A Study of Rodatristat Ethyl in Patients With Pulmonary Arterial Hypertension (Core OLE): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Rodatristat Ethyl in Patients With Pulmonary Arterial Hypertension (Core OLE) (NCT04712669), a randomized phase 2 study. The primary outcome is Percent Change From Baseline of Pulmonary Vascular Resistance (PVR) at Week 24.

2. Clinical Question

The clinical question is framed around a measured change in pulmonary vascular resistance (PVR), rather than a direct measure of symptoms or survival. The record describes a phase 2, dose-ranging, randomized, double-blind, placebo-controlled, multicenter study. The primary outcome is reported as a least-squares mean with standard error in the intention-to-treat population.

The posted arm estimates are 63.08 for rodatristat ethyl 300 mg BID, 64.22 for 600 mg BID, and 5.813 for placebo. The record’s comparison analyses estimate a positive difference for each active dose relative to placebo. Those numerical contrasts describe the reported endpoint; they do not, by themselves, establish what change is clinically desirable or whether patients experienced meaningful improvement. A direction-of-benefit threshold or interpretation rule is not reported in the registry record.

The study also lists change from baseline in WHO Functional Class, six-minute walk distance, and NT-proBNP as secondary outcomes. Their presence broadens the questions beyond PVR, but does not change the stated primary endpoint. The registry record does not provide numerical results for every listed secondary outcome.

3. Trial Design

The registry record describes NCT04712669 as a completed phase 2 randomized, quadruple-masked, parallel-group study of rodatristat ethyl in patients with pulmonary arterial hypertension. The title identifies it as a dose-ranging, double-blind, placebo-controlled, multicenter study. Enrollment is listed as 108. The recorded start date is 2021-03-15 and the primary completion date is 2023-06-05.

In the main study, participants were assigned to rodatristat ethyl 300 mg BID, rodatristat ethyl 600 mg BID, or matching placebo. Each main-study arm description includes standard-of-care medication(s) and a 24-week treatment period. The active regimens and placebo are described as tablets taken BID. The registry’s masking classification is quadruple; details of which roles were masked are not reported in the registry record.

The posted primary analysis includes 36 participants in each main-study arm. It compares each dose group with placebo, rather than presenting a direct 300 mg versus 600 mg comparison. The reported analyses use ANCOVA and identify the comparison parameter as mean difference in final values. The primary endpoint description, in contrast, names percent change from baseline at 24 weeks. The registry record does not explain this wording difference or provide the full model specification.

Arm descriptions also list open-label phase treatment sequences, including participants who received placebo during the double-blind phase and then rodatristat ethyl, and participants who continued or changed dose. These later treatment groups are distinct from the three main-study arms used for the primary endpoint comparison. The registry record does not provide enough detail to infer how the open-label observations relate to the primary analysis or how participants were selected for those sequences.

The original design assumptions, sample-size justification, randomization details, interim analyses, and planned analysis hierarchy are not reported in the registry record. Their absence limits reconstruction of the original design decisions, but does not change the description of the posted comparisons.

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: Out of 108 subjects who are dosed in Double Blind phase 76 Subjects have enrolled in Open Label extension phase.

Only the first 6 of 8 groups are shown.

Double Blind Phase

Reasons for not completing this period:

Open Label Phase

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITT population

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: Safety Population

Only the first 6 of 9 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percent Change From Baseline of Pulmonary Vascular Resistance (PVR) at Week 24, measured over 24 Weeks.

The primary endpoint is percent change from baseline in pulmonary vascular resistance at Week 24. PVR was measured by right heart catheterization, and the analysis is identified as a least-squares mean in the intention-to-treat population. PVR describes resistance to blood flow through the pulmonary circulation; it is used in pulmonary arterial hypertension research as a hemodynamic measure of the circulatory burden being studied.

In general, a change-from-baseline endpoint compares a follow-up measurement with a participant’s starting measurement, then summarizes those changes across a group. Expressing change as a percentage relates the follow-up shift to baseline rather than presenting only an absolute-unit change. Least-squares means are model-based adjusted group summaries; their interpretation depends on the model and covariates used. The registry record does not report the covariates or full calculation details for this endpoint.

The arm summaries are 63.08 for 300 mg BID, 64.22 for 600 mg BID, and 5.813 for placebo. The registry record labels these values as percent change and reports standard errors of 18.53, 18.01, and 18.05, respectively. The endpoint is useful for comparing the groups’ measured hemodynamic changes over the stated period, but it is not itself a direct report of symptoms, functional capacity, or quality of life. A clinically meaningful threshold for PVR change is not reported in the registry record.

7. Results Posted in the Registry

• Rodatristat Ethyl 300 mg BID: mean 63.08 versus 5.81 on control; difference 57.27 (95% CI 6.57 to 107.97), standardized effect d = 0.52; z-test p = 0.027.
• Rodatristat Ethyl 600 mg BID: mean 64.22 versus 5.81 on control; difference 58.41 (95% CI 8.42 to 108.39), standardized effect d = 0.54; z-test p = 0.022.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Change From Baseline in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Levels

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Rodatristat Ethyl 300 mg BID: mean 1,146 versus 19.80 on control; difference 1,126 (95% CI 427.63 to 1,824), standardized effect d = 0.74; z-test p = 0.002.
  • Rodatristat Ethyl 600 mg BID: mean 886.10 versus 19.80 on control; difference 866.30 (95% CI 256.80 to 1,476), standardized effect d = 0.66; z-test p = 0.005.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Rodatristat Ethyl 300 mg BID than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Rodatristat Ethyl 600 mg BID than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry record lists secondary outcomes covering WHO Functional Class, six-minute walk distance, and NT-proBNP. Numerical results are posted for NT-proBNP, while numerical results for WHO Functional Class and six-minute walk distance are not reported in the registry record. The available secondary information therefore gives an incomplete view of whether the primary PVR pattern was accompanied by changes in functional status or walking capacity.

For NT-proBNP, the posted mean changes are 1146.0 for 300 mg BID, 886.1 for 600 mg BID, and 19.8 for placebo. The sponsor-reported mixed-model comparisons give mean differences of 1125.9 and 866.3, with 95% confidence intervals of 437.39 to 1814.39 and 265.41 to 1467.16. These reported contrasts are positive. The registry record does not provide a clinical interpretation threshold or a full account of how this secondary endpoint was incorporated into an overall testing strategy.

In broad terms, the available numerical NT-proBNP pattern is directionally consistent with the positive primary contrast in the sense that the active-arm estimates exceed the placebo estimate. That consistency is not independent confirmation of the primary result: the endpoints are measured in the same trial population and may reflect related aspects of disease. Nor can an overall pattern be established across all listed secondary outcomes when numerical results for some are absent.

Unadjusted secondary results generally carry less confirmatory weight when many outcomes or comparisons are examined. In general, testing multiple hypotheses increases the chance of at least one apparently notable result by chance unless the analysis plan accounts for multiplicity. The registry record does not report whether or how multiplicity was controlled, so secondary p-values should be considered exploratory rather than treated as definitive evidence. The planned hierarchy and interpretation rules are not reported in the registry record.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Change From Baseline in World Health Organization (WHO) Functional Class (FC)
• Change From Baseline in Six-minute Walk Distance (6MWD)
• Change From Baseline in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Levels

9. Statistical Interpretation

10. Statistical Methods Explained

What does randomization contribute?

In general, random allocation is intended to make treatment groups comparable at the point of assignment, including for factors that are not measured. It supports a fairer comparison than choosing treatment according to prognosis or preference. Randomization does not guarantee that groups will be identical, especially in a study of limited size, and it does not remove the need to define how outcomes and missing data are handled. The registry record identifies the study as randomized, but the sequence-generation and allocation-concealment details are not reported in the registry record.

What does masking mean?

In general, masking can reduce the influence of knowledge about assigned treatment on participant experience, clinical care, outcome assessment, or analysis. The registry record classifies masking as quadruple and describes the main study as double-blind and placebo-controlled. It does not identify the specific roles covered by quadruple masking, so those roles should not be inferred. A placebo comparator helps distinguish the assigned active-treatment experience from the study context and accompanying standard-of-care medication(s), but it does not by itself resolve other design or analysis questions.

What is a least-squares mean?

In general, a least-squares mean is a model-based estimate of a group mean, often adjusted for variables specified in the analysis model. It can differ from a simple arithmetic average if adjustment is used. The primary outcome lists least-squares means and standard errors, but the model covariates and details are not reported in the registry record. Therefore the posted arm summaries should be understood as model-based summaries, without assuming which baseline variables or other terms were included.

How should the ANCOVA results be understood?

ANCOVA, or analysis of covariance, is a general method for comparing groups while accounting for selected covariates. The sponsor-reported analyses identify ANCOVA and report a mean difference in final values for each active-dose versus placebo contrast. A confidence interval describes a range of values compatible with the estimate under the model and its assumptions. A p-value describes how inconsistent the data are with a specified null model, assuming the analysis assumptions hold; it is not the probability that the null hypothesis is true, nor a measure of clinical importance. The registry record does not report the ANCOVA covariates or the complete specification.

What is the recalculation?

The recalculated contrasts are simple, unadjusted comparisons based on posted summary statistics. They are useful as a check on the scale and direction of the reported contrasts, but they do not reproduce a model that adjusts for covariates, uses participant-level data, or applies the sponsor’s analysis choices. The recalculated standard deviations are approximate because the posted arm-level dispersion is reported as standard error. In general, converting between an estimated mean’s standard error and participant-level variability depends on sample size and the summary-statistic structure; the recalculation should therefore be treated as an approximation rather than an independent definitive analysis.

The recalculated 95% confidence intervals are 6.568 to 108.0 for 300 mg BID versus placebo and 8.423 to 108.4 for 600 mg BID versus placebo. Their widths express substantial uncertainty around the corresponding simple contrasts. The sponsor-reported intervals are narrower, but the methods and model inputs differ. Comparing intervals across different methods does not establish that one analysis is correct or that the treatment effect is precisely known.

Why can over-dispersion matter?

In general, over-dispersion occurs when outcome variability is greater than a model assumes. If a model understates variability, standard errors may be too small and confidence intervals too narrow; if variability is modeled appropriately, uncertainty is more accurately represented. This is a general statistical consideration, not a finding that over-dispersion occurred in this trial. The primary endpoint is continuous, and the registry record reports standard errors, but does not describe a variance diagnostic or an over-dispersion assessment.

Why are endpoint definitions important?

The primary endpoint title specifies percent change from baseline at Week 24, whereas the sponsor-reported ANCOVA parameter is called mean difference in final values. The registry record does not explain whether the analysis used transformed, adjusted, or otherwise derived endpoint values. Readers should retain the distinction between the stated endpoint and the analysis parameter rather than assume that every label describes precisely the same computation. The similar reported and recalculated point estimates are informative, but do not fill in missing model details.

What can the analysis establish?

In general, a randomized comparison estimates differences between assigned groups under the analysis population and methods used. It does not automatically establish that a difference is clinically meaningful, that it applies to people outside the study population, or that it persists beyond the assessment period. The primary analysis is identified as intention-to-treat, but the registry record does not describe its missing-data handling, participant flow into the analysis, or sensitivity analyses. Those omissions limit assessment of robustness.

11. Confidence Intervals and Precision

The sponsor-reported 95% confidence interval for the 300 mg BID comparison runs from 8.716 to 105.824, around an estimated mean difference of 57.27. For 600 mg BID, the interval runs from 10.272 to 106.54, around an estimate of 58.406. Both intervals exclude zero, but each spans a wide range of possible differences. The posted data therefore support a positive estimated contrast under the reported analyses while leaving considerable uncertainty about its magnitude.

In general, a confidence interval is a range generated by a method that, under repeated use and its assumptions, captures the target parameter at the stated frequency. It is not a range containing a stated proportion of individual participant responses, and it is not a guarantee that the true value lies within the interval. The 95% label refers to the method’s long-run coverage property, not a 95% probability assigned to this particular interval after calculation.

The recalculated unadjusted 95% intervals are 6.568 to 108.0 for 300 mg BID and 8.423 to 108.4 for 600 mg BID. These intervals are also wide and exclude zero, but they are not identical to the sponsor’s ANCOVA intervals. Different estimation methods can yield different uncertainty estimates because they use different information and assumptions. The registry record does not provide participant-level data or full model specifications to resolve those differences independently.

The arm standard errors—18.53, 18.01, and 18.05—also indicate uncertainty around the respective least-squares means. They should not be read as the range of individual PVR changes. The registry record does not report a clinically meaningful difference threshold, so statistical precision cannot be translated into a judgment about whether the estimated effects matter to patients.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size illustrations translate the recalculated observed contrasts into hypothetical future-study planning values. For these continuous outcomes, the figures are participants per arm, not total events. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each scenario uses the stated fraction of the observed effect as the effect to detect. The original trial’s own sample-size assumptions and justification are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm that would yield an 80% chance of detecting the specified effect under those assumptions, if the planning model and assumptions hold. The 90% power column uses a higher target chance of detection and consequently gives a different planning requirement. These are design calculations, not a promise about a future study’s result. This is not observed power: it does not measure how likely the completed study was to detect an effect after the results were known.

Each set of rows represents planning for 100%, 75%, or 50% of the observed effect. Smaller effects need more participants because they are harder to distinguish from random variation when outcome variability is otherwise similar. The estimates are tied to the effect sizes observed in this study, so planning around the full observed effect can be optimistic if the observed estimate is imprecise. The illustrations are not the trial’s original design calculation and should not be interpreted as a recommendation for a definitive study. Decisions about future design would also require choices about endpoint definition, analysis model, multiplicity, missing data, and clinically meaningful effects; those choices are not established by these illustrations.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 57.270; pooled standard deviation σ = 109.752.
2. n = 2 × (1.96 + 0.842)² × 109.752² / 57.270² = 57.7, rounded up to 58 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 57.27                      # observed difference in means
sigma <- 109.752329405804                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(4712669)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 58 (80% power), 78 (90% power)
 75% of observed effect: n per arm = 103 (80% power), 138 (90% power)
 50% of observed effect: n per arm = 231 (80% power), 309 (90% power)
power.t.test: 58.6 
Simulated power at n = 58 per arm: 0.799 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The registry-reported sponsor analyses compare each rodatristat ethyl dose with placebo using ANCOVA. For 300 mg BID, the reported mean difference in final values is 57.27, with a 95% confidence interval from 8.716 to 105.824. For 600 mg BID, it is 58.406, with a 95% confidence interval from 10.272 to 106.54. The corresponding sponsor-reported p-values are 0.021 and 0.017.

The simple recalculations from posted summary statistics estimate differences of 57.27 and 58.41. Those point estimates are close to the sponsor-reported estimates, while the recalculated intervals differ: 6.568 to 108.0 and 8.423 to 108.4. This is expected to be possible because the recalculation is unadjusted and approximate, whereas the sponsor analysis is described as ANCOVA. The registry record does not provide the full model specification or participant-level data needed to reproduce the sponsor analysis.

The record does not flag a discrepancy between the posted and recalculated findings. The sponsor’s own analysis remains the primary reported inferential result; the recalculation is best used as a transparent, supplementary comparison. Neither approach establishes clinical importance, and the registry record does not report a threshold for that judgment.

15. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when statistical tests are conducted across multiple endpoints, treatment comparisons, time points, or subgroups. In general, the more hypotheses examined, the greater the chance that one or more results will appear statistically notable by chance if each test is judged independently. Methods such as a prespecified hierarchy or adjusted significance thresholds can control this issue, but the suitable approach depends on the trial’s objectives and analysis plan.

This study has a primary endpoint and several listed secondary outcomes, and the posted primary results include two dose-versus-placebo comparisons. The registry record does not report a multiplicity adjustment, a testing hierarchy, or whether the reported p-values are intended to be confirmatory. The primary comparisons can be described as reported, but their status within a broader family of tests cannot be reconstructed from the registry record. The secondary findings warrant particular caution if their p-values are read without a documented multiplicity strategy.

The endpoint identifies the intention-to-treat population, but the registry record does not explain how missing Week 24 measurements were handled, whether all randomized participants contributed to the analysis, or whether sensitivity analyses assessed alternative assumptions. In general, missing-data methods matter because results can depend on why measurements are unavailable and what values are assumed for them. The record does not provide enough information to judge whether missingness could have influenced the estimated contrasts.

The record also does not report the original statistical analysis plan, sample-size justification, interim analyses, or model covariates. These omissions do not invalidate the posted estimates, but they limit an independent assessment of prespecification, robustness, and the relationship between the planned and reported analyses. The posted record identifies ANCOVA for the primary comparisons and mixed models for the NT-proBNP comparisons; more detailed specifications are not reported in the registry record.

16. 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 0.05% 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 (13.3%), right ventricular failure (9.1%), device malfunction (6.7%), pulmonary embolism (6.2%), acute respiratory failure (6.2%).

For the main-study groups, the registry lists serious adverse events affecting 9 participants in the 300 mg BID group, 6 in the 600 mg BID group, and 1 in the placebo group; each group has 36 participants at risk in the posted safety data. Other adverse events affected 32, 34, and 27 participants, respectively. Deaths are listed as 1 in the 300 mg BID group, 0 in the 600 mg BID group, and 0 in the placebo group.

These counts describe reported participants with events in the specified groups; they are not rates adjusted for duration or exposure, and they do not establish that treatment caused an event. The open-label sequence groups are also listed separately, with different numbers at risk and event counts. They should not be combined casually with the main-study groups because the treatment sequences and observation contexts differ. The registry record does not provide a detailed attribution analysis or enough information to compare those sequence groups as if randomized in the main study.

The listed serious-event terms include pulmonary arterial hypertension, right ventricular failure, device malfunction, pulmonary embolism, acute respiratory failure, and hypoxia, with percentages reported in the record. These terms describe reported serious events, not necessarily treatment-related events. Safety counts need clinical context, follow-up duration, and attribution details, which are not fully reported in the registry record.

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

The posted results describe a 24-week comparison of PVR change in the intention-to-treat population. The sponsor’s ANCOVA analyses estimate positive differences for both rodatristat ethyl doses relative to placebo, and their 95% confidence intervals exclude zero. The numerical estimates and their uncertainty are the clearest claims supported by the posted primary results.

Those results do not establish that the observed differences are clinically meaningful. The registry record does not state a threshold for a meaningful change in PVR, nor does the primary endpoint directly report how participants felt or functioned. The study lists functional class, walking distance, and NT-proBNP as secondary outcomes, but numerical findings are not posted for all of them. The available results therefore do not permit a complete assessment of how the primary measure relates to other dimensions of health.

The findings also do not establish which dose is preferable. Both doses were compared separately with placebo, and a direct comparison between the 300 mg and 600 mg regimens is not reported in the registry record. Similar estimates in two placebo comparisons do not constitute a statistical test of dose equivalence or dose response.

As a phase 2 study, the record supplies an estimate from a particular trial population, treatment period, endpoint, and analysis. It does not by itself establish results in other populations or settings, or outcomes beyond the 24-week main study. The registry does not provide enough information to assess all features of missing-data handling, multiplicity control, or model specification. These limits matter when judging how robustly the findings can be interpreted.

Safety counts should likewise be read descriptively. The posted serious adverse event and death counts do not establish causation, and the open-label sequence groups are not interchangeable with the randomized main-study arms. Overall, the registry results support a description of measured group differences and their statistical uncertainty, not a treatment recommendation or a conclusion about individual benefit.

18. Why This Trial Matters Statistically

This trial illustrates why a treatment comparison is more than a difference between two arm estimates. The posted primary endpoint is a continuous measure, summarized as least-squares means with standard errors, while the sponsor’s inferential results come from ANCOVA. Understanding the distinction between adjusted model estimates and simple unadjusted recalculations helps readers avoid treating all point estimates and intervals as if they came from the same procedure.

The two dose-versus-placebo estimates are close in the posted results, but that does not answer whether the doses differ. A direct contrast is a separate statistical question and is not reported in the registry record. This is an important design-reading principle: separate comparisons with a shared control do not automatically provide a dose-to-dose test.

The confidence intervals also make precision visible. They exclude zero in the sponsor-reported comparisons, yet span a wide range of possible effects. Statistical evidence against a zero difference and precision about the size of the difference are related but distinct questions. Neither one alone answers whether the effect is clinically important.

The record further demonstrates the limits of interpreting secondary outcomes when the testing hierarchy and multiplicity approach are not reported. Numerical patterns across endpoints can provide context, but selective emphasis on individual p-values risks overstating evidence. Missing details about covariates, missing data, and the original sample-size rationale likewise constrain independent evaluation.

Finally, the safety data include randomized main-study arms and open-label treatment sequences. Keeping those contexts separate is necessary for a sound reading of event counts. The statistical value of this record lies in examining how estimates, uncertainty, methods, endpoints, and reporting completeness jointly shape interpretation.

19. 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 reporting gaps limit interpretation. The primary endpoint is described as percent change from baseline, while the sponsor’s ANCOVA parameter is labeled mean difference in final values. The registry record does not explain the relationship between those definitions, the model covariates, or the precise calculation used for the reported comparison. This makes it difficult to reconstruct the analysis from the registry alone.

The registry record does not report the original sample-size justification, the planned analysis hierarchy, multiplicity control, interim analyses, or the full statistical analysis plan. It also does not describe missing-data handling or provide sensitivity analyses for the primary endpoint. These details would help assess whether the reported methods followed prespecified choices and how dependent conclusions are on analytic assumptions.

Numerical secondary results are incomplete: NT-proBNP results are posted, but numerical results for WHO Functional Class and six-minute walk distance are not reported in the registry record. The record also does not provide a clinically meaningful threshold for PVR or NT-proBNP change, limiting translation from statistical differences to clinical importance.

The primary endpoint is assessed at 24 weeks. The registry record lists open-label phase sequences, but does not provide enough detail to establish longer-term comparative effects or how those observations were analyzed. The main-study safety counts and open-label sequence counts also arise in different treatment contexts; the record does not provide a detailed exposure-adjusted comparison or complete event-attribution account.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Study of Rodatristat Ethyl in Patients With Pulmonary Arterial Hypertension (Core OLE) — NCT04712669.
• Registry record last updated 2025-06-04; status last verified 2025-06.
• Results first posted 2025-06-04.
• 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.

23. Record Summary

NCT04712669 is a completed, randomized, quadruple-masked, parallel-group phase 2 study of rodatristat ethyl in pulmonary arterial hypertension. The main study compared 300 mg BID and 600 mg BID with matching placebo, alongside standard-of-care medication(s), over 24 weeks. Enrollment is listed as 108.

The primary endpoint was percent change from baseline in PVR at Week 24, measured by right heart catheterization in the intention-to-treat population. The sponsor-reported ANCOVA analyses estimated positive mean differences versus placebo for both doses, with 95% confidence intervals excluding zero. The numerical results do not establish clinical importance, a difference between doses, or outcomes beyond the reported assessment.

The record lists several secondary outcomes and reports numerical NT-proBNP results, but not numerical results for every listed secondary endpoint. Serious adverse event counts are reported for the main-study and open-label sequence groups. Details about multiplicity, missing-data handling, the original sample-size rationale, and full model specifications are not reported in the registry record.