Inhaled Treprostinil in Participants With Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease (PH-COPD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Inhaled Treprostinil in Participants With Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease (PH-COPD) (NCT03794583), a na phase 3 study. The primary outcome is Number of Participants With Treatment-Emergent Adverse Events (TEAEs).

2. Clinical Question

3. Trial Design

This was a Phase 3, open-label extension study of inhaled treprostinil in participants with pulmonary hypertension due to chronic obstructive pulmonary disease. Its stated purpose was to evaluate the safety of continued therapy among participants who had completed Study RIN-PH-304. The registry record describes the extension as a single-group study, with no masking and no allocation to competing treatment arms. Enrollment was 41.

The intervention was inhaled treprostinil solution, recorded as 0.6 milligrams per milliliter, 6 mcg/breath, QID during waking hours. Because there was no concurrent control group, the design describes outcomes among treated participants rather than a treatment contrast. The earlier RIN-PH-304 study is mentioned as the source of participants and as context for the extension’s safety hypothesis; it is not the control group for this study.

The primary outcome was the number of participants with treatment-emergent adverse events, assessed up to 4 years. The safety population was defined as participants receiving at least one dose. Secondary outcomes were change from baseline to Week 6 in 6-minute walk distance, Borg Dyspnea Score, and N-terminal Pro-brain Natriuretic Peptide. The registry status is terminated. The recorded start date is 2018-12-21 and the primary completion date is 2022-11-29; the reason for termination is not reported in the registry record.

The registry record does not report the planned statistical methods, a sample-size justification, or an interim-analysis plan. It also does not explain whether follow-up duration varied between participants or how discontinuation was handled in the analyses. Those omissions limit assessment of how the design and conduct relate to the reported outcomes.

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: 41 participants, who either successfully completed or were administratively terminated due to the COVID-19 pandemic from Study RIN-PH-304 (NCT03496623), chose to enroll in Study RIN-PH-305 (NCT03794583) open-label extension study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety population included all participants who received at least 1 dose of inhaled treprostinil.

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 included all participants who received at least 1 dose of inhaled treprostinil.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-Emergent Adverse Events (TEAEs), measured over Up to 4 years.

The primary endpoint counts participants with treatment-emergent adverse events. In the registry definition, an adverse event is an unfavorable or unintended sign, symptom, or disease temporally associated with use of the study drug, whether or not it is considered related to the drug. A treatment-emergent event is one that occurs or worsens after a participant is exposed to study drug and through 7 days after the last dose. The stated timeframe for the endpoint is up to 4 years.

A participant count is a binary-outcome summary: each participant is classified according to whether an event meeting the endpoint definition occurred. This gives a direct description of how many participants in the safety population experienced an event, rather than a count of every event episode. The registry defines that safety population as participants who received at least one dose of inhaled treprostinil.

Adverse-event monitoring is relevant to an extension study because the stated objective is to assess safety during continued therapy. However, an event recorded during treatment is not necessarily caused by treatment. The record explicitly includes events regardless of whether they are related to the medicinal product. In addition, the adverse-event summary lists serious and other events regardless of causality; those summaries should not automatically be read as the primary endpoint result. The registry record does not report an explicit numerical result for the primary treatment-emergent adverse-event endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry classifies the study as single-group and open-label. These design features determine what statistical conclusions can reasonably be drawn. A single-group study can describe outcomes among treated participants, but it has no concurrent randomized group to estimate a treatment contrast. Open-label conduct means masking was absent, which can matter for outcomes involving participant reports or investigator judgments. These design features do not establish that reporting was biased; they identify considerations when interpreting the results.

What does a participant count represent?

The primary outcome is a count of participants with treatment-emergent adverse events. For this type of endpoint, a participant is counted if they meet the event definition during the specified observation period. The number of participants with an event is not the same as the number of event episodes: one participant may experience more than one event, while the endpoint title is about participants. The registry’s definition also sets a temporal boundary, from after exposure to study drug through 7 days after the last dose. The record says the endpoint timeframe is up to 4 years.

Counts should be interpreted with their population and denominator in view. The stated safety population includes all participants who received at least one dose. The adverse-event summary separately identifies participants at risk and participants affected for serious and other events. Those labels are useful for understanding the summary, but they do not establish that the serious and other event totals are the primary treatment-emergent endpoint result. Nor do counts by themselves show causation: the registry says the adverse-event summaries include events regardless of causality.

Why does the design affect comparisons?

In a randomized comparison, treatment groups are formed to support a like-for-like contrast, subject to the assumptions and limitations of the trial. This extension has no such control arm. A count observed in its treated group can be described, but there is no internal comparison that separates treatment effects from the underlying condition, changes over time, other care, or other influences. Comparing these results informally with a different study would not recreate randomization and could be affected by differences in participants, follow-up, and methods.

In general, a confidence interval communicates the uncertainty around an estimated quantity under a statistical model. A narrow interval generally indicates more precise estimation than a wide interval, while a wide interval signals greater uncertainty. The registry record does not report confidence intervals or other uncertainty estimates for the outcomes described. No precision statement should be inferred from participant counts alone.

How should serious-event terms be read?

The adverse-event summary distinguishes participants at risk from participants affected, and lists serious-event terms with percentages. These summaries are descriptive. A serious-event term is not necessarily a separate participant-level outcome, and the registry excerpt does not specify whether a participant could contribute to more than one term or the denominator used for each percentage. In general, adverse-event categories can overlap when participants experience different events. For that reason, term percentages should not be added together or treated as mutually exclusive shares unless the reporting method establishes that interpretation.

The event definition includes events whether or not they are related to study drug. This is important because temporal occurrence during a study and causal attribution are different questions. The posted counts describe recorded events under the registry’s reporting definitions; they do not alone establish that treatment caused an event or that treatment prevented one.

What can the listed analysis information establish?

The registry record reports no statistical analyses. It does not report a statistical model, adjustment strategy, confidence-interval method, hypothesis-testing procedure, handling of repeated events, or method for the secondary outcomes. The sample-size justification and interim-analysis plan are also not reported in the registry record. These details should not be inferred from the Phase 3 designation or from the fact that the study followed participants over time.

General planning illustrations are different from observed evidence. A planned sample size can be calculated using assumptions about an effect, significance level, allocation, and statistical approximation, but it does not indicate the power actually achieved after a study is completed. The registry’s stated planning assumptions refer to a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a fraction of an observed effect. Those assumptions describe a planning illustration, not this single-group extension’s randomized design or an observed analysis. The record does not report a trial-specific sample-size justification.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Treprostinil")
n      <- c(41)
events <- c(35)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Treprostinil  41  35  85.4  70.8  94.4  71.6  93.1  71.5  93.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary safety outcome and three secondary outcomes: change from baseline to Week 6 in 6-minute walk distance, Borg Dyspnea Score, and N-terminal Pro-brain Natriuretic Peptide. The record does not report a multiplicity strategy for interpreting results across these outcomes, nor does it report statistical analyses for them. Without a stated analysis plan, it is not possible to determine whether or how multiple testing was addressed. The secondary outcome titles alone do not establish that numerical results were analyzed or reported.

Missing-data methods are not reported in the registry record. The available description does not state how missing visits or measurements were handled, whether participants who stopped treatment continued follow-up, or how incomplete observation periods affected the safety summaries. In general, incomplete follow-up can affect event ascertainment and estimates if participants with missing observations differ from those with complete follow-up. That is a methodological concern, not evidence that a particular pattern of missingness occurred in this study.

The safety population is defined as participants who received at least one dose of inhaled treprostinil. The record does not provide additional analysis-population definitions for the secondary outcomes or explain whether every outcome used the same population. The registry also does not report an intention-to-treat analysis, a per-protocol analysis, or how participants who discontinued were treated in analyses.

There is no reported statistical analysis plan, adjustment for covariates, or interim-analysis plan. The reason for the terminated status is not reported in the registry record. These omissions limit assessment of how outcome selection, multiplicity, missing observations, and stopping decisions were handled. They do not establish that any particular analysis or procedure was used.

12. 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 (12.2%), acute respiratory failure (9.8%), acute myocardial infarction (4.9%), cardiac arrest (4.9%), sudden death (4.9%).

The serious-event summary lists 41 participants at risk and 13 affected in the Treprostinil group. The other-adverse-event summary lists 41 at risk and 22 affected. The record also lists 8 deaths. These are participant counts in the registry’s adverse-event summary, not necessarily counts of event episodes, and the record describes the serious and other events as regardless of causality. The death count alone does not establish cause or relationship to treatment.

The serious-event terms listed are chronic obstructive pulmonary disease at 12.2%, acute respiratory failure at 9.8%, and acute myocardial infarction, cardiac arrest, sudden death, and COVID-19 pneumonia at 4.9% each. The registry excerpt does not explain the denominator or counting convention for these percentages. They should be read as reported term percentages, not converted into participant counts or summed.

These safety summaries are not explicitly identified as the primary endpoint result. The primary endpoint is the number of participants with treatment-emergent adverse events, whereas the serious and other event summaries are stated to include events regardless of causality. A temporal association with treatment, treatment-emergence, seriousness, and causal attribution are related but distinct concepts. The posted information does not establish that the listed events were caused by inhaled treprostinil.

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

The registry record describes safety observations during an open-label extension of inhaled treprostinil among participants who had completed the earlier RIN-PH-304 study. It reports serious and other adverse-event summaries and identifies several serious-event terms. These data provide a descriptive account of events recorded in this treated group under the registry’s stated reporting definitions.

The results do not provide a randomized comparison. There is no concurrent placebo or alternative-treatment arm, so the record cannot show how event counts compare with what would have occurred under another treatment. Events recorded during treatment are not, by themselves, evidence of causation. Likewise, the absence of a listed event in a summary would not prove that an event could not occur or that treatment has no effect on risk.

The primary endpoint is defined as participants with treatment-emergent adverse events up to 4 years, but the registry record does not report an explicit numerical result for that endpoint. The serious and other event counts should not be treated as its substitute. The three secondary outcome titles describe Week 6 changes in walking distance, dyspnea score, and a biomarker, but numerical results for those outcomes are not reported in the registry record. No statistical analyses or uncertainty estimates are reported.

The findings also apply most directly to the extension participants, who were drawn from those who completed the earlier study. The record does not provide enough information to determine how representative they were of a broader population with pulmonary hypertension due to chronic obstructive pulmonary disease. The study’s terminated status is recorded, but its reason is not reported in the registry record. The information therefore supports a limited descriptive reading, not a conclusion about comparative efficacy, causal safety effects, or generalizability to all people with these conditions.

14. Why This Trial Matters Statistically

This study is statistically useful to read as an example of the distinction between describing safety and estimating a comparative treatment effect. A single-group extension can record adverse events during continued exposure and characterize outcomes among participants who entered follow-up. Without a concurrent randomized control group, it cannot isolate treatment effects from other influences in the way a randomized comparison is designed to do.

The distinction between the primary endpoint and the adverse-event summaries also matters. The primary outcome concerns participants with treatment-emergent adverse events, defined by a specific period around exposure. The serious and other adverse-event summaries are explicitly described as regardless of causality. These are not interchangeable labels, and keeping them separate prevents a descriptive safety summary from being mistaken for a causal treatment estimate.

The extension context is another important feature. Participants had completed an earlier study before entering this one. Results from such a selected group can be informative about the participants observed in the extension, while offering less direct information about people who would not have entered it. This is a question of population and design, not a reason to dismiss the recorded observations.

Finally, the registry record illustrates why analysis transparency matters. It identifies outcome definitions, the safety population, and several adverse-event summaries, but does not report statistical analyses, missing-data methods, or a statistical analysis plan. Those details affect how readers assess precision, outcome handling, and the scope of conclusions. In their absence, interpretation should remain descriptive and closely tied to the information the registry actually reports.

15. 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 absence of a concurrent control group is a central design limitation for comparative interpretation. The study is open-label and single-group, so observed outcomes cannot establish how participants would have fared under a different treatment. The registry record also does not report masking or allocation because no allocation to comparison arms is described.

The extension enrolled participants who had completed Study RIN-PH-304. This selection means the results describe the extension population, not necessarily all participants who might begin treatment or all people with pulmonary hypertension due to chronic obstructive pulmonary disease. The registry record does not report enough participant-characteristic detail to assess representativeness.

The record does not report statistical analyses, confidence intervals, hypothesis tests, or adjusted estimates. It also does not report how missing measurements, treatment discontinuation, or incomplete follow-up were handled. The numerical result for the stated primary treatment-emergent adverse-event endpoint is not explicitly reported, and numerical results for the listed secondary outcomes are not reported in the registry record.

The adverse-event summary includes events regardless of causality, and the term percentages are not accompanied in the record excerpt by a stated denominator or counting convention. The serious and other event summaries should therefore not be treated as causal estimates or assumed to be the primary endpoint result. The registry status is terminated, but the reason is not reported in the registry record. These limitations constrain interpretation; they do not establish what unreported analyses or procedures may have been conducted.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Inhaled Treprostinil in Participants With Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease (PH-COPD) — NCT03794583.
• Registry record last updated 2026-05-27; status last verified 2026-05.
• Results first posted 2023-12-18.
• 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.

19. Record Summary

The registry record describes a Phase 3, open-label, single-group extension study of inhaled treprostinil in participants with pulmonary hypertension due to chronic obstructive pulmonary disease who completed Study RIN-PH-304. The recorded enrollment is 41, and the safety population includes participants who received at least one dose. Treatment was inhaled treprostinil solution at 0.6 milligrams per milliliter, 6 mcg/breath, QID during waking hours.

The primary outcome was the number of participants with treatment-emergent adverse events up to 4 years. Secondary outcomes were Week 6 changes in 6-minute walk distance, Borg Dyspnea Score, and N-terminal Pro-brain Natriuretic Peptide. The registry lists serious and other adverse-event summaries, but does not report statistical analyses or an explicit numerical result for the primary endpoint. The record is terminated; its reason is not reported in the registry record.