Study to Evaluate the Treatment Effect of PT003 on Cardiovascular Hemodynamics in Subjects With Moderate to Severe COPD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate the Treatment Effect of PT003 on Cardiovascular Hemodynamics in Subjects With Moderate to Severe COPD (NCT02685293), a randomized phase 3 study. The primary outcome is Change From Baseline in Right Ventricular End Diastolic Volume Index (RVEDVi) at 2-3 Hours Post-dose on Day 8.

2. Clinical Question

The primary outcome focuses on a cardiovascular imaging measure rather than a symptom score or a measure of airflow. RVEDVi is right ventricular end diastolic volume adjusted for body surface area. The registry describes MRI assessment and defines baseline as the pre-dose value on Day 1 of treatment period 1. The endpoint compares the treatment-period value on Day 8 with that baseline.

The clinical question is specifically about cardiovascular hemodynamics after chronic dosing. It does not ask whether PT003 changes COPD symptoms, exacerbations, or long-term outcomes. The secondary outcomes listed in the registry include other ventricular volume measures, cardiac output, pulmonary artery measurements, and pulmonary vascular resistance. Those outcomes provide additional descriptions of cardiovascular physiology, but they do not replace the primary RVEDVi question.

3. Trial Design

The registry identifies this as a randomized Phase IIIb study with a crossover model, conducted at a single center. Its official title describes a two-period, two-treatment, chronic-dosing study comparing PT003 with placebo. Enrollment was 4. The study started on 2016-12-09, had primary completion on 2018-06-06, and its status is terminated.

In a crossover design, participants receive each treatment in separate periods, allowing each participant's results under one treatment to be considered alongside their results under the other. This differs from a parallel-group study, in which different participants receive the different treatments. The registry record does not report the treatment sequence, the method used to assign sequence, or whether a washout interval was used. Those details matter for understanding possible period or carryover effects and should not be inferred from the crossover label alone.

The interventions are GFF MDI (PT003) and Placebo MDI. The brief summary calls the study double-blind and placebo-controlled, while the registry masking field records triple masking. The exact roles included in the masking designation are not reported in the registry record. The official title also describes chronic dosing for 7 days, and the outcome timeframe places the primary assessment at 2-3 hours after dosing on Day 8 of either treatment period.

The endpoint population is identified as all randomized subjects. The results list n=4 for each treatment condition. In a crossover study, those counts should not be read as evidence of two separate groups of participants; the design calls for treatment periods within participants. Details about the number of participants who completed both periods, withdrawals, and exclusions from the primary endpoint analysis are not reported in the registry record.

The registry does not report why the study was terminated. Termination status alone does not establish whether the reason was operational, administrative, related to recruitment, or related to results.

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: Subjects were randomly assigned, in a 1:1 ratio, to receive either Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler (GFF MDI) then Placebo MDI or Placebo MDI then GFF MDI in two 7-day treatment periods, separated by a washout period of between 7 and 21 days.

Treatment Period 1

Washout Period

Treatment Period 2

Analysis population for the primary outcome, as defined in the registry: All randomized subjects.

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 Change From Baseline in Right Ventricular End Diastolic Volume Index (RVEDVi) at 2-3 Hours Post-dose on Day 8, measured over Baseline and Day 8 of either treatment period 1 or 2, as applicable..

The primary endpoint is change from baseline in right ventricular end diastolic volume index (RVEDVi), measured at 2-3 hours post-dose on Day 8. The registry describes MRI assessment of right ventricular volume. Right ventricular end diastolic volume is the amount of blood in the right ventricle at the end of filling; indexing it to body surface area expresses the measurement in relation to body size. The endpoint unit is cm^3/m^2.

For this outcome, baseline is the pre-dose measurement on Day 1 of treatment period 1. The endpoint description states that MRI was performed 2-3 hours after dosing on Day 8 of each treatment period. The registry therefore defines a within-person baseline reference and a later measurement associated with each treatment period. The posted outcome is a mean change, with standard deviation as the measure of spread.

RVEDVi is used in this study as an imaging measure relevant to right ventricular structure and cardiovascular hemodynamics. It is one component of a broader set of physiological measurements. The secondary outcomes include other measures of ventricular volume, cardiac output, pulmonary artery characteristics, and pulmonary vascular resistance. These related outcomes can describe different aspects of cardiovascular function, but the primary endpoint is specifically RVEDVi.

The registry record does not report a clinically meaningful threshold for interpreting a change in RVEDVi. It also does not report whether a particular direction or size of change was designated as favorable. The endpoint should therefore be read as a measurement comparison, not as a stand-alone statement about clinical benefit or harm.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary measure is continuous: RVEDVi change from baseline, reported as a mean with standard deviation. A mean gives the arithmetic average of the observed values. A standard deviation describes their spread around that average. It is not the uncertainty of the mean or of the treatment contrast. Those uncertainties are usually expressed with a confidence interval or a standard error, neither of which is reported for the primary comparison in the registry record.

For GFF MDI, the posted mean change is 6.1 cm^3/m^2 and the standard deviation is 7.69. For Placebo MDI, the mean change is -7.93 cm^3/m^2 and the standard deviation is 8.64. Each condition has n=4 in the results. The means summarize the change values within the treatment conditions; the standard deviations give context about variability among those values. Neither summary alone indicates whether an observed difference is statistically distinguishable from sampling variation.

A treatment contrast would compare the changes under GFF MDI and placebo. In a crossover study, that contrast can take advantage of the fact that the same participants receive both treatments. Such an analysis needs to reflect the within-participant pairing and potentially relevant period effects. A paired analysis typically evaluates each participant's treatment difference, whereas an unpaired analysis treats the treatment groups as distinct. The crossover model is reported, but the registry record does not describe the specific statistical model, the pairing used, or adjustment for period or sequence. It is therefore not possible to verify the analysis approach from the registry entry.

A confidence interval around the treatment contrast would show a range of values compatible with the observed data under the analysis assumptions. Its width would communicate precision: wider intervals indicate less precision, and narrower intervals indicate more. The registry record does not report a confidence interval for this endpoint comparison. A p-value would address compatibility of the data with a specified null hypothesis under a statistical model, but no primary comparison p-value is reported either. Neither inferential measure should be reconstructed from the posted group summaries when the crossover pairing and analysis details are unavailable.

General statistical note: over-dispersion occurs when observed variability exceeds what a chosen model assumes. It can make model-based standard errors and tests unreliable if the analysis does not accommodate that extra variability. The posted endpoint is continuous, with standard deviations reported; the registry does not report a model-based assessment of over-dispersion or a model specification from which to evaluate it. The issue is a general consideration, not a reported finding from this trial.

Sample-size planning is distinct from interpreting observed results. The record does not report the trial's own sample-size justification. A planning illustration based on an observed effect is not the same as a prospective design calculation, and a sample size associated with a power target is not observed power. Observed power is not a substitute for an interval estimate of the treatment effect. Numerical sample-size planning results are not reported in the registry record.

General statistical note: a crossover comparison can be more informative than an unpaired comparison when within-participant measurements are correlated, because each participant can serve as their own reference. However, its validity depends on design and analysis details, including period effects and possible carryover. The registry identifies two periods and two treatments but does not report the sequence assignments or washout arrangements. These limitations prevent a complete assessment of the assumptions behind a crossover analysis.

The registry lists the primary analysis population as all randomized subjects. The outcome summaries list n=4 in each treatment condition, but the record does not explain whether all randomized subjects contributed usable observations in both periods or how missing measurements were handled. It reports 0 analyses, and the comparison is marked as not estimable for a two-arm continuous endpoint. Accordingly, the displayed means and standard deviations should be understood as descriptive results rather than as a complete inferential analysis.

Multiplicity arises when a study evaluates more than one outcome or performs multiple statistical tests. Repeated testing can increase the chance of at least one apparently unusual finding if no strategy is used to control interpretation or error rates. The registry lists 14 secondary outcomes as well as the primary outcome, but the statistical plan for multiplicity is not reported in the registry record. No conclusion about adjustment, test ordering, or confirmatory status of secondary outcomes can be drawn from the list alone.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("GFF MDI", "Placebo MDI")
n   <- c(4, 4)
m   <- c(6.1, -7.93)
sp  <- c(7.69, 8.64)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  GFF MDI  4  6.100  7.690  -6.137  18.337
CARM  Placebo MDI  4  -7.930  8.640  -21.678  5.818

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary outcome: change from baseline in RVEDVi at 2-3 hours post-dose on Day 8. It also lists 14 secondary outcomes, including measures of left and right ventricular volumes, pulmonary artery velocity, cardiac output, pulmonary vascular resistance, and pulmonary artery-to-aortic diameter ratio. The record does not report a multiplicity strategy, such as a hierarchy for testing outcomes or an adjustment to account for multiple comparisons. It also does not report which secondary outcomes, if any, were considered confirmatory.

The registry outcome population is all randomized subjects. The endpoint summaries list n=4 for each treatment condition. The record does not report how many participants completed both treatment periods, whether every randomized subject had an evaluable MRI measurement, or how any missing outcome values were handled. Missing-data assumptions and sensitivity analyses are not reported in the registry record.

The crossover design makes the completeness of paired observations relevant. If a participant has a measurement in only one treatment period, the information available for a within-participant comparison may differ from that available for a participant with measurements in both periods. The registry does not describe missingness by period or treatment, nor does it state how incomplete pairs were incorporated into the analysis.

The registry lists 0 analyses and indicates that values are missing or not estimable for a two-arm comparison of the continuous endpoint. The posted mean and standard deviation summaries do not resolve the absence of an inferential comparison. Details of the analysis population, missing-data handling, and multiplicity plan are not reported in the registry record.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse event summaries list 4 participants at risk in each treatment condition. There were 0 serious adverse events in the GFF MDI group and 0 in the placebo group. The registry also reports 0 deaths in each group. These counts describe the safety information posted for this small study; they do not establish that serious events are impossible or that the treatments have equivalent safety.

For other, non-serious adverse events, the registry lists 0 affected participants among 4 at risk with GFF MDI and 1 affected participant among 4 at risk with placebo. No serious adverse event terms are listed. The record does not provide details about the nature, timing, duration, or severity of the non-serious event in this summary.

In general, adverse-event counts describe what was recorded during the study, not the probability of events in a broader population. With only 4 participants at risk per treatment condition, the summaries have limited ability to characterize uncommon events. In a crossover study, participants may contribute exposure to both conditions, so these counts should not be interpreted as coming from two wholly separate participant groups. Further detail about event attribution and exposure is not reported in the registry record.

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

The posted outcome gives descriptive information about RVEDVi change under GFF MDI and placebo in a randomized crossover study of subjects with moderate to severe COPD. The mean change was 6.1 cm^3/m^2 for GFF MDI and -7.93 cm^3/m^2 for placebo, with standard deviations of 7.69 and 8.64, respectively. Each treatment condition has n=4 listed. These numbers describe the observed summaries; the registry does not report a formal treatment contrast or confidence interval.

The results do not establish whether the observed difference represents a reliable treatment effect. A treatment effect estimate with uncertainty, together with a clearly described crossover analysis, would be needed to assess how precisely the data distinguish between treatment conditions. The treatment-period means alone do not account for the within-participant pairing or reveal whether period effects influenced the results.

The primary endpoint is an imaging measure of right ventricular volume indexed to body surface area. A change in that measure is not, by itself, a direct measure of symptoms, daily function, exacerbations, or long-term clinical outcomes. The registry record does not report a threshold that would define a clinically important change, so the clinical importance of the posted mean changes cannot be determined from these summaries alone.

The study's status is terminated, but the reason is not reported in the registry record. The endpoint summaries do not explain the termination. The record also does not describe a sample-size justification, analysis model, missing-data approach, or multiplicity strategy. Those omissions limit assessment of how the planned analysis compares with the posted results.

The safety summary reports no serious adverse events or deaths in either treatment condition, and one other adverse event in the placebo condition. Because the study enrolled 4 participants, those observations provide a limited account of safety and should not be generalized as evidence about event rates in a larger population. Overall, the posted results are a small descriptive dataset, not a definitive estimate of comparative clinical effect or safety.

14. Why This Trial Matters Statistically

This trial is statistically notable for combining a crossover design with an imaging-based continuous endpoint. In a crossover study, each participant can contribute measurements under both treatments, making within-person comparisons potentially informative. That advantage depends on complete treatment-period data and an analysis that reflects pairing and period structure. The registry reports the crossover model but does not report the details needed to evaluate those features.

The study also illustrates the difference between descriptive summaries and inferential evidence. Treatment-specific means and standard deviations communicate the observed changes and their variability, but they do not show the precision of a treatment contrast. A confidence interval or an appropriate model-based estimate would be needed to characterize uncertainty. Neither is reported for the primary comparison.

Enrollment was 4, and the results list n=4 for each treatment condition. Such a small set of observations makes estimates sensitive to the individual measurements and limits the information available about variability. This does not justify dismissing the results, but it does make clear why treatment contrasts and uncertainty are central to interpretation.

The registry lists 14 secondary outcomes spanning several cardiovascular measurements. When multiple outcomes are considered, a prespecified interpretation strategy matters because isolated findings can be difficult to distinguish from chance patterns. The registry record does not report a multiplicity plan or analyses for those outcomes. The result is that the available record supports a focused description of the primary outcome summaries rather than an integrated set of inferential findings.

Finally, the status is terminated, while the reason is not reported. This underscores the importance of separating what the record documents from explanations that cannot be verified. The statistical value of this study record lies in its explicit outcome definition and treatment-period summaries, alongside clear limits on what can be concluded without analysis details and uncertainty estimates.

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 primary comparison is not accompanied by a reported treatment contrast, confidence interval, or p-value. The record lists 0 analyses and indicates that values are missing or not estimable for a two-arm comparison of the continuous endpoint. Thus, the posted means and standard deviations do not provide a formal inferential result.

Enrollment was 4, and n=4 is listed for each treatment condition. The registry does not report whether all randomized subjects completed both treatment periods or contributed complete paired measurements. It also does not report missing-data handling, participant flow, or sensitivity analyses. These omissions are particularly relevant to a crossover design, where paired observations and period-specific completeness affect the analysis.

The registry identifies the crossover model but does not report the treatment sequence, washout arrangements, or statistical model. It is not possible to assess how the analysis addressed within-participant correlation, period effects, or possible carryover. The record also gives different masking descriptions: the masking field records triple, while the brief summary describes double-blind. The roles included in the masking designation are not reported in the registry record.

The registry lists 14 secondary outcomes but does not report their analyses or a multiplicity strategy. The trial's own sample-size justification is not reported in the registry record. The reason for termination and any clinical threshold for interpreting RVEDVi change are also not reported. Together, these gaps constrain interpretation of both statistical precision and clinical meaning.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study to Evaluate the Treatment Effect of PT003 on Cardiovascular Hemodynamics in Subjects With Moderate to Severe COPD — NCT02685293.
• Registry record last updated 2019-08-28; status last verified 2019-08.
• Results first posted 2019-08-28.
• 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

NCT02685293 evaluated GFF MDI (PT003) versus Placebo MDI for cardiovascular hemodynamics in subjects with moderate to severe COPD. It was a randomized, Phase IIIb, single-center crossover study with two treatment periods and chronic dosing for 7 days. Enrollment was 4. The study began on 2016-12-09, reached primary completion on 2018-06-06, and is listed as terminated.

The primary endpoint was change from baseline in RVEDVi at 2-3 hours post-dose on Day 8. The posted mean changes were 6.1 cm^3/m^2 for GFF MDI and -7.93 cm^3/m^2 for placebo. The registry lists standard deviations of 7.69 and 8.64 and n=4 for each treatment condition. It does not report a formal comparison estimate or its uncertainty. The reason for termination, analysis details, missing-data approach, and multiplicity strategy are not reported in the registry record.