A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/ZENITH): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/ZENITH) (NCT04896008), a randomized phase 3 study. The primary outcome is Time to First Confirmed Morbidity or Mortality Event.

2. Clinical Question

The registry describes a phase 3 study with randomized allocation, triple masking, and a parallel-group design. Its objective was to evaluate the effects of adding sotatercept to background therapy compared with adding placebo. The primary outcome combines distinct events: death, lung transplantation, and a qualifying hospitalization related to worsening PAH. These events were adjudicated by a blinded, independent committee of clinical experts, with the registry specifying that only adjudication-confirmed lung transplants and qualifying PAH-related hospitalizations entered the primary analysis. First events that were deaths were included regardless of adjudication.

The clinical question is consequently both comparative and time-based: whether the observed time until the first event differed between the assigned groups during follow-up. The registry reports arm-level Kaplan–Meier medians but does not report a sponsor hazard ratio or a primary between-group test in the registry record. The available primary endpoint summaries therefore describe the observed time-to-event results, but do not alone provide a reported estimate of the relative event rate over follow-up.

3. Trial Design

ZENITH, registered as NCT04896008, was a phase 3, randomized, double-blind, placebo-controlled study with triple masking and a parallel design. It enrolled 173 participants with PAH who were WHO functional class III or IV and at high risk of mortality. The study compared sotatercept plus maximum tolerated background PAH therapy with placebo plus maximum tolerated background therapy. The registry lists Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA, as the sponsor.

Sotatercept was given by subcutaneous injection every 21 days, beginning at 0.3 mg/kg with a target dose of 0.7 mg/kg. Placebo was also given by subcutaneous injection every 21 days. The planned contrast was thus between two groups receiving background PAH therapy, with the assigned study injection differing between groups.

The study start date was 2021-12-01, primary completion was 2024-07-26, and the registry status is completed. The primary endpoint timeframe is described as up to approximately 31 months. The primary-outcome population is defined as all randomized participants who received at least one dose of study treatment. The displayed arm summaries each include 86 participants. Although the registry reports overall enrollment of 173, it does not explain the relationship between that enrollment figure and the primary-outcome arm counts.

The registry lists overall survival, transplant-free survival, mortality events, risk-score outcomes, and measures of PAH status among the secondary outcomes. It lists 12 secondary outcomes and 13 outcome measures. A detailed statistical analysis plan, including the planned handling of interim analyses or sample-size justification, is not reported in the registry record.

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: Protocol-specified final analysis of all outcome measures is reported here. Per protocol, participants completing this study may have been eligible to enroll in an open-label, long-term follow-up study (MK-7962-004; NCT04796337).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All randomized participants who received at least one dose of study 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.

Population: Of the 173 participants randomized in the study, one participant was randomized in error to the placebo arm and then immediately discontinued. This participant did not receive study treatment, and no data was collected. As pre-specified in the SAP, this participant was excluded from all study analyses. 4 participants were randomized in violation of the protocol with a REVEAL score of \<9.

6. Primary Endpoint

The registry lists the primary outcome as Time to First Confirmed Morbidity or Mortality Event, measured over Up to approximately 31 months.

The primary endpoint measures the time from randomization until a participant’s first confirmed morbidity or mortality event. The composite includes all-cause death, lung transplantation, or hospitalization related to worsening PAH that lasts at least 24 hours. Combining these events allows the analysis to capture a range of serious outcomes rather than considering only one type of event. It also makes the timing of the first event relevant, not just whether an event occurred by a single fixed visit.

The registry states that a blinded, independent committee of clinical experts adjudicated events. Only adjudication-confirmed lung transplantation and qualifying PAH-worsening-related hospitalization were included in the primary analysis. Deaths that were a participant’s first event were included regardless of adjudication. This distinction matters because the endpoint is not simply a count of every suspected event; its components follow the registry’s stated confirmation rules.

The registry reports the time-to-event endpoint using the non-parametric Kaplan–Meier method and presents the median time in months. A median is the time by which the estimated event-free proportion reaches the halfway point, if that point can be estimated from follow-up. It is a summary of the timing distribution, not a direct measure of the number of events or of the relative event rate between groups. The endpoint is useful for describing how long participants remained without a first event, while interpretation of a treatment contrast also depends on comparative estimates and their uncertainty.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a time-to-event measure. Rather than recording only whether an event happened by a particular visit, it uses the interval from randomization to the first qualifying event. Participants who do not experience an event during observed follow-up can still contribute information up to the time they were last observed, depending on the analysis and censoring rules. Those rules are not reported in the registry record.

What does the Kaplan–Meier median describe?

The Kaplan–Meier method is a non-parametric way to estimate the probability of remaining free of the event over time. In general, it accounts for participants having different observed follow-up durations by incorporating their event-free time until an event or censoring. The median is the time at which the estimated event-free probability reaches one half, when that point can be determined. If the estimate does not reach that point during observed follow-up, the median is not reached. That outcome does not mean that the event never occurred in the group; it means the estimated curve did not fall to the median threshold within the available analysis.

A median confidence interval describes uncertainty around the estimated median. It is not a range containing a fixed proportion of individual participants’ event times. The registry reports a 95% confidence interval for the primary medians, but the sotatercept upper limit is not reported in the registry record. The median summaries do not by themselves quantify a relative treatment effect. A hazard ratio, for example, would summarize a relative event rate under its model assumptions, but a sponsor-reported hazard ratio is not reported in the registry record.

How are the events defined?

The primary composite includes all-cause death, lung transplantation, and PAH-worsening-related hospitalization lasting at least 24 hours. A blinded, independent committee of clinical experts adjudicated events. The registry specifies that only adjudication-confirmed lung transplantation and qualifying PAH-related hospitalization entered the primary analysis; deaths that were a participant’s first event were included regardless of adjudication. These rules define which potential events count toward the endpoint and should be kept in mind when interpreting its results.

How should the secondary comparisons be read?

Several secondary outcomes are expressed as percentages, including mortality events, attainment of a REVEAL Lite 2 risk-score threshold at Week 24, and improvement in WHO functional class. A risk difference expresses the difference between two observed proportions. Its confidence interval indicates the range of values compatible with the data under the calculation’s assumptions. If the interval includes no difference, the data do not rule out no difference at the corresponding confidence level. A p-value is a measure of how unusual the observed data would be under a specified null hypothesis and analysis; it is not the probability that the null hypothesis is true.

The additional secondary comparisons are labeled as recalculated, simple, unadjusted calculations from the posted summary statistics. They are not the registry’s reported sponsor analyses. The registry lists no reported analyses for these posted outcomes. Thus, their intervals and p-values should be understood as descriptive recalculations rather than as evidence that the sponsor used the same method or that the results formed part of a prespecified confirmatory test.

Why does multiplicity matter?

When several outcomes are examined, the chance of observing at least one apparently unusual result can increase, even if none of the underlying effects is real. In general, a multiplicity plan specifies how the analysis accounts for testing several hypotheses, often by controlling an overall error rate or by ordering tests. The registry does not report a multiplicity procedure or a hierarchy for the secondary outcomes. Consequently, unadjusted secondary p-values should not be interpreted as if they were protected by a reported family-wise testing plan.

What do the planning illustrations mean?

The sample-size illustrations are planning calculations based on the observed effect, not the study’s own design justification and not observed power. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. Such calculations show how the number of participants per arm would vary under those assumptions and effect choices. They do not establish the probability that this completed study detected an effect, and they do not describe the actual design rationale. The study’s sample-size justification is not reported in the registry record.

More generally, no statistical analysis plan, interim-analysis details, or full missing-data procedures are reported in the registry record. That absence limits what can be concluded about planned estimands, handling of follow-up, or adjustments to the testing strategy. Statistical interpretation should therefore distinguish the registry’s stated endpoint definitions and summaries from analyses that are not reported.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary time-to-first-event outcome and lists a broad range of secondary outcomes. It does not report a multiplicity adjustment, an ordered testing strategy, or a statistical hierarchy governing confirmatory interpretation. This matters because testing multiple outcomes can increase the chance of apparently notable findings under a setting where all null hypotheses are true. In the absence of a reported plan, the unadjusted secondary comparisons should not be treated as though they preserve a stated overall type I error rate.

The registry reports no sponsor analyses for the secondary results discussed with recalculated comparisons. Those calculations are unadjusted and based on posted summary statistics; they do not establish what methods were used in the sponsor’s analysis. The primary outcome also lacks a reported hazard ratio or primary between-group test in the registry record. Therefore, a complete account of the intended inferential pathway—from the primary hypothesis through secondary tests—is not available.

The primary-outcome population is defined as all randomized participants who received at least one dose of study treatment. The arm summaries each list 86 participants, while overall enrollment is 173. The registry record does not explain the difference in those counts or give enough detail to resolve it. Secondary outcomes use varying participant counts, including the Week 24 risk-score outcome, but reasons for the available analysis populations or any exclusions are not reported in the registry record.

Missing-data methods, censoring rules, and the handling of participants without measurements at a given time are not reported in the registry record. For the time-to-event outcome, censoring is relevant to the Kaplan–Meier estimate; for fixed-time outcomes, missing measurements can affect which participants contribute. Without the analysis details, the extent and consequences of missing data cannot be assessed from the registry summaries alone. Interim analyses and any associated adjustments are also not reported in the registry record.

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: pulmonary arterial hypertension (27.9%), right ventricular failure (19.8%), cardiac failure (9.3%), pneumonia (9.3%), pulmonary hypertension (7.0%).

The registry reports serious adverse events in 52 of 86 participants in the sotatercept group and 64 of 86 participants in the placebo group. Other adverse events are reported in 82 of 86 participants receiving sotatercept and 77 of 86 receiving placebo. The death counts listed in the adverse-event summary are 13 and 20, respectively. These are descriptive counts; they do not by themselves establish whether a difference between groups is statistically reliable or caused by the assigned treatment.

The registry also lists serious adverse event terms with percentages, including pulmonary arterial hypertension at 27.9%, right ventricular failure at 19.8%, cardiac failure at 9.3%, pneumonia at 9.3%, pulmonary hypertension at 7.0%, and atrial fibrillation at 5.8%. The registry record does not provide enough detail in these figures to infer event timing, recurrence, severity grading, or the precise denominator for each listed term. The terms may not represent mutually exclusive groups of participants, so they should not be added together.

Safety counts describe events recorded during the study and are not a substitute for a comparative safety analysis that accounts for exposure and follow-up. They also do not establish causality. Interpretation should remain bounded to the posted counts and the definitions available in the registry record.

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

The primary endpoint results describe the observed time-to-first-event experience in the two study groups. The sotatercept median was not reached, with a reported lower 95% confidence limit of 25.4 months; the placebo median was 9.6 months, with a 95% confidence interval from 5.9 to 14.8 months. This tells the reader that the median could not be estimated for one group within the analysis, while it could be estimated for the other. It does not provide a direct estimate of the relative event rate across the full follow-up period.

The registry does not report a primary hazard ratio, confidence interval for a comparative effect, or primary p-value. As a result, the arm-specific medians should not be treated as a complete statistical test of the primary comparison. The available figures do not establish the size or precision of a primary treatment effect, and they do not determine whether the observed difference could plausibly reflect chance under the study’s planned analysis.

Secondary outcomes add information on mortality events, functional class, risk score, and other measures, but those outcomes differ from the primary composite and have their own timeframes and analysis populations. Recalculated secondary comparisons are unadjusted, and sponsor-reported analyses are not listed. They should therefore not be used to replace the missing primary comparative result or to claim a multiplicity-controlled conclusion.

These findings also do not establish what would happen for every participant with PAH, for people outside the study’s high-risk WHO functional class III or IV population, or under background treatment different from that described. The registry record gives group summaries, not individual participant trajectories or a full account of the statistical analysis plan. The most defensible reading is that the posted data describe a completed randomized comparison and its outcome summaries, while important details needed for a full assessment of comparative efficacy and inferential strength are not reported in the registry record.

13. Why This Trial Matters Statistically

This study is statistically notable because its primary outcome combines serious clinical events and analyzes the time until the first event. That approach preserves information about when events occur, rather than reducing follow-up to a single yes-or-no status at one visit. It also makes the endpoint dependent on clear component definitions and consistent event confirmation. The registry’s description of blinded independent adjudication, together with its distinct rules for deaths and other components, is therefore important to understanding what the endpoint represents.

The study also illustrates why an arm-level median is not the same as a comparative treatment estimate. A median that is not reached can be informative about the estimated event-free experience, but a direct assessment of the contrast requires a comparative analysis and its uncertainty. The registry record reports the medians but does not report the sponsor’s primary hazard ratio or a primary test. That omission constrains the statistical conclusions even when the arm summaries appear different.

Multiple secondary outcomes broaden the clinical picture, but they also make prespecification and multiplicity handling important. The registry lists outcomes across survival, functional status, risk scoring, and physiological measures, while not reporting a testing hierarchy or multiplicity procedure. This is a useful example of why a set of favorable-looking unadjusted findings cannot automatically be read as a collection of confirmatory results.

Finally, the trial has an explicitly defined high-risk population and a comparison that adds the study injection to background PAH therapy in both groups. Those design features shape the interpretation and limits of generalization. The registry summaries can inform how the study was structured and what was posted, while the absent analysis details and primary comparative estimate leave material questions about precision and inferential strength unresolved.

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 trial-specific limitation in the posted statistical record is that the primary endpoint is presented as arm-level medians without a reported primary comparative estimate or test. The sotatercept median is not reached, and its upper confidence limit is not reported in the registry record. As a result, the summaries do not quantify a relative effect or fully describe uncertainty in the primary group contrast.

The primary endpoint is a composite of death, lung transplantation, and qualifying PAH-related hospitalization. Such components differ in nature, and the registry does not provide component-specific primary event counts in the posted primary summary. The adjudication rules are described, but further detail about the adjudication process and event timing is not reported in the registry record. The listed timeframe extends up to approximately 31 months, so the summaries do not describe longer-term outcomes.

The reported overall enrollment is 173, while the primary-outcome arm summaries each include 86 participants. The registry record does not explain that difference. The primary population definition also requires at least one dose of study treatment, and reasons for any differences between randomized, treated, and analyzed participants are not reported in the registry record. Secondary outcomes have differing analysis counts and timeframes, with no reported explanation for missing measurements or exclusions.

Further limitations include the absence of a posted statistical analysis plan, sample-size justification, interim-analysis details, censoring rules, and missing-data procedures. The registry also does not report multiplicity control for the secondary outcomes. Recalculated secondary comparisons are unadjusted rather than sponsor-reported analyses. These gaps limit assessment of whether the posted summaries correspond to prespecified methods and how much confidence to place in exploratory differences.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/ZENITH) — NCT04896008.
• Registry record last updated 2026-05-29; status last verified 2026-05.
• Results first posted 2025-08-22.
• 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

NCT04896008, titled A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/ZENITH), is a completed phase 3 randomized, double-blind, placebo-controlled parallel study. It enrolled 173 participants with high-risk PAH in WHO functional class III or IV. Sotatercept was compared with placebo, with both groups receiving maximum tolerated background PAH therapy.

The primary outcome was time to the first confirmed morbidity or mortality event, defined as all-cause death, lung transplantation, or PAH-worsening-related hospitalization lasting at least 24 hours. The registry reports a median not reached in the sotatercept group and a median of 9.6 months in the placebo group. It does not report a primary comparative hazard ratio or test.

The registry lists secondary outcomes across survival, mortality, risk scores, functional class, biomarkers, and hemodynamic measures. It also reports adverse-event counts. Detailed multiplicity, missing-data, and analysis-plan information is not reported in the registry record.