This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Feasibility, Safety and Efficacy of Nebulized Long-Acting Bronchodilators (Formoterol and Revefenacin) vs. Short-Acting Bronchodilators (Albuterol and Ipratropium) in Hospitalized Patients With AECOPD (NCT04655170), a randomized phase 4 study. The primary outcome is Difference in Modified Borg Dyspnea Scale Scores Between Groups.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04655170 |
| Phase | Phase 4 |
| Condition | COPD Exacerbation |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 60 |
| Arms in the primary outcome | 2 |
| Lead sponsor | University of Tennessee Graduate School of Medicine |
| Results posted | Yes |
2. Clinical Question
Population
Hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The registry record identifies COPD exacerbation as the condition; further eligibility criteria are not reported in the registry record.
Intervention
Nebulized revefenacin 175 μg once per day and formoterol 20 μg twice per day, administered by jet nebulizer for 7 days or until discharge if discharge occurred earlier.
Comparator
Nebulized albuterol and ipratropium every 6 hours over the 7-day treatment period or until discharge if discharge occurred earlier. The registry describes this as standard-of-care therapy.
Primary question
How did Modified Borg Dyspnea Scale scores during treatment compare between the two randomized groups? The registry reports model-derived marginal means using available assessments from enrollment through the end of treatment at Day 7.
The trial addressed feasibility, safety, and efficacy in the context of hospitalization for AECOPD. Its primary endpoint was a repeated symptom score, rather than a single measurement taken only at the end of treatment. Participants rated breathing difficulty on a scale that begins at 0, meaning no difficulty, and extends to 10, meaning maximal difficulty. The scores were recorded before dosing twice a day, between 7 and 9 am and between 7 and 9 pm.
The comparison is between treatment strategies as assigned in this randomized, parallel-group study. It does not isolate the effect of one drug from the other drug in its combination, and the trial’s primary result concerns the reported model-based scores rather than a separately reported treatment contrast with its own confidence interval. The registry record does not report further details of eligibility or the target population beyond hospitalized patients with AECOPD.
3. Trial Design
This was a Phase 4, randomized, parallel-group trial with no masking. The registry lists an enrollment of 60 participants. The two groups each had 30 participants in the reported primary outcome results. The study status is completed; the recorded start date is 2020-12-09 and the primary completion date is 2023-01-19.
The experimental group received nebulized revefenacin and formoterol. The registry describes revefenacin 175 μg once per day and formoterol 20 μg twice per day by jet nebulizer, for 7 days or until discharge if discharge came earlier. The active comparator received nebulized albuterol and ipratropium every 6 hours during the same treatment period, ending at 7 days or earlier discharge. The registry labels this comparator standard of care.
Random allocation and a parallel-group model define the broad design, but the method used to generate the allocation sequence, whether allocation was concealed, and any stratification factors are not reported in the registry record. Masking is listed as none; who knew treatment assignments and whether outcome assessment was otherwise protected from knowledge of assignment are not reported in the registry record.
The trial’s primary outcome was the difference in Modified Borg Dyspnea Scale scores between groups from enrollment to the end of treatment at Day 7. The reported values are marginal means from a repeated-measures statistical model using all available assessments collected during treatment. The registry also lists six secondary outcomes concerning medication administration, doses, rescue treatment, treatment changes, treatment failure, and supplemental oxygen. Detailed results are not available in the record details for most of those outcomes. The registry does not report a sample-size justification, recruitment targets beyond the recorded enrollment, or detailed eligibility criteria.
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.
Overall Study
| Stage | Experimental: Group 1: Revefenacin (YUPELRI) & Formoterol (Perforomist) | Active Comparator: Group 2: Ipratropium Bromide (Atrovent) & Albuterol(Ventolin) as Standard of Care |
|---|---|---|
| STARTED | 30 | 30 |
| COMPLETED | 30 | 30 |
| NOT COMPLETED | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: The reported values are marginal means derived from a repeated-measures statistical model using all available assessments collected during the treatment period.
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.
| Characteristic | Unit | Experimental: Group 1: Revefenacin (YUPELRI) & Formoterol (Perforomist) | Active Comparator: Group 2: Ipratropium Bromide (Atrovent) & Albuterol(Ventolin) as Standard of Care | Total |
|---|---|---|---|---|
| Participants analysed | 30 | 30 | 60 | |
| Age, Continuous | years | 61.8 (SD 9.51) | 64.5 (SD 9.05) | 63.2 (SD 9.30) |
| Sex: Female, Male: Female | Participants | 12 | 13 | 25 |
| Sex: Female, Male: Male | Participants | 18 | 17 | 35 |
| Race/Ethnicity, Customized: White | Participants | 26 | 28 | 54 |
| Race/Ethnicity, Customized: Black | Participants | 3 | 2 | 5 |
| Race/Ethnicity, Customized: Non-White Hispanic/Asian | Participants | 1 | 0 | 1 |
| Smoking status: Active tobacco use | Participants | 20 | 19 | 39 |
| Smoking status: Previous tobacco use | Participants | 10 | 9 | 19 |
| Smoking status: Does not smoke | Participants | 0 | 2 | 2 |
| CCI Score | Scores on a scale | 4.7 (SD 2.59) | 4.7 (SD 2.20) | 4.7 (SD 2.38) |
| CCI estimated 10-y survival % | Percentage | 43.9 (SD 37.16) | 40.8 (SD 35.14) | 42.3 (SD 35.89) |
| Comorbidity according to CCI score: No comorbidity (score ≤ 1) | Participants | 3 | 0 | 3 |
| Comorbidity according to CCI score: Mild comorbidity (score2) | Participants | 3 | 5 | 8 |
| Comorbidity according to CCI score: High comorbidity (score ≥ 3) | Participants | 24 | 25 | 49 |
| No. of comorbid diseases: At least 3 diseases | Participants | 3 | 3 | 6 |
| No. of comorbid diseases: 4-7 diseases | Participants | 13 | 5 | 18 |
| No. of comorbid diseases: 8-11 diseases | Participants | 5 | 11 | 16 |
| No. of comorbid diseases: ≥ 12 diseases | Participants | 9 | 11 | 20 |
6. Primary Endpoint
The registry lists the primary outcome as Difference in Modified Borg Dyspnea Scale Scores Between Groups, measured over From enrollment to the end of treatment at Day 7.
| Element | Registry entry |
|---|---|
| Result type | Least Squares Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | scores on a scale |
| Endpoint classification | Continuous Endpoint |
The Modified Borg Dyspnea Scale is a patient-reported rating of breathing difficulty. Its range runs from 0, indicating no difficulty at all, through to 10, indicating maximal difficulty. The primary endpoint compares scores between the two treatment groups over the period from enrollment to the end of treatment at Day 7. Participants recorded the score before dosing twice daily, between 7 and 9 am and between 7 and 9 pm.
Repeated ratings can describe symptom trajectories during treatment more fully than a single measurement at one time point. A repeated-measures model can account for the fact that multiple ratings from one participant are related, rather than treating each rating as if it came from a different person. The registry reports marginal means derived from such a model and states that all available assessments collected during treatment were used.
As a general statistical point, a marginal mean represents an average at the group level under the fitted model. The reported mean and its confidence interval therefore describe modeled group scores, not the range of individual participants’ scores or the amount of change experienced by each participant. The registry does not provide a clinically meaningful threshold for interpreting score differences, nor does it state a responder definition. The endpoint is a symptom measure; it does not by itself summarize all aspects of feasibility, safety, or clinical course.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The reported marginal mean Modified Borg score was 1.89 in the revefenacin-plus-formoterol group, with a 95% confidence interval from 1.34 to 2.45. In the albuterol-plus-ipratropium group, the reported marginal mean was 1.92, with a 95% confidence interval from 1.37 to 2.46. These are model-derived averages across available assessments during treatment, not endpoint scores from a single measurement occasion.
The registry reports a Generalized Estimating Equations analysis with p = 0.95 for the comparison. This result does not indicate a statistically detectable difference in the reported analysis. It is not evidence that the treatments are identical, and it does not establish that any difference is absent. A high p-value is not the probability that the null hypothesis is true. It describes how compatible the observed test result is with the null model under the analysis assumptions.
The individual group confidence intervals express uncertainty around each marginal mean. They are not a confidence interval for the between-group contrast. The registry record does not report an estimate or confidence interval for that contrast, so its precision cannot be assessed directly from the contrast itself. Group-specific intervals alone do not give the same information as an interval for the difference, particularly when measurements are repeated and modeled jointly.
The reported analysis draws on all available assessments collected during treatment, but the registry does not state how missing assessments were handled, why measurements were unavailable, or how many observations contributed at each time point. Consequently, the estimates should be read as model-based summaries of available data, not as proof that every participant contributed every planned rating. The registry also does not report a clinically meaningful score threshold, so the practical importance of a possible difference cannot be established from these results alone.
The trial enrolled 60 participants and followed treatment for up to 7 days, with earlier treatment end at discharge. The primary result is therefore specific to the short treatment period and the hospitalized AECOPD population represented in the trial. It should not be extended to other populations, settings, treatment durations, or outcomes without evidence. The registry record does not report a sample-size justification, and the reported p-value does not establish whether the study could reliably identify differences of a particular size.
9. Statistical Methods Explained
The primary outcome consists of repeated continuous scores. The Modified Borg Dyspnea Scale produces a numeric rating from 0 to 10, and the registry describes scores taken before dosing twice each day during treatment. Measurements from the same participant are generally correlated: a person’s ratings over time are not statistically independent observations. A method that recognizes this dependence is appropriate for repeated measurements.
What does a Generalized Estimating Equations analysis do?
Generalized Estimating Equations (GEE) is a general method for estimating average, or population-level, relationships when observations are clustered or repeated within individuals. In a repeated-measures setting, GEE accounts for within-person dependence when estimating uncertainty. The registry reports GEE for the primary comparison and states that the arm values are marginal means from a repeated-measures model using all available assessments during treatment.
That description does not reveal every modeling choice. The working correlation structure, any covariates, the exact specification of time, and any adjustments are not reported in the registry record. Without those details, the analysis cannot be fully reproduced from the registry information. GEE is not a guarantee that every pattern of missing observations is harmless; the validity of estimates can depend on assumptions and on how incomplete data arise.
How should marginal means and confidence intervals be read?
A marginal mean is a model-based average for a group across the modeled observations or conditions. The reported means are 1.89 for revefenacin plus formoterol and 1.92 for albuterol plus ipratropium. The corresponding 95% confidence intervals are 1.34 to 2.45 and 1.37 to 2.46. In general, a confidence interval describes uncertainty in an estimated quantity under the model and its assumptions. It is not a range containing a fixed proportion of individual participants’ scores, and it is not a direct interval for the contrast between groups unless the contrast itself is estimated and reported.
The registry’s reported p-value is 0.95. In general, a p-value measures how unusual the test statistic would be under a specified null hypothesis and statistical model. It is not the probability that the null hypothesis is true, nor does it show the size or clinical relevance of an effect. The registry does not report the between-group contrast estimate, its confidence interval, or enough model details to reconstruct them from the group means.
Why can repeated observations matter?
When the same participant contributes multiple measurements, treating every measurement as independent would ignore the shared participant and could misstate uncertainty. Repeated-measures methods use the structure of the data to estimate group-level patterns while allowing observations within a participant to be related. The registry says all available assessments during treatment entered the primary repeated-measures model. It does not report the count of observations by group or time point, the amount or pattern of missingness, or a specific missing-data strategy. A general explanation of GEE does not resolve those unreported details.
For continuous outcomes, over-dispersion refers broadly to variability greater than assumed by a chosen model. More generally, variance assumptions matter because uncertainty estimates depend on how the model represents the spread and dependence of the data. The registry identifies a GEE model but does not report a dispersion estimate or enough detail to assess alternative variance specifications. No conclusion about over-dispersion can be drawn from the group means and confidence intervals alone.
What is the role of a recalculation?
A simple unadjusted recalculation from posted summary statistics is not a substitute for the registry-reported repeated-measures analysis. Such recalculations may not preserve the within-participant correlation or the model’s use of observations across treatment. In this case, the available summary values do not yield a reported recalculated two-group contrast; the registry record does not give the contrast estimate and its uncertainty. The primary interpretation should therefore remain tied to the reported GEE result, without presenting an unsupported independent estimate.
The registry also describes planning illustrations based on the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect to detect set as a fraction of the observed effect. Such calculations, when displayed, are hypothetical planning scenarios. They are not the trial’s original design justification, do not describe observed power, and do not show the probability that the completed trial detected an effect. The registry does not report its own sample-size justification or design assumptions.
10. Analyses Reported by the Sponsor
| Method | Estimate | 95% CI | P-value |
|---|---|---|---|
| Generalized Estimating Equations | not reported | 0.950 |
The registry reports a Generalized Estimating Equations analysis for the primary repeated-measures comparison, with p = 0.95. It also reports the model-derived marginal means and their 95% confidence intervals for each group. These are the main inferential results available for the primary endpoint in the registry record.
A separate unadjusted recalculation of the between-group contrast is not available from the reported summary values. The arm means and confidence intervals do not, on their own, provide the repeated-measures covariance information or the contrast uncertainty needed to reproduce the GEE result. The registry record also does not list a contrast estimate or its confidence interval. Accordingly, the reported GEE result should not be replaced by a newly inferred treatment difference based only on the arm summaries.
The registry’s analysis is the available model-based comparison, while an independent summary-statistic recalculation would answer a different, more limited question and would not reproduce the repeated-measures model. No discrepancy between a reported result and a recalculation is identified in the registry record. The p-value should still be interpreted with the limitations of the reported model details and missing-data information in mind.
11. Multiplicity, Missing Data and Analysis Populations
The registry identifies a primary outcome and six secondary outcomes. It records 10 analyses overall, but does not report a plan for controlling multiplicity, such as a prespecified hierarchy or adjustment across outcomes. When several hypotheses are tested, interpreting each unadjusted p-value as if it were the only test can overstate the strength of evidence. This is a general statistical concern; it does not establish that any particular result is false. The registry record does not explain how the analyses were prioritized or whether any secondary results were intended to be confirmatory.
The primary outcome description states that the reported marginal means came from a repeated-measures model using all available assessments collected during treatment. This indicates that available measurements were used, but it does not specify the treatment of missing observations. Reasons for missingness, participant-level completion, time-specific observation counts, imputation, and sensitivity analyses are not reported in the registry record. Generalized Estimating Equations can account for within-person correlation, but the method name alone does not establish that missing-data assumptions are satisfied.
The analysis population is also not described in detail. The registry does not say whether the primary analysis followed an intention-to-treat principle, whether participants were excluded after randomization, or whether any per-protocol analysis was conducted. The reported arm sizes of 30 each describe the groups contributing to the posted primary results, but do not by themselves resolve those population definitions.
Further details that would help assess reproducibility are not reported in the registry record, including the GEE working correlation structure, covariate adjustment, handling of departures from the intended dosing schedule, and any sensitivity analyses. These omissions limit independent evaluation of model assumptions and robustness. They do not invalidate the reported results, but they make the extent to which alternative reasonable choices would change the estimates difficult to judge.
12. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Experimental: Group 1: Revefenacin (YUPELRI) & Formoterol (Perforomist) | 0 | 30 | 0.0% |
| Active Comparator: Group 2: Ipratropium Bromide (Atrovent) & Albuterol(Ventolin) as Standard of Care | 0 | 30 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Experimental: Group 1: Revefenacin (YUPELRI) & Formoterol (Perforomist) | 0 of 30 |
| Active Comparator: Group 2: Ipratropium Bromide (Atrovent) & Albuterol(Ventolin) as Standard of Care | 0 of 30 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 1% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Experimental: Group 1: Revefenacin (YUPELRI) & Formoterol (Perforomist) | 0 of 30 |
| Active Comparator: Group 2: Ipratropium Bromide (Atrovent) & Albuterol(Ventolin) as Standard of Care | 1 of 30 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Experimental: Group 1: Revefenacin (YUPELRI) & Formoterol (Perforomist) | Active Comparator: Group 2: Ipratropium Bromide (Atrovent) & Albuterol(Ventolin) as Standard of Care |
|---|---|---|---|
| Oxygen desaturation | Respiratory, thoracic and mediastinal disorders | 0 of 30 | 1 of 30 |
In the registry’s adverse-event figures, no participants in either group are reported as affected by a serious adverse event, and no deaths are reported. For other adverse events, zero participants are reported in the revefenacin-plus-formoterol group and one in the albuterol-plus-ipratropium group. These are counts among 30 participants in each group.
These figures are descriptive. A small number of observed events, including no reported serious events, does not establish that a treatment has no safety risk. The registry record does not provide serious adverse event terms, because no serious-event terms are listed, and does not provide details about the one other adverse event, its severity, timing, or relationship to treatment. The event categories and reported counts should therefore be read as the registry’s recorded summary, not as a comprehensive comparison of every possible safety outcome.
The study followed treatment for up to 7 days, with treatment ending earlier if a participant was discharged. The safety counts pertain to the reported trial record and do not determine risks outside this study’s size, population, or observation period.
13. What the Result Does, and Does Not, Mean
The primary result describes modeled average Modified Borg Dyspnea Scale scores during treatment for two randomized groups of hospitalized patients with AECOPD. The reported marginal means were 1.89 for revefenacin plus formoterol and 1.92 for albuterol plus ipratropium. The registry-reported GEE comparison had p = 0.95. Taken together, the registry analysis did not detect a statistically significant difference in the primary outcome.
That finding does not establish that the treatment strategies are equivalent or that their effects are exactly the same. Equivalence or non-inferiority requires a prespecified margin and an analysis designed to evaluate that question; such a margin is not reported in the registry record. The record also does not report a confidence interval for the treatment contrast, so the range of contrast values compatible with the model cannot be read directly from a contrast interval.
The result does not establish that either treatment improves breathing difficulty, because the reported primary endpoint is a comparison between groups and the record does not provide a treatment-versus-no-treatment comparison. It also does not establish efficacy for outcomes beyond the measured symptom scale, or beyond the treatment period. The record lists several secondary measures, but detailed numerical results for most are not available in the registry record details.
The result is bounded by the study design and its reporting. The trial was open-label, enrolled 60 participants, and evaluated treatment for up to 7 days or until discharge. The registry does not report a sample-size justification, detailed missing-data methods, or a clinically meaningful threshold for the symptom scale. Those limitations make it inappropriate to interpret a non-significant p-value as proof of no meaningful difference. The sound conclusion is narrower: the posted primary model analysis did not detect a difference, while its precision and clinical importance cannot be fully established from the registry information.
14. Why This Trial Matters Statistically
This trial illustrates why the method used for repeated clinical measurements matters. A symptom scale recorded twice daily produces multiple observations from each participant. Those observations are related, and a model that recognizes within-participant dependence can estimate group-level averages more appropriately than a method that treats every rating as independent. The registry’s use of a repeated-measures GEE model reflects that structure.
It also illustrates the distinction between separate group summaries and a direct comparison. The registry reports a marginal mean and confidence interval for each arm, as well as a p-value for the GEE comparison. It does not report a confidence interval for the between-group contrast. Those summaries answer related but not identical questions: the arm intervals describe uncertainty in each modeled mean, while a contrast interval would describe uncertainty in the difference itself.
The study also highlights limits on what a non-significant result can establish. A high p-value is not proof of equality, and without a reported contrast interval or a stated equivalence margin, the result cannot establish that any possible difference is small enough to be clinically unimportant. The absence of a sample-size justification further limits evaluation of the study’s ability to distinguish effects of particular sizes.
Finally, open-label treatment, a short treatment period, incomplete reporting of missing-data methods, and unreported multiplicity procedures all shape interpretation. These are not reasons to discard the results; they identify which questions the registry record can answer and which remain uncertain. Careful reading separates the observed model-based comparison from broader claims about clinical benefit, safety, equivalence, or generalizability.
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 trial was conducted without masking. When participants and clinical staff know assigned treatment, expectations or treatment practices could influence subjective ratings, care decisions, or reporting. The primary endpoint is a patient-reported breathing-difficulty scale, so the absence of masking is particularly relevant to interpretation. The registry does not report whether any independent blinded outcome assessment was used.
The enrolled population numbered 60, with 30 participants in each arm in the primary results. The registry does not report a sample-size justification or the effect size the trial was designed to detect. It is therefore not possible to determine from the record whether the study was adequately sized for a specified clinically important difference. The non-significant primary p-value should not be treated as evidence of equivalence.
The observation period was limited to treatment for 7 days or until discharge if earlier. That short period constrains what can be said about outcomes over longer follow-up. The primary symptom measure was recorded twice daily before dosing, but the record does not report the number of completed ratings, reasons for missing assessments, or the handling of missing data beyond saying that all available assessments were used in the model.
Reporting also limits independent appraisal. Details of eligibility criteria, allocation sequence generation, allocation concealment, GEE model specification, and multiplicity control are not reported in the registry record. The primary contrast estimate and its confidence interval are not reported, and the secondary results available in the record details are incomplete. These limitations restrict assessment of precision, reproducibility, and the consistency of findings across outcomes. They are specific constraints on interpretation, not proof that the analysis is invalid.
16. Related Tutorials
17. Related Statistical Calculators
18. Sources
- ClinicalTrials.gov: Feasibility, Safety and Efficacy of Nebulized Long-Acting Bronchodilators (Formoterol and Revefenacin) vs. Short-Acting Bronchodilators (Albuterol and Ipratropium) in Hospitalized Patients With AECOPD — NCT04655170.
- Registry record last updated 2026-08-03; status last verified 2026-07.
- Results first posted 2026-08-03.
- 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.
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19. Record Summary
The registry record describes a completed Phase 4 randomized, parallel-group, unmasked trial of nebulized revefenacin plus formoterol versus nebulized albuterol plus ipratropium in hospitalized patients with AECOPD. Enrollment was 60. The experimental regimen was revefenacin 175 μg once per day and formoterol 20 μg twice per day; the comparator was albuterol and ipratropium every 6 hours. Both regimens were administered for up to 7 days or until earlier discharge.
The primary outcome was the Modified Borg Dyspnea Scale from enrollment to the end of treatment at Day 7. Reported marginal means were 1.89 and 1.92, with respective 95% confidence intervals of 1.34 to 2.45 and 1.37 to 2.46. The registry reports a GEE comparison with p = 0.95. A confidence interval for the between-group contrast is not reported in the registry record.
No serious adverse events or deaths are reported in either group; one other adverse event is reported in the comparator group. The registry lists six secondary outcomes, but the available record details do not support a full assessment of their overall pattern. Sample-size justification, multiplicity handling, and detailed missing-data methods are not reported in the registry record.