Patient Global Impression Questions for Activity-Induced Symptoms in Participants With PAH: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Patient Global Impression Questions for Activity-Induced Symptoms in Participants With PAH (NCT03888365), a registered phase not stated study. The primary outcome is Change From Baseline in Patient Global Impression of Severity (PGI-S) Score in Cohort A Participants at Approximately 30 Minutes of Previous Dose of Inhaled Treprostinil (the Expected Peak Level) on Day 1.

2. Clinical Question

The PGI-S questions concerned overall PAH symptoms, shortness of breath, and physical fatigue. Participants rated severity on a scale from 1, Not present, to 5, Very Severe; higher scores represented worse symptoms. The endpoint is therefore a patient-reported measure of symptom severity rather than an objective measure of exercise capacity or a clinical event.

The study also included a symptom-inducing activity and repeated symptom assessments around that activity, including during recovery. The registry record lists a secondary outcome concerning change from baseline in modified Borg dyspnea scores at Day 1. The primary question is narrower: it concerns the specified PGI-S assessment in Cohort A, not a randomized comparison between the medication cohorts.

The registry record does not report numerical results for the primary change-from-baseline outcome. It therefore does not establish the size or precision of any observed change in PGI-S scores. The question can be described from the endpoint definition, but its numerical answer is not reported in the registry record.

3. Trial Design

This was an observational, multicenter, single-day, Phase 2 study. The registry record describes a 14-day Screening Period followed by a Study Day 1 clinic visit. Enrollment was 43, and the record lists the study status as completed. The recorded study start was 2019-04-01, and primary completion was 2019-09-19.

Participants were grouped according to PAH medication use rather than randomly assigned. Cohort A included participants currently prescribed and using inhaled treprostinil. Cohort B included participants taking other PAH medications instead of inhaled treprostinil. The registry record does not state an allocation procedure. Because the cohorts were observational, their differences cannot be interpreted as the effect of assigning one medication rather than another.

On Study Day 1, participants were required to perform an activity intended to induce PAH symptoms. The record describes symptom-severity assessments before activity, immediately afterward, and through the 30-minute recovery. For the primary outcome, the relevant Cohort A participants were those whose ISWT began approximately 30 minutes after the previous inhaled treprostinil dose. The registry describes this timing as the expected peak level.

The primary completion date marks the recorded timing of primary completion; it does not supply the missing numerical endpoint results. The record lists seven outcome measures, but the listed outcome definitions alone do not establish what the observed values were. The full statistical analysis plan, including any planned tests, covariate adjustments, or interim analyses, is not reported in the registry record.

The design is suited to describing symptom ratings in the study setting and their timing around an activity challenge. It does not, by itself, make the medication cohorts equivalent in their underlying characteristics. The registry record does not report random assignment, and it does not describe a protocol for controlling differences between participants using different PAH medications.

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: The 2 periods for Cohort A: an ISWT initiated at 30 minutes (m) of previous dose (the expected peak level period) and an ISWT initiated at 3-4 hours (h) of previous dose of inhaled treprostinil (the expected trough level period). The 2 periods for Cohort B: an ISWT initiated at \~4h after morning dose of PAH medication (Period 1) and an ISWT initiated at ≥1h following completion of previous ISWT (Period 2). Peak and trough levels are the highest and lowest concentrations of a drug in plasma.

Cohort A Peak Level/Cohort B Period 1

Rest - At Least 1 h

Cohort A Trough Level/Cohort B Period 2

Analysis population for the primary outcome, as defined in the registry: All Participants: Participants who consented to the study protocol. Data for participants in Cohort A who included an ISWT initiated at 30 m of previous dose (expected peak level) are presented.

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: All Participants: Participants who consented to the study protocol.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in Patient Global Impression of Severity (PGI-S) Score in Cohort A Participants at Approximately 30 Minutes of Previous Dose of Inhaled Treprostinil (the Expected Peak Level) on Day 1, measured over Baseline, Approximately 30 m of previous dose of inhaled treprostinil (the expected peak level) on Day 1.

The primary endpoint is change from baseline in the PGI-S score for Cohort A participants at approximately 30 minutes after the previous inhaled treprostinil dose on Day 1. The record describes a global index comprising three questions about PAH symptoms, shortness of breath, and fatigue. Each question uses a five-point severity scale: 1 means Not present, 2 Mild, 3 Moderate, 4 Severe, and 5 Very Severe. Higher scores indicate worse symptom severity.

Baseline is defined as the average of the respective severity ratings measured 15 minutes and 0 minute before the ISWT. If one of those pre-ISWT ratings is missing, the other non-missing rating is used as baseline. Change is defined as the post-baseline value minus baseline. Only participants with both a baseline measurement and a measurement at the specified post-baseline visit are summarized.

Patient-reported ratings can capture how participants experience symptoms, which may not be fully represented by a physiological measurement alone. The activity challenge provides a context in which symptoms are assessed over time. These are general reasons such measures can be useful; they do not establish that this particular endpoint is valid for every purpose or that a change is clinically important.

The registry record does not report the observed mean change or its standard deviation. It also does not report a threshold for interpreting the clinical importance of a score change, or a rule explaining how the three individual questions are combined into any single summary score.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the change score represent?

The primary measure is continuous: it is a score-based outcome summarized using a mean and standard deviation. The registry defines change as the post-baseline score minus the baseline score. This sign convention matters when reading a result. Since higher scores mean worse severity, a negative change would correspond to a lower severity rating relative to baseline, while a positive change would correspond to a higher rating. These are general interpretations of the scale and formula, not statements about the study’s unreported observed result.

A change score compares measurements from the same participant rather than comparing unrelated measurements as if they came from different people. This can be useful when the question concerns change over time. However, a mean change alone would not show whether all participants changed similarly or whether individual changes varied substantially. The standard deviation describes spread in the observed scores; it is not the same as the uncertainty around the mean.

What does the standard deviation tell the reader?

In general, a standard deviation describes how dispersed individual measurements are around their mean. A relatively broad spread can indicate that participants’ symptom ratings or changes differed from one another. It does not directly quantify the precision of the mean estimate. A confidence interval, when reported, would address uncertainty around an estimated quantity, with its width depending on the data and analysis method. Neither a confidence interval nor the primary outcome’s mean and standard deviation is reported in the registry record.

The outcome uses individual severity questions with ordered response categories. The registry describes calculating a mean and standard deviation for the primary measure, but it does not report additional distributional summaries or explain how the three questions are combined into a single score. Readers should not infer a summation, averaging, or weighting procedure beyond what the registry record states.

Why does the timing matter?

The endpoint is tied to an activity challenge and to a specific interval after the previous inhaled treprostinil dose. The record calls approximately 30 minutes the expected peak level and specifies that the ISWT began at that timing for the Cohort A data of interest. That timing defines the context of the measurement; it does not establish that a peak concentration was measured for each participant.

Repeated assessments around activity can describe symptom ratings at different moments. A rating before activity provides a reference for change, and ratings after activity and during recovery can describe how reported symptoms vary over the observation period. This is a general explanation of repeated symptom measurement. The record does not provide the numerical results for each time point or a statistical model for comparing them.

What is the role of missing-data rules?

The registry states that baseline is the average of ratings at 15 minutes and 0 minute before the ISWT. If one pre-ISWT rating is missing, the other non-missing rating is used as baseline. It also states that only participants with both baseline and the relevant post-baseline measurement are summarized. This means the change calculation is based on paired measurements for the specified visit; participants without both measurements are not included in that summary as described.

That rule does not explain why measurements might be missing, how many participants had missing measurements, or whether missingness was related to symptom severity or other participant characteristics. The registry record does not report a broader missing-data analysis or a method for assessing the effect of missing measurements on the result.

What do the planning assumptions mean?

The record describes planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. In general, a significance level is a threshold used in a testing procedure, and a normal approximation is a mathematical assumption used to estimate a sampling distribution. These are stated assumptions for the illustrations, not evidence that the trial used those methods for its own analysis.

The stated planning effect is a fraction of the observed effect. Such scenarios ask how planning requirements would change if a future study aimed to detect a proportion of an effect estimate. They are not observed power, and they do not show the probability that this completed study detected an effect. The record says that non-time-to-event illustrations are expressed as participants per arm, while time-to-event illustrations use a total event count. The primary outcome is continuous, not time-to-event.

The registry record does not report the primary observed effect needed to evaluate those illustrations, nor does it report a sample-size justification for the original study. The planning assumptions should therefore be kept separate from evidence about the trial’s actual results or its design rationale.

What statistical analysis can be identified?

The outcome description specifies a mean and standard deviation and defines the change calculation. Those details describe the estimand and summary format, not a complete statistical analysis plan. The registry record does not report a test, model, confidence-interval procedure, covariate adjustment, or interim-analysis plan. A method should not be inferred simply from the outcome’s continuous scale or from the planning assumptions.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists seven outcome measures, including the primary PGI-S change outcome and a secondary outcome for change from baseline in modified Borg dyspnea scores at Day 1. It does not report how multiplicity across outcomes, questions, time points, or analyses was handled. In general, when several outcomes or comparisons are examined, the chance of at least one apparently unusual result can increase; statistical plans may address this with prespecified hierarchies or adjustments. No such approach is reported in the registry record.

The primary outcome description specifies the analysis population for the summary: only participants with both a baseline value and the relevant post-baseline value are included. Baseline uses the average of the 15-minute and 0-minute pre-ISWT ratings, with the available rating used if one is missing. The record does not state how many measurements were missing, why they were missing, or whether missingness was assessed for possible bias.

The endpoint’s population description refers to participants who consented to the protocol, then specifies Cohort A participants whose ISWT began at approximately 30 minutes after the previous inhaled treprostinil dose. This is not equivalent to a statement that all enrolled participants contributed to the primary summary. The record does not report the number included in that endpoint analysis or provide a participant flow accounting for exclusions and missing values.

The full statistical analysis plan, including any planned handling of multiplicity, missing data, or analysis populations beyond the stated paired-measurement rule, is not reported in the registry record. The numerical primary outcome result is also not reported there, limiting assessment of precision and robustness.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry record reports serious adverse events for Cohort A, Treprostinil, among 20 participants at risk, and for Cohort B, Non-Treprostinil PAH Medications, among 23 participants at risk. The reported number affected by serious adverse events was 0 in each cohort. Deaths were reported as 0 in both cohorts. No serious-event terms are listed.

For other adverse events, the record reports 0 affected among 20 at risk in Cohort A and 9 affected among 23 at risk in Cohort B. These are descriptive counts in an observational study. They should not be read as evidence that medication use caused or prevented events, because the cohorts were not randomized and are not described as like-for-like controls.

In general, a zero count means that no event was recorded in the specified category for the reported cohort; it does not prove that an event is impossible or that risk is absent. The registry record does not provide further event details, such as timing, severity for the other adverse events, or an assessment of causal relationship. It also does not report a statistical comparison of safety outcomes between cohorts. The counts should therefore be interpreted as registry safety summaries, not as a causal treatment comparison.

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

The registry record defines a focused question about patient-reported symptom severity in Cohort A around an activity challenge. It specifies the PGI-S topics, the response scale, the baseline construction, the timing of the primary assessment, and the rule that both baseline and post-baseline values are needed for a participant to contribute to the change summary. These details clarify what the endpoint was intended to measure.

However, the numerical primary result is not reported in the registry record. Without the mean change and its variability, the size and precision of the observed change cannot be described. The record also does not report a confidence interval or a statistical test for this endpoint. A result’s direction and magnitude should not be inferred from the endpoint description or from the study status.

The study’s observational design also limits causal interpretation. Participants were categorized according to their existing PAH medication use, and the record does not state that treatment was assigned randomly. The medication cohorts are not a like-for-like control comparison. Any differences between them could reflect factors other than medication, and a within-participant change around an activity challenge would not by itself isolate a medication effect.

The study can be understood as characterizing patient-reported symptoms in a defined setting and at specified times. It does not, on the information reported, establish whether a treatment caused a change, how large any change was, or whether a change was important to participants. The registry record does not report a threshold for clinical importance for the PGI-S score.

The safety counts are also descriptive. They report no serious adverse events or deaths in either cohort, while other adverse events were reported in Cohort B and not Cohort A. These figures do not establish comparative safety because the study was observational and the record provides no causal analysis. Overall, the registry supports a description of the study’s question and measurement approach, but not a numerical conclusion about the primary symptom outcome.

13. Why This Trial Matters Statistically

This study is statistically notable for focusing on the timing and measurement of patient-reported symptoms rather than on a randomized treatment contrast. The endpoint links symptom ratings to an activity challenge and to a defined interval after a previous inhaled treprostinil dose. That makes the measurement context central to interpretation: a score is not just a general report of PAH symptoms, but a rating collected in a specified study setting and at a specified time.

Repeated symptom measurement can be informative because participants may report different severity before activity, after activity, and during recovery. A pre-activity baseline also gives a reference for describing within-participant change. These are general features of longitudinal symptom measurement. They do not, on their own, resolve whether a change is due to the activity, medication timing, natural variation, or other influences.

The study also illustrates why cohort labels should not be mistaken for randomized arms. Cohort A and Cohort B were defined by medication use, and the record does not report random assignment. The groups are therefore not described as equivalent in their characteristics. This distinction matters when interpreting both symptom outcomes and adverse-event counts.

The registry record gives useful operational detail about the scale and baseline rule, but does not report the numerical primary outcome result or a full statistical analysis plan. As a result, readers can understand what was intended to be measured, but cannot evaluate the observed change’s size, precision, or statistical evidence from the reported information. That gap underscores the importance of complete outcome reporting alongside clear endpoint definitions.

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 primary limitation for interpreting the endpoint is that its numerical result is not reported in the registry record. The record does not provide the mean change, standard deviation, confidence interval, or test result. The size and precision of the observed change therefore cannot be assessed.

The study is observational, and the registry record does not state an allocation procedure. Cohort A and Cohort B are defined by current medication use, not random assignment. Their comparison is not described as like-for-like, so differences in symptoms or adverse events cannot be attributed to medication from these data alone.

The primary endpoint pertains to Cohort A participants whose ISWT began at approximately 30 minutes after the previous inhaled treprostinil dose. The record does not report the number contributing to that analysis. It describes a paired-measurement rule and a baseline substitution rule when one pre-ISWT rating is missing, but does not report the amount or pattern of missing data.

The registry record does not report how the three PGI-S questions are combined into a score, a threshold for clinical importance, or the statistical methods used to analyze the endpoint. It also does not report how multiplicity across the listed outcome measures was handled. The single-day assessment and activity-challenge setting define the scope of the observations; the record does not establish how well they represent symptoms outside that setting.

Finally, the safety summaries are counts without reported causal assessment or a statistical comparison between cohorts. These limitations apply to interpretation of the registry record and do not establish that unreported analyses or details were absent from other study documents.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Patient Global Impression Questions for Activity-Induced Symptoms in Participants With PAH — NCT03888365.
• Registry record last updated 2021-03-16; status last verified 2021-02.
• Results first posted 2021-03-16.
• 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

NCT03888365, titled Patient Global Impression Questions for Activity-Induced Symptoms in Participants With PAH, is recorded as a completed observational, multicenter, single-day, Phase 2 study. The registry lists enrollment of 43, a study start of 2019-04-01, and primary completion on 2019-09-19.

The study grouped participants by medication use: Cohort A used inhaled treprostinil, while Cohort B used other PAH medications instead. Participants performed an activity intended to induce symptoms, with assessments before activity, immediately afterward, and through the 30-minute recovery.

The primary outcome was change from baseline in PGI-S severity scores for specified Cohort A participants at approximately 30 minutes after the previous inhaled treprostinil dose. The record defines the scale and baseline rule, but does not report the numerical primary outcome result or the statistical analysis plan.

The registry reports 0 serious adverse events and 0 deaths in both cohorts. Other adverse events were reported for 0 participants in Cohort A and 9 in Cohort B. These are descriptive safety counts in an observational study.