A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (PAH): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (PAH) (NCT03496207), a randomized phase 2 study. The primary outcome is Base Study: Change From Baseline in Pulmonary Vascular Resistance (PVR) at 24 Weeks.

2. Clinical Question

The registry identifies this as a Phase 2, randomized, parallel-group study with quadruple masking. Its stated purpose was to compare the efficacy and safety of sotatercept with placebo when each was added to SOC. The clinical question is about the study-period comparison, not a comparison of sotatercept with no care: participants in every Base Study arm received SOC.

The record also describes a 30-month extension period, during which all participants would receive sotatercept, followed by a follow-up period after the last study drug treatment for all treated participants. Those later periods do not preserve the original placebo comparison in the same way as the placebo-controlled Base Study. The primary clinical question is therefore anchored to the 24-week endpoint.

3. Trial Design

This was a Phase 2, randomized, parallel-group, placebo-controlled study in adults with PAH. The registry reports enrollment of 106 participants and identifies quadruple masking. It does not describe which groups of people were masked or give further details about how masking was maintained. The sponsor is Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA.

During the 24-week Base Study treatment period, participants received placebo plus SOC, sotatercept 0.3 mg/kg plus SOC, or sotatercept 0.7 mg/kg plus SOC. Study drugs were administered by subcutaneous injection once every 3 weeks. The sotatercept arm descriptions state that doses could be titrated per protocol. The registry does not report the allocation ratio or the number assigned to each arm in the design description.

After the placebo-controlled period, participants were eligible to enroll in a 30-month extension period in which all participants would receive sotatercept. The adverse-event record separates extension groups by their prior Base Study assignment and extension treatment. All treated participants were also to undergo follow-up after their last study drug treatment.

The study started on 2018-06-13, had a primary completion date of 2022-03-09, and is listed as completed. These dates describe the registry record and do not by themselves establish when every analysis was completed or reported. The registry lists 23 outcome measures and 4 analyses. It does not report the full statistical analysis plan, the sample-size justification, or the allocation procedure beyond identifying the study as randomized.

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.

Base Study

Reasons for not completing this period:

Extension Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All randomized participants administered their assigned treatment who received at least 6 of the same doses during Base Study, had baseline and post-Base Study PVR assessment and End of Treatment (EOT) assessment. Note: Data from participants whose dose was down-titrated were analyzed according to dose received at least 6 times rather than dose originally assigned. Per protocol, only participants who consistently received in 0.3 mg/kg or 0.7 mg/kg of sotatercept were planned to be analyzed.

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 Base Study: Change From Baseline in Pulmonary Vascular Resistance (PVR) at 24 Weeks, measured over Baseline and 24 weeks.

The primary endpoint was change from baseline in pulmonary vascular resistance (PVR) at 24 weeks, measured in dynes*sec/cm^5. PVR was measured at rest in the supine position by right heart catheterization at baseline and at 24 weeks. The endpoint uses each participant’s difference between those assessments, then describes the outcome as a mean for the relevant group.

PVR is a hemodynamic measure of resistance to blood flow through the pulmonary circulation. In general, measuring it can help characterize pulmonary vascular physiology and track how that measure changes over the study period. A change-from-baseline endpoint focuses on how the measurement changes within participants rather than comparing only the final measurement. Randomized groups can then be compared on their average changes, subject to the analysis methods and population used.

The registry identifies the endpoint parameter as a mean and its dispersion as standard deviation. A standard deviation describes the spread of individual observations around the group mean; it does not, by itself, indicate how precisely the mean has been estimated. A confidence interval would help express uncertainty around an estimated group effect, but a numerical endpoint estimate, its uncertainty, and a p-value are not reported in the registry record. The measurement description and endpoint definition can therefore be explained, but the magnitude and precision of the observed result cannot be interpreted from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a change-from-baseline mean represent?

For this endpoint, the measurement at baseline is compared with the measurement at 24 weeks for each participant. A group mean change summarizes those participant-level changes. In general, a mean is useful for describing the average response on a continuous scale, while the standard deviation describes how dispersed individual changes are around that average. These quantities answer different questions: the mean concerns the center of the observations, and the standard deviation concerns their variability.

A mean change does not reveal whether every participant changed in the same direction. Some individual measurements may be above the group average and some below it. General statistical interpretation therefore considers both the estimated average and the uncertainty around it, as well as how much individual responses vary. The registry identifies mean and standard deviation as the endpoint summary measures, but does not report their numerical values for the primary endpoint.

Why compare randomized groups?

Random allocation is intended, in general, to make treatment groups comparable on average at the time of assignment, including with respect to factors that are measured and factors that are not measured. This supports interpreting a difference in outcomes between groups as an estimate of the effect of assignment to the compared study regimens, subject to adherence, missing data, analysis choices, and other study limitations. Randomization does not guarantee that every group characteristic will be identical in a particular trial.

Here, the treatment contrast is sotatercept plus SOC versus placebo plus SOC. The two sotatercept doses are separate study arms, and the protocol allowed dose titration. The registry describes the study as randomized but does not report the allocation ratio, the randomization method, or the detailed statistical comparison plan. It is therefore not possible to reconstruct the exact analysis from the registry record.

What does a confidence interval add?

In general, a confidence interval presents uncertainty around an estimated effect. A narrower interval indicates greater precision under the analysis assumptions; a wider interval indicates less precision. An interval can help readers distinguish an estimate that is relatively precise from one that remains compatible with a broad range of effects. Its interpretation depends on the endpoint, analysis population, model, and assumptions used.

No numerical confidence interval or estimated primary between-group effect is reported in the registry record. A p-value is also not reported for this endpoint. Without these quantities, the primary result cannot be evaluated for statistical compatibility with a null hypothesis or for precision. The study’s randomized design alone does not supply those missing results.

Why can over-dispersion matter?

General explanation: over-dispersion occurs when observed variability is greater than a statistical model expects. If a model assumes less variability than the data actually contain, standard errors can be too small and uncertainty can be understated. For a continuous outcome, the spread of measurements and the chosen model affect precision estimates. The registry describes PVR as a continuous measure summarized by a mean and standard deviation, but does not report a model or state whether over-dispersion was assessed. No claim about whether it mattered in this study can be made.

How should planning illustrations be read?

General explanation: sample-size planning asks how many participants might be needed under specified assumptions to detect an effect with a chosen significance level and power. Such calculations depend on assumptions about the effect to detect, variability, allocation, and analysis. They are planning exercises, not a measure of the probability that a completed trial found a real effect. A retrospective calculation based on an observed effect is not observed power.

The planning illustration associated with the study is described as using the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Its target effect is expressed as a stated fraction of the observed effect. Those are assumptions for an illustration, not reported features of the trial’s original design. The sample-size justification used by the investigators is not reported in the registry record. The illustrative participant counts should not be interpreted as the number enrolled, the number analyzed, or evidence about the strength of the trial’s result.

For comparisons involving a continuous outcome, a planning calculation may express the required sample size as participants per arm for a chosen power. The displayed planning values should be read according to the assumptions attached to them, and not as observed results. The registry does not establish that the trial was designed using those retrospective assumptions.

Why does the analysis population affect interpretation?

The registry’s primary endpoint population requires treatment administration, at least 6 of the same doses, baseline and post-Base Study PVR assessments, and an End of Treatment assessment. In general, restricting an analysis to participants with specified treatment exposure and measurements can make the analyzed group different from all randomized participants. This can affect how broadly a result applies and can introduce bias if inclusion is related to outcomes or treatment response. Whether that occurred cannot be determined from the population definition alone.

The registry does not report the number of participants included in the primary analysis, a complete description of the analysis model, or the procedures used for missing measurements. It also does not report whether analyses were adjusted for baseline values or other covariates. These are important details for understanding precision and the assumptions behind any reported estimate, and they are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 23 outcome measures and 4 analyses. The secondary outcomes include changes in 6-minute walk distance, NT-proBNP, TAPSE, CAMPHOR score, and SF-36 score, as well as clinical worsening, improvement in WHO functional class, and adverse events. These outcomes cover different types of measures and time points. Their presence does not establish which comparisons were considered confirmatory or how their results were prioritized.

When multiple outcomes or comparisons are evaluated, the chance of obtaining at least one apparently notable result can increase. General statistical practice may address this through a prespecified hierarchy, adjustment, or clearly labeled exploratory interpretation. The registry does not report a multiplicity-control strategy or identify a testing hierarchy. It also does not report a complete statistical analysis plan, so it is not possible to determine how multiplicity was handled.

Missing-data methods are not reported in the registry record. The primary endpoint population requires baseline and post-Base Study PVR assessments and an End of Treatment assessment. That definition identifies assessment availability as a criterion for inclusion, but does not explain how missing values were handled in any analysis, why assessments may have been unavailable, or how many participants were excluded for that reason. It is also not reported whether imputation or sensitivity analyses were used.

The registry does not provide the complete analysis population counts for each endpoint or explain whether all analyses used the same participants. Those omissions limit assessment of the potential effects of missing data and population selection. A complete interpretation would require the analysis methods and results, including relevant participant flow and uncertainty estimates; these details are 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: device malfunction (13.3%), pneumonia (8.3%), tachycardia paroxysmal (6.7%), bronchitis (6.7%), gastrointestinal infection (6.7%).

The Base Study safety groups report participants at risk and participants affected for serious adverse events, other adverse events, and deaths. For example, the placebo group lists 32 participants at risk for serious adverse events and 3 affected; the 0.3 mg/kg sotatercept group lists 32 at risk and 2 affected; and the 0.7 mg/kg group lists 42 at risk and 10 affected. These are group-specific counts, not adjusted comparisons.

For other adverse events, the corresponding counts are 25 of 32 in the placebo group, 29 of 32 in the 0.3 mg/kg group, and 33 of 42 in the 0.7 mg/kg group. Deaths are listed as 0, 0, and 1 for those Base Study groups, respectively. The extension groups are reported separately and occur after participants entered a period in which they received sotatercept. They should not be treated as additional concurrent randomized comparisons with the Base Study placebo group.

The registry also lists serious adverse event terms, including Device malfunction at 13.3%, Pneumonia at 8.3%, Tachycardia paroxysmal at 6.7%, Bronchitis at 6.7%, Gastrointestinal infection at 6.7%, and Pyelonephritis at 6.7%. The denominator and detailed event-counting rules for these percentages are not reported in the registry record.

In general, adverse-event counts describe events observed in the recorded groups; they do not alone establish causation or a comparative safety effect. Exposure duration, definitions, and analysis methods matter, and detailed comparative safety methods are not reported in the registry record.

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

The study design addresses a specific statistical question: how PVR changed over the 24-week placebo-controlled treatment period in participants assigned to sotatercept plus SOC compared with participants assigned to placebo plus SOC. The endpoint definition, measurement method, treatment groups, and primary analysis population are described in the registry. These details help define what an eventual estimate would represent.

However, numerical results for the primary endpoint are not reported in the registry record. There is no reported estimate of the average change by group, no between-group contrast, and no interval or p-value to describe precision or statistical uncertainty. The direction and magnitude of the primary finding therefore cannot be stated. The study’s existence, enrollment, and design do not establish an efficacy result.

Even where safety counts are reported, they need to be read as counts within the listed groups and periods. The extension groups are not equivalent to the original placebo-controlled comparison because the extension period involved sotatercept for all participants. Counts alone do not show whether an event was caused by study treatment or whether rates differed after accounting for exposure and other factors. Detailed event definitions and comparative analyses are not reported in the registry record.

In general, a statistically estimated difference and its clinical importance are distinct questions. Statistical precision concerns how uncertain an estimate is under its model and assumptions. Clinical importance requires context about the measurement and what magnitude of change matters. Neither can be assessed for the primary endpoint without its numerical estimate and uncertainty, and the registry does not report a threshold for interpreting a meaningful PVR change.

The appropriate conclusion from this record is limited: it describes a randomized, masked, placebo-controlled design and a 24-week PVR endpoint, but does not report the numerical primary outcome results needed to determine what the study observed. This absence should not be converted into a claim of benefit, lack of benefit, or equivalence.

13. Why This Trial Matters Statistically

This trial illustrates why statistical interpretation begins with the exact endpoint and analysis population. PVR was measured at baseline and 24 weeks by right heart catheterization, and the primary outcome was change from baseline. That specification distinguishes the measurement, timing, and summary target from the broader study purpose of evaluating efficacy and safety.

The three-arm Base Study also makes the comparison structure important. Each sotatercept dose was added to SOC, while the comparator received placebo plus SOC. The two dose groups should be considered separately unless a prespecified analysis combines them; whether any such combination was planned is not reported in the registry record. Dose titration was allowed in the sotatercept groups, another feature relevant to how an assigned regimen is interpreted.

The study’s extension period raises a further design distinction. All participants received sotatercept during that period, so the extension can contribute follow-up and safety information but does not maintain the original placebo-controlled contrast. Separating Base Study and extension data avoids treating groups from different treatment periods as if they were concurrent randomized arms.

Finally, this record shows the difference between a defined trial and a fully interpretable result. A randomized design can support comparative inference in principle, but readers still need the estimated effects, uncertainty, analysis populations, and handling of missing data and multiple outcomes. Those numerical efficacy results and several analysis details are not reported in the registry record. Clear reporting is essential for judging both what was observed and how precisely it was estimated.

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.

Several trial-specific limitations of interpretation arise from what is not reported in the registry record. Numerical results for the primary PVR endpoint are absent, including group summaries, a between-group estimate, confidence intervals, and p-values. Without them, neither the direction nor the precision of the primary result can be evaluated.

The primary endpoint population is defined by treatment exposure and assessment availability: participants had to receive assigned treatment, receive at least 6 of the same doses, have baseline and post-Base Study PVR assessments, and have an End of Treatment assessment. The number meeting these criteria and the reasons others may not have met them are not reported in the registry record. The definition therefore limits the population to which an endpoint result would directly apply, while the impact of those criteria cannot be assessed.

The record does not report the complete statistical analysis plan, the endpoint model, covariate adjustment, handling of dose titration in analysis, missing-data methods, or sensitivity analyses. It also does not report the sample-size justification used for trial design or how multiplicity across outcomes was handled. These omissions restrict assessment of assumptions, robustness, and the interpretation of any isolated result.

The safety information separates the placebo-controlled Base Study from the extension, but detailed event definitions, exposure-adjusted comparisons, and the denominator for the listed serious-event percentages are not reported in the registry record. The extension involved sotatercept for all participants and therefore does not retain the original placebo comparison. These limitations concern interpretation of the posted registry information and do not establish that unreported analyses were or were not performed.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (PAH) — NCT03496207.
• Registry record last updated 2023-04-19; status last verified 2023-03.
• Results first posted 2023-04-19.
• 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

This is a completed Phase 2 randomized, parallel-group, quadruple-masked study of sotatercept plus SOC compared with placebo plus SOC in adults with PAH. The registry reports enrollment of 106 participants. The Base Study treatment period lasted 24 weeks, with sotatercept 0.3 mg/kg and 0.7 mg/kg arms and a placebo arm; dosing was by subcutaneous injection once every 3 weeks, with titration permitted in the sotatercept arms.

The primary outcome was change from baseline in PVR at 24 weeks, measured by right heart catheterization and summarized as a mean with standard deviation. Participants were eligible for a 30-month extension period during which all received sotatercept, followed by post-treatment follow-up for treated participants.

The registry lists 23 outcome measures and 4 analyses, but numerical primary efficacy results and key analysis details are not reported in the registry record. The available information supports description of the trial design and endpoint, not a conclusion about the observed primary treatment difference.