified statistical model and null hypothesis. It does not measure the probability that a treatment works, nor does it establish causation. The registry record lists no analyses and reports no p-values for the primary outcome. There is therefore no inferential test to interpret for this endpoint.

Why are serious-event terms not a comparative result?

The serious-event information identifies participants at risk, participants affected, and terms reported for the macitentan group. Those data can describe what was recorded in this study. They do not create a comparison group or show whether a term occurred more often than it would have without the intervention. The record does not clarify whether the listed terms overlap within participants or how event-term counts relate to the number of affected participants.

General statistical practice also distinguishes an event’s seriousness from its severity or causal relationship to a treatment. The registry provides serious-event counts and terms, but it does not provide a detailed severity scale or causal-attribution results. The listed terms should therefore be read as reported safety information, not as proof of a drug-related cause.

How should planning illustrations be understood?

The record describes sample-size assumptions for planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect. These assumptions describe an illustration, not the design of this single-arm extension. The record does not provide a trial-specific sample-size justification, and no sample-size illustration can be interpreted as observed power. Planning calculations concern hypothetical future study designs; they do not change what the four participants’ observed counts mean.

General power calculations depend on a specified effect, variability or event frequency, design, and analysis assumptions. If those inputs do not represent a future study, the resulting planning numbers may not apply. The registry record does not report a planned comparative hypothesis or trial-specific power rationale for this extension.

What can be concluded from the reported analysis?

The primary outcome is a descriptive safety count in the stated extension population. Since no analysis results beyond event counts are reported, statistical significance, adjusted effects, and precision estimates cannot be assessed. The study’s design and the small analysis set also prevent a reliable comparative interpretation. These are limits of the information and design, not evidence that an event did or did not occur outside the recorded participants.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome measure and zero analyses. It does not report a multiplicity-adjustment procedure, a hierarchy of outcomes, or a prespecified strategy for controlling the chance of false-positive findings across multiple tests. Because no inferential analyses are listed, there are no reported p-values whose multiplicity adjustment can be evaluated. The presence of one listed primary measure does not establish that no other outcomes were collected; other outcome details are not reported in the registry record.

The primary-outcome population is explicitly described as four participants who transitioned from AC-055-401 to the extension. The adverse-event record also lists four participants at risk in the macitentan group. This defines the denominator for the posted safety counts, but the record does not describe whether any participants had incomplete follow-up, how missing safety information was handled, or whether any data were excluded from specific summaries.

Missing-data methods matter because incomplete observation can affect what event counts capture. As a general principle, a participant with less follow-up may have less opportunity for an event to be recorded. The record provides a follow-up window ending at a visit 30 days after drug discontinuation, but it does not report individual exposure or follow-up times, missing-data assumptions, or imputation methods. It is therefore not possible to assess the influence of incomplete data from this record.

The named Extension Analysis Set is the stated population for the primary endpoint. A broader definition of analysis populations, such as a safety population or an intention-to-treat population, is not reported in the registry record. The record also does not describe whether all enrolled participants completed the extension or how the terminated status affected analysis populations.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: chronic obstructive pulmonary disease exacerbation (25.0%), pulmonary arterial hypertension exacerbation (25.0%), pulmonary hypertension exacerbation (25.0%), right heart failure (25.0%).

The serious adverse-event figures indicate that one of the four participants at risk in the macitentan group was recorded as affected by a serious adverse event. The record lists four serious-event terms, each reported as 25.0%: chronic obstructive pulmonary disease exacerbation, pulmonary arterial hypertension exacerbation, pulmonary hypertension exacerbation, and right heart failure. No deaths were recorded. These figures describe the safety information reported for this group; they do not compare risk with another group.

The term-level percentages should not automatically be read as four distinct participants. The registry does not state whether terms overlapped within a participant, whether multiple events occurred in one person, or whether the term list represents unique people or event records. The one participant affected by a serious event and the four listed terms therefore cannot be reconciled into a unique-participant pattern from the record alone.

Three participants were recorded as affected by other adverse events. The record does not provide further detail about their event types in this summary. Seriousness is a reporting classification, not necessarily a measure of intensity or proof of causation. The registry record does not report causal attribution for these events. Because the study was open-label, single-arm, and included four participants, these counts are descriptive and cannot establish comparative risk or determine whether an event was caused by macitentan.

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

The result establishes a limited descriptive fact: adverse events were recorded in the four-person extension analysis set during the stated observation window. One participant was affected by a serious adverse event, three by other adverse events, and no deaths were recorded. The serious-event terms and their reported percentages provide additional descriptions, but the record does not clarify whether terms overlapped within participants.

The result does not show how the event counts compare with those under another treatment or no treatment. There is no separate comparator group, and allocation is listed as not applicable. Consequently, the study cannot estimate a treatment difference or determine whether macitentan caused a particular event. These limitations apply even when an event is clinically important: its appearance in a safety record does not alone establish its cause.

The counts also do not establish how precisely the observed pattern represents participants beyond this small extension group. No confidence intervals are reported, and the registry does not provide a person-time denominator or individual follow-up durations. The endpoint is a participant count, notwithstanding the word “rate” in its title. It should not be interpreted as an incidence rate over a known amount of time.

The stated objective was to assess long-term safety beyond treatment in AC-055-401. The record documents an extension and its adverse-event result, but it does not report a comparative long-term estimate or detailed duration of exposure. The title references psychometric validation of PAH-SYMPACT, yet the primary outcome listed is an adverse-event count; psychometric results are not reported in the registry record.

Finally, the terminated status is part of the record, but the reason for termination and its implications for the planned study are not reported. It is not possible to infer from the status alone whether termination affected event reporting, completion, or interpretation. The appropriate conclusion is descriptive and specific to the recorded participants, not a general claim about safety in a wider population.

13. Why This Trial Matters Statistically

This study illustrates why endpoint labels, denominators, and design need to be read together. The primary outcome title uses the phrase “Incident Rate,” while the listed parameter is a count of participants. Without person-time, the result does not express an event rate over time. Recognizing the distinction prevents a count from being interpreted as a rate with a time denominator that is not reported.

It also demonstrates the limits of an extension cohort as a source of safety information. The four participants were not an independently randomized sample: they transitioned from completion of AC-055-401. The extension can record events in these participants during continued follow-up, but its single-group design provides no contemporaneous comparison. The result is therefore useful as a description of observed events, not as a comparative estimate.

Small analysis populations make transparent reporting especially important. The registry gives the number at risk and the number affected, along with serious-event terms, but does not explain whether terms overlap or provide participant-level event histories. That missing detail affects how the event-term list should be understood. It also underscores the importance of reporting denominators and clear definitions alongside percentages.

The record separates two ideas that can otherwise be conflated: the study title references psychometric validation of PAH-SYMPACT, while the primary endpoint reported is adverse events. A study’s title and objective do not substitute for outcome-specific results. Readers need to assess what the registry actually reports for each endpoint and what is absent.

More broadly, this record is a reminder that descriptive safety information and causal evidence are different. Counts can document events in a particular group and observation window. They cannot alone show what would have happened to the same participants under a different treatment, or identify the cause of an event. A cautious interpretation preserves the value of the observations without asking them to answer questions the design and reporting do not address.

14. 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 is the size and composition of the extension analysis set: four participants, all of whom transitioned after completing AC-055-401. The registry does not report a concurrent comparator, randomization, or masking. This leaves the event counts descriptive and limits their relevance to people outside this selected group.

The event outcome is described as an incident rate, but its parameter is a count of participants. No person-time denominator, individual follow-up duration, or exposure duration is reported. The follow-up window is specified as ending at a visit 30 days after discontinuation, but the record does not describe how long each participant remained on treatment or under observation.

The serious-event terms are listed with percentages, but the record does not say whether the terms overlap within participants or whether multiple events were counted for any person. It also does not report event-level dates, severity, causal attribution, adjudication procedures, or a detailed account of other adverse events. These gaps constrain interpretation of the safety summaries.

The record lists no analyses. It does not provide confidence intervals, p-values, adjusted estimates, missing-data methods, a multiplicity strategy, or a trial-specific sample-size justification. The reasons for termination and the effect, if any, of termination on follow-up or analysis are not reported in the registry record. The title refers to psychometric validation of PAH-SYMPACT, but results for that instrument are not reported in the registry record. These limitations mean the available information cannot answer comparative, causal, or psychometric questions.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Clinical Study of Macitentan in Patients With PAH to Psychometrically Validate PAH-SYMPACT Instrument — NCT01847014.
• Registry record last updated 2018-08-22; status last verified 2018-06.
• Results first posted 2018-08-22.
• 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.

18. Record Summary

NCT01847014 is a Phase 3b, open-label, single-arm extension study of macitentan in pulmonary arterial hypertension. It is described as an extension of AC-055-401, with a stated objective of assessing long-term safety beyond treatment in that study. Four participants transitioned into the Extension Analysis Set and received macitentan tablets at 10 mg once daily.

The primary outcome is a count of participants with adverse events from Visit 1 through the post-treatment safety follow-up visit, 30 days after drug discontinuation. The posted safety results record one participant with a serious adverse event, three with other adverse events, and zero deaths. Four serious-event terms are listed, each at 25.0%.

The study is listed as terminated. It has no separate comparator group, and the registry lists no analyses. Reasons for termination, confidence intervals, missing-data methods, and comparative or psychometric results are not reported in the registry record. The safety counts are descriptive observations from this four-participant extension, not comparative treatment estimates.