Differentiating the Effects of Long-acting Bronchodilators Administered by Nebulizer Versus Dry Powder Inhaler in Symptomatic Patients With Chronic Obstructive Pulmonary Disease
Phase: PHASE4
Conditions: COPD (Chronic Obstructive Pulmonary Disease)
Sponsor: University of Tennessee Graduate School of Medicine

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TITLE: Differentiating the Effects of Long-acting Bronchodilators Administered by Nebulizer versus Dry 
Powder Inhaler in Symptomatic Patients with Chronic Obstructive Pulmonary Disease 
 
Coordinating Center: 
University of Tennessee Graduate School of Medicine 
Department of Medicine 
Principal Investigator: 
Rajiv Dhand, MD 
Professor and Chair, Department of Medicine 
UT Graduate School of Medicine 
1924 Alcoa Highway, U114 
Knoxville, TN 37920 
phone: 865-305-9341 fax: 865-305-9144 
 
Study Team 
 
Name 
Role 
 
Rajiv Dhand, MD 
PI 
 
Isaac Biney, MD 
Co-I 
 
Samuel Treat, MD 
Co-I 
 
Paul Terry, PhD 
Co-I 
 
Jennifer Ferris, MS 
Research Support 
 
Tracy Walker 
Study Coordinator 
 
Daniel Church, RRT, RPFT 
Respiratory Therapist 
 
Lee Ann Holbert, RRT, CPFT 
Respiratory Therapist 
 
Shonda Smith, RRT, CPFT 
Respiratory Therapist 
 
Cody Epling, RRT 
Respiratory Therapist 
 
Steve Young, RRT 
Respiratory Therapist 
 
Michelle McGregor, RRT 
Respiratory Therapist 
 
Robert Heidel, PhD 
Statistician/Data Analyst 
 
Jesse Woodall, MD 
Participating Physician 
 
Mahmoud Shorman, MD 
Independent Safety Monitor 
 
Savannah Allen, MPH 
Study Coordinator 
 
Danielle Dennis, PharmD 
Pharmacy Support 
 
 
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Contents 
1. 
Background ..................................................................................................................................................... 6 
COPD and inhaled treatment ...............................................................................................................................6 
Choice of Inhalation Device ................................................................................................................................ 6 
Lung function: Inhalers vs. Nebulizers ............................................................................................................... 6 
Adherence and Training ...................................................................................................................................... 7 
Patient-reported outcomes: Inhalers vs. nebulizers ............................................................................................. 7 
Long-acting bronchodilators ................................................................................................................................8 
Lung hyperinflation ..............................................................................................................................................9 
Biological mechanisms ..................................................................................................................................... 10 
2. 
Specific Aims and Hypotheses ...................................................................................................................... 10 
Underlying hypothesis ....................................................................................................................................... 10 
Specific Aim 1 ................................................................................................................................................... 10 
Specific Aim 2 ................................................................................................................................................... 10 
3. 
Significance ................................................................................................................................................... 10 
4. 
Outcomes ....................................................................................................................................................... 11 
The primary outcome measures .........................................................................................................................11 
Secondary outcomes .......................................................................................................................................... 11 
5. 
Study Design ................................................................................................................................................. 12 
6. 
Study Population ........................................................................................................................................... 12 
7. 
Selection of Study Participants ...................................................................................................................... 12 
8. Inclusion/Exclusion Criteria ............................................................................................................................ 12 
Inclusion criteria ................................................................................................................................................ 12 
Exclusion criteria .............................................................................................................................................. 12 
8. 
Study Duration: ............................................................................................................................................. 13 
9. 
Study Environment and Facilities: ................................................................................................................ 13 
10. 
Summary of Study Visits and Timeline ..................................................................................................... 14 
Screening Visit/Run-in period ........................................................................................................................... 15 
Baseline Study Visit 2 (within one week of screening/start of Run-in Visit) ± two days: ............................... 15 
Pre-Dosing .....................................................................................................................................................15 
Post-Dosing ...................................................................................................................................................16 
Phone Call Week 4 ............................................................................................................................................ 17 
Phone Call Week 8 ............................................................................................................................................ 17 
Study Visit 3 ...................................................................................................................................................... 17 
Pre-Dosing .....................................................................................................................................................17 
Post-Dosing ...................................................................................................................................................18 
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End of Study Visits: .......................................................................................................................................... 18 
11. 
Reasons for withdrawal/unblinding: ........................................................................................................... 18 
12. 
Ethical and safety issues: ............................................................................................................................ 19 
13. 
Device Training: ......................................................................................................................................... 19 
14. 
Study Therapies .......................................................................................................................................... 19 
Group A: DPI .................................................................................................................................................... 19 
Group B: Nebulizer treatment ........................................................................................................................... 19 
Blinding ............................................................................................................................................................. 19 
Packaging, labeling, and re-supply ................................................................................................................... 19 
Storage conditions ............................................................................................................................................. 20 
Drug accountability ........................................................................................................................................... 20 
Other Medications: ............................................................................................................................................ 20 
15. 
Pre-Pulmonary Function Testing Restrictions ............................................................................................ 20 
16. 
Quality assurance procedures: ..................................................................................................................... 21 
17. 
Sample size: ............................................................................................................................................... 21 
18. 
Data analysis: ............................................................................................................................................. 21 
19. 
Risks to the Subjects: ..................................................................................................................................21 
20. Anticipated Problems and Pitfalls: ................................................................................................................. 22 
21. Anticipated Outcomes and Deliverables: ....................................................................................................... 23 
22. Adverse Events and Serious Adverse Events ................................................................................................. 23 
Adverse Event Definitions ................................................................................................................................ 23 
Unexpected Adverse Event ........................................................................................................................... 23 
Serious Adverse Event .................................................................................................................................. 23 
Adverse Event Assessment and Documentation ............................................................................................... 23 
Relationship ................................................................................................................................................... 24 
Severity ......................................................................................................................................................... 24 
Action Taken ................................................................................................................................................. 24 
Outcome ........................................................................................................................................................ 24 
Reporting ........................................................................................................................................................... 25 
23. Patient Recruitment and Informed Consent ................................................................................................... 25 
Recruitment ....................................................................................................................................................... 25 
Informed Consent .............................................................................................................................................. 25 
Withdrawal of Consent ..................................................................................................................................... 25 
24. Study Management .......................................................................................................................................... 26 
25. Protocol Deviations ......................................................................................................................................... 26 
26. Data Quality Assurance .................................................................................................................................. 26 
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27. Source Documents .......................................................................................................................................... 26 
Direct Access to Source Data and Documents .................................................................................................. 27 
28. Completion of Trial ........................................................................................................................................ 27 
29. SUMMARY .................................................................................................................................................... 27 
30. REFERENCES ............................................................................................................................................... 28 
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1. Background 
 
COPD and inhaled treatment 
Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death in the U.S., affecting over 
15 million Americans[1] and over 300 million individuals worldwide.[2] Patients with COPD rely heavily on 
inhaled bronchodilators and corticosteroids (ICS) to control symptoms, maximize quality of life, and avoid 
exacerbations and costly hospitalizations. These drugs are typically delivered by inhalers, either pressurized 
metered dose inhalers (pMDIs), dry powder inhalers (DPIs), or soft mist inhalers (SMIs), or by nebulizers. Each 
aerosol delivery device has advantages and disadvantages related to portability, ease and speed of use, and cost.[3, 
4] The relative convenience of inhalers has led to their widespread acceptance by physicians as the primary mode of 
inhalation delivery for maintenance therapy in ambulatory settings,[5] whereas nebulizers are mainly prescribed for 
rescue treatment with short-acting bronchodilators for relief of acute dyspnea. However, a large majority, up to 
94%, of patients with COPD do not receive optimal relief from disabling symptoms because they do not use 
their inhalers appropriately (Table 1).[6] Hence, it has been hypothesized that the widespread preferential use 
of inhalers over nebulizers may account for substantial excess morbidity and healthcare costs related to 
COPD.[7] 
 
Choice of Inhalation Device 
Besides the choice of inhaled drugs, key aspects influencing effectiveness of treatment are the choice of the 
most appropriate aerosol delivery device, proper 
education, device training, and adherence.[5] For 
patients with COPD, the lack of a large clinical trial of 
inhalers vs. nebulizers using comparable, newly 
available long-acting drugs in both devices, especially 
studies that account for aerosol delivery device 
training and patient-reported outcomes, has been 
described as a notable gap in the current literature by 
leading experts in the field.[8] In this proposal, we 
will address this gap by comparing measures of 
lung function and patient-reported outcomes using therapy with long-acting bronchodilators (umeclidinium 
and vilanterol) administered by DPI and long-acting bronchodilators of similar pharmacological classes 
(revefenacin and formoterol) administered by jet nebulizer in a prospective, randomized, parallel group, 
double dummy, phase four, 12-week clinical trial. 
 
Lung function: Inhalers vs. Nebulizers 
The comparative effectiveness and outcomes of nebulized versus inhaler-based therapy for COPD 
maintenance remains unclear.[9] In 2005, Dolovich and colleagues published a systematic review of device 
selection and outcomes of aerosol therapy,[10] which included only two studies that compared the 
effectiveness of inhalers versus nebulizers in patients with stable COPD. A randomized crossover trial by 
Balzano and coworkers[11] found a 19% greater change in FEV1 after treatment with a multidrug combination 
via nebulizers compared with inhalers among 20 patients (12 with COPD and 8 with asthma), a result that was 
not statistically significant. Another randomized crossover trial by Hansen and colleagues[12] found no 
appreciable or statistically significant difference in lung function between terbutaline delivered by a DPI and 
nebulizer in 22 patients with severe COPD. These studies examined short-term effects of short-acting drugs 
over short study periods, with small sample sizes; in other words, the two studies are methodologically very 
weak. Nonetheless, the review by Dolovich and colleagues has been often cited as evidence for the equivalent 
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treatment effectiveness of inhalers and nebulizers in patients receiving long-term therapy for COPD. A few 
additional trials were weak in similar ways, and some even compared different drugs in the two devices.(7) 
These limitations may explain the conflicting results of those studies, which alternatively showed nebulizer- 
inhaler equivalence, nebulizer superiority, or nebulizer inferiority. Participants in those clinical trials also 
tended to receive atypical training to use their prescribed inhalers until they were able to show proficiency, in 
contrast with “real life” situations where most patients with COPD do not use inhalers appropriately, due to 
inadequate training or physical/cognitive limitations.[6] Moreover, those studies tended to focus on objective 
measures of FEV1, which does not correlate well with patient-reported dyspnea symptoms or quality of life 
measures.[13] 
 
Adherence and Training 
Poor adherence to inhalation therapy further compounds the problem of “inhaler misuse”[6] and frequent 
monitoring is essential for patients with COPD to achieve maximal benefits from their treatment. Among the 
available aerosol generating devices, it is easier to train patients to use nebulizers because minimal 
coordination and effort is needed for proper use. Because drug aerosol is delivered over several breaths, 
compared to one or two breaths with inhalers, nebulizers are more forgiving to poor inhalation technique 
than inhalers. Regarding training, there is 
evidence that even extensive training may 
not largely mitigate patients’ misuse of 
inhalers because of physical/cognitive 
limitations in patients with COPD. For 
example, in the survey conducted by 
Hanania and colleagues,[14] 79% of patients 
with COPD reported at least one physical or 
cognitive impairment that could limit their 
ability to correctly manipulate an inhaler 
device, including arthritis, poor eyesight, 
poor hearing, memory problems, tremor, 
difficulty with fine motor activities, 
depression, or anxiety, and more than half 
of the respondents had multiple limitations. In a previous publication,[15] the PI and several expert colleagues 
from North America identified key clinical situations where nebulizers are preferred over inhalers for 
maintenance therapy in patients with COPD (Table 2). 
 
Patient-reported outcomes: Inhalers vs. nebulizers 
There is additional evidence to suggest that use of nebulizers may improve symptoms in patients with COPD more 
than use of inhalers, even without producing significant differences in tests of lung function (Table 3). For 
example, nebulizers were shown to provide more patient-reported symptom relief than pMDIs.[16] Likewise, data 
from 2,164 clinically stable COPD patients in the ECLIPSE Cohort[17] found that forced expiratory volume (FEV1) 
was an unreliable marker of the severity of breathlessness, exercise limitation and health status impairment. 
Patients preferred nebulizers over inhalers for long-term therapy.[18, 19] It has been suggested that 
hospitalizations can be reduced[20] and quality of life improved[21] with nebulized therapy. A survey of patients 
with COPD showed that nebulized treatment helped them feel comfortable and more in charge of their own 
symptom control.[22] In another random survey of 400 patients and 400 caregivers, participants showed 
preference for nebulized therapy (~80%) and patients believed that their overall quality of life had improved 
since beginning nebulized treatments.[23] Two web-based surveys, one in patients with COPD and another in 
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U.S. pulmonologists reported responses that were favorable for use of nebulizers.[24, 25]The majority of patients 
(54%) who had used nebulizers preferred them to other inhalation devices.[25] 
 
Table 3. Limited evidence supporting better symptom control with nebulizers vs. inhalers 
 
Author, year 
Study type 
Sample size 
Study Findings 
O’Driscoll, 
199219 
Clinical trial of usual inhaler 
treatment followed by nebulizer 
treatment 
34 with COPD 
About half of patients who remain breathless despite 
receiving bronchodilators delivered by pMDIs or DPIs 
derived additional benefits from home nebulizer use; 
the majority of patients with COPD in this study 
chose to remain on nebulizers for long term therapy 
Corden, 199721 
Nebulizer therapy compliance vs. 
self-reported quality of life and St. 
George's Respiratory Questionnaire 
82 with COPD 
Compliance with nebulized therapy positively 
associated with quality of life scores 
Godden, 199820 
In-home questionnaires and 
hospital records were reviewed 
208 with COPD 
Hospitalizations can be reduced when patients are 
given nebulizers 
Barta, 200222 
Patient survey (via postal 
questionnaire) 
82 with COPD 
Nebulized treatment at home helped patients feel 
comfortable and more in charge of their own 
symptom control; compliance was generally excellent 
Tashkin, 200716 
A 12-week randomized clinical trial 
of patients comparing inhalers, 
nebulizers, and concomitant 
therapy 
126 with COPD 
Nebulizers showed better patient-reported outcomes 
including questionnaire symptoms and quality of life; 
peak flow and FEV1 showed no significant 
differences; concomitant therapy was better than 
either alone 
de Monte, 
200718 
Postal survey regarding use of 
nebulized therapy 
3,674 physicians in 
France 
“Patient request” was a significant reason for 
prescribing nebulized therapy; however, no question 
pertained specifically to hand-held inhalers 
Agusti, 201017 
Prospective cohort study (ECLIPSE) 
2,164 with stable 
COPD 
Severity of airflow limitation was poorly related to 
the degree of breathlessness, health status, exercise 
capacity and number of exacerbations 
Sharafkhaneh, 
201323 
Telephone survey of randomly 
selected patients and caregivers 
400 patients with 
COPD and 400 
caregivers 
Most patients and caregivers (~80%) preferred 
therapy with nebulizer vs. inhalers for controlling 
symptoms and improving quality of life 
Dhand, 201825 
Online survey using the Harris Poll 
Online panel 
254 patients with 
COPD 
54% of patients with COPD preferred nebulizers to 
other inhalation devices 
 
 
Likewise, the majority of pulmonologists (70%) believed that nebulizers were more effective than DPIs or 
pMDIs and 56% were of the opinion that nebulizers were essential for some patients.[24] Thus, in contrast with 
earlier small, short-term trials of device choice and lung function, patient-centered research tends to show better 
symptom relief with use of nebulized therapy. 
 
Long-acting bronchodilators 
Long-acting bronchodilators, LABAs and LAMAs, are currently the preferred agents for use in the management 
of stable COPD and have several advantages over shorter-acting drugs.[5, 8] Until recently, there were no FDA 
approved LAMAs for nebulizer delivery. Recently, 2 LAMAs (glycopyrrolate (Lonhala MagnairTM, Sunovion) and 
Revefenacin (Yupelri™; Mylan/Theravance) were approved for maintenance therapy with nebulizers in COPD. 
Because glycopyrrolate is administered by a dedicated, specialized vibrating mesh nebulizer, its use would 
require the use of a separate nebulizer for delivery of formoterol, which would not be convenient for patients. 
Revefenacin is a once-daily, bronchodilator administered by jet nebulizer which is well tolerated, with minimal 
reports of systemic anti-cholinergic effects. It has been shown to be an effective bronchodilator in patients 
with severe COPD. Thus, a combination of nebulized revefenacin with formoterol administered by jet 
nebulizer provides a LAMA/LABA combination that are available as solutions for nebulization and have similar 
pharmacological classes as medications delivered by inhalers. In long-term studies, both revenfenacin and 
formoterol have been shown to be safe and effective in patients with COPD.[26, 27] In combination, nebulized 
formoterol and revefenacin improved lung function to a similar extent compared to sequential administration 
of the two drugs.[28] 
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In patients with stable COPD, the combination of beta agonists with anticholinergics produces additive 
bronchodilation with a good safety profile.[29] In such patients, long-acting bronchodilators, both 
anticholinergics and beta-2-adrenergic agonists provide larger reductions in hyperinflation compared to 
short-acting bronchodilators.[30] However, the differential effects of long-acting bronchodilators administered 
by nebulizers versus DPIs on hyperinflation have not been determined in patients with COPD. 
 
Figure 1: Effects of bronchodilation on air trapping/hyperinflation. Nebulizers produce fine particle aerosols 
which may deliver bronchodilators to more peripheral airways than dry powder inhalers and offer greater 
relief from air trapping/hyperinflation (as in panel C). This differential effect could explain greater relief of 
symptoms with long-acting bronchodilators administered by nebulizers than dry powder inhalers. 
(Reproduced from Beeh KM, Beier J. Adv Ther 2010;27:150-59) 
 
Lung hyperinflation 
In a significant proportion of people with COPD, reduced lung elastic recoil (due to emphysema) combined 
with expiratory flow limitation (due to luminal narrowing of peripheral airways) leads to lung hyperinflation 
during the course of the disease.[31] Increased frequency of breathing (tachypnea), increased respiratory 
neural drive, and fear or anxiety are also major contributors to development of dynamic hyperinflation. The 
consequences of lung hyperinflation include increased elastic load, increased inspiratory threshold load, 
decreased inspiratory muscles pressure generating capacity, impaired gas exchange, impaired 
cardiopulmonary interaction, mechanical volume restriction, increased functional residual capacity (FRC) and 
reduced inspiratory capacity (IC).[31] These pathophysiologic features contribute significantly to the 
development of dyspnea, exercise intolerance, skeletal muscle limitations, reduced physical activity levels, 
various morbidities, and mortality associated with COPD. [31, 32] 
 
The major goal of treatment in patients with severe COPD is lung deflation by intensive bronchodilator 
therapy that reduces airway resistance, accelerates time constants for lung emptying, restores 
neuromechanical coupling and relieves dyspnea. In subjects with COPD, bronchodilators of all classes 
consistently reduce lung hyperinflation and pulmonary gas trapping, resulting in increases in inspiratory 
capacity (IC) and vital capacity (VC).[33, 34] Both β2-agonists and anti-muscarinic bronchodilators increase IC by 
~10-15% in people with COPD,[34, 35] with the largest increase in IC observed in those people with the greatest 
lung hyperinflation at baseline.[36] This clinical trial seeks to determine if use of long-acting bronchodilators 
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given by nebulizer reduce hyperinflation to a greater extent than long-acting bronchodilators of similar classes 
administered by DPI. 
 
Biological mechanisms 
The biological mechanisms that might underlie the differences in response between nebulizers and inhalers are 
unknown, but it is possible that with several slow inhalations over time, aerosolized medications delivered by 
nebulizer have more peripheral versus central deposition compared with inhalers.[37-39] Conceivably, the longer 
duration of inhaling bronchodilators by nebulization leads to more effective reduction in resting and dynamic lung 
hyperinflation (Figure 1), with consequent improvements in exercise tolerance and perceived breathlessness 
during exertion, even if nebulizers and inhalers still produce similar effects on FEV1.[40] In any case, as detailed 
above, patients appear to sense a difference in response to medication delivered by nebulizer compared with 
inhalers, in that they perceive an improvement in their breathlessness. Hence, studies that compare inhaler 
devices and only consider objective measures of lung function, such as FEV1, may not adequately capture 
meaningful differences in patients’ subjective disease and treatment experiences, leading to a considerable 
knowledge gap when choosing the appropriate inhalation device for each patient. For this reason, it is 
important to consider the patient’s perspective(s) in how they perceive relief of dyspnea with various 
inhalation delivery devices 
 
 
2. Specific Aims and Hypotheses 
In this study, we will compare the effectiveness of inhaled bronchodilators delivered via nebulizers vs. DPIs in 
symptomatic participants with COPD who have airflow obstruction (FEV1/FVC ≤ 70%) and show significant air 
trapping (RV ≥ 120% of predicted). 
 
Underlying hypothesis 
In patients with symptomatic COPD, therapy with a LAMA/LABA combination administered by nebulizer will 
improve hyperinflation (increase in inspiratory capacity and reduction in residual volume) and reduce 
symptoms related to COPD to a greater extent than LAMA/LABA therapy given by a DPI. 
Specific Aim 1: Compare the values of IC and RV in patients receiving LAMA/LABA by DPI with those receiving 
LAMA/LABA by nebulizer 
Specific Aim 2: Compare patient reported outcomes (COPD Assessment Test (CAT score), Baseline/Transition 
Dyspnea Index (BDI/TDI) and the ST. George Respiratory Questionnaire (SGRQ) in symptomatic patients with 
COPD receiving LAMA/LABA by DPI with those receiving LAMA/LABA by nebulizer. 
 
 
3. Significance 
If our central hypothesis that nebulizers are more effective than inhalers in reducing patients’ symptoms and 
improving their quality of life is shown to be correct, then there exists a tremendous potential to improve the 
lives of many millions of patients with COPD. Whether the choice of the inhalation device (nebulizer vs inhaler) 
influences hyperinflation, symptoms, health-related quality of life (QOL), or other clinical outcomes will be of 
enormous clinical and economic significance. This hypothesis has yet to be adequately tested given the lack of 
large-scale, long-term prospective data addressing inhaler device selection and technique, as well as therapy 
adherence, as a means to improve dyspnea symptom control and QOL in patients with COPD using newly- 
available long-acting drugs by nebulizers.[8, 14] A rigorous test of this hypothesis, whether supported or refuted, 
will lead to better understanding of the roles of device selection, training, and adherence in COPD 
maintenance from the patient perspective, information currently deemed to be necessary but lacking.[8, 9] 
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In their statement of vital research questions in COPD, the American Thoracic Society / European Respiratory 
Society noted the importance of addressing the comparative efficacy and outcomes of nebulized versus 
handheld long-acting bronchodilator therapy for COPD maintenance.[9] 
 
The present study seeks to address this important gap in knowledge. We anticipate that our results will be of 
immense interest not only to patients and their caregivers, but also to their physicians, and many other 
stakeholders including the national American Thoracic Society (ATS), American College of Chest Physicians 
(ACCP), American Association for Respiratory Care (AARC) and the International (European Respiratory Society 
(ERS), Global Initiative for Chronic Obstructive Lung Disease (GOLD), International Society for Aerosols in 
Medicine (ISAM) specialist organizations. The outcome of this project will also be actively supported by many 
national patient advocacy groups, such as the American Lung Association (ALA), COPD Foundation and US 
COPD Coalition. 
 
 
4. Outcomes 
The primary outcome measures 
• Difference between the values of area under the response curve for inspiratory capacity (IC) from 
baseline through six hours (AUC IC 0-6h) after inhalation of LAMA/LABA combination with a nebulizer 
versus a DPI OR 
• Proportion of participants achieving improvement of >2 points in their CAT score compared to baseline 
OR 
• Proportion of participants achieving reduction of 4 points in SGRQ score compared to baseline 
 
Secondary outcomes 
Secondary outcomes that will be analyzed include comparing the following parameters after inhalation of 
LAMA/LABA combination with a nebulizer versus a DPI: 
• Percentage change in RV from baseline after inhalation of LAMA/LABA combination 
• Percentage change in TLC from baseline after inhalation of LAMA/LABA combination 
• Percentage change in airway resistance (Raw) from baseline after inhalation of LAMA/LABA 
combination 
• Maximum % change in inspiratory capacity between 0 and 6 hours after LAMA/LABA combination 
• Maximum % change in RV between 0 and 6 hours after LAMA/LABA combination 
• Maximum % change in airway resistance between 0 and 6 hours after LAMA/LABA 
• Correlation of peak inspiratory flow rate with peak IC change from baseline 
• Comparison of CAT scores in patients receiving medications with DPI vs nebulizer 
• Comparison of SGRQ scores in patients receiving medications with DPI vs nebulizer 
• Change in TDI in patients receiving medications with DPI vs nebulizer 
• Change in CAT scores in patients receiving medications with DPI vs nebulizer 
• Change in SGRQ scores in patients receiving medications with DPI vs nebulizer 
• Correlation of CAT with LF and LH change (inspiratory capacity and residual volume change) with 
patient-reported outcomes. 
• Correlation of LH with patient-reported outcomes 
• For select variables, we will compare VISIT 1 with VISIT 2 to identify variation 
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5. Study Design 
A prospective, randomized, parallel group, double dummy, phase four, 13-week clinical trial with 1:1 
allocation comparing long-acting anti-muscarinic agent (LAMA; Umeclidinium 62.5 μg once daily) and long- 
acting beta-agonist (LABA; Vilanterol 25 μg once daily) delivered by DPI (Group A), vs a nebulized LAMA/LABA 
combination (revefenacin 175 μg once daily and formoterol 20 μg twice daily) (Group B) among symptomatic 
subjects with stable COPD. 
 
6. Study Population 
Seventy-two symptomatic patients (36 in each group) with a primary diagnosis of COPD will be enrolled if they 
meet all inclusion and exclusion criteria. 
 
7. Selection of Study Participants 
Patients will primarily be recruited from the UTMC Pulmonary Function Testing Lab and the Internal Medicine 
resident clinic. GSM faculty, staff, UPCC clinicians, and respiratory testing staff will help identify and refer 
potential patients. 
 
The nature and purpose of the study will be explained to patients who meet inclusion and exclusion criteria by 
one of the study team members. The patient will be given a copy of the informed consent to review. The 
investigator or study coordinator will answer any questions the patient may have prior to their signing the 
consent. The signed informed consent will be kept in the patient’s research chart and a copy will be given to 
the patient. No study related interventions will be performed until the patient signs the informed consent. 
 
8. Inclusion/Exclusion Criteria 
Inclusion criteria 
1. Age > 40 years 
2. Either sex 
3. Current smoker or past cigarette smoking history of > 10 pack-years 
4. Symptoms of COPD (cough, sputum production, shortness of breath) 
5. Modified Medical Research Council Dyspnea Scale (mMRC) score ≥2 or CAT score ≥10 at 
Screening/Run-in visit 
6. A PIFR > 30 at screening 
7. FEV1/FVC ratio < 70% (within the past 12 months) 
8. Residual volume (RV) ≥ 120% predicted (within the past 12 months) 
Exclusion criteria 
Subjects with any of the following conditions will be excluded: 
1. Diagnosis of asthma (Verification via medical record and/or patient report) 
2. Previously diagnosed atrial fibrillation with rapid ventricular response (heart rate > 110 bpm) or 
ventricular arrhythmia (ventricular tachycardia) (Verification via medical record and/or patient 
report) 
3. Acute myocardial infarction within 12 weeks of patient study registration (Verification via medical 
record and/or patient report) 
4. Acute exacerbation of congestive heart failure (Verification via medical record and/or patient 
report) 
5. Acute exacerbation of COPD within 8 weeks (Verification via medical record and/or patient report) 
6. Recent (within 8 weeks) h/o eye surgery (Verification via medical record and/or patient report) 
7. Uncontrolled glaucoma (Verification via medical record and/or patient report) 
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8. Known diagnosis of liver cirrhosis (Verification via medical record and/or patient report) 
9. Known diagnosis of chronic renal insufficiency (defined as a previous serum creatinine > 2.5 mg/dL 
- Verification via medical record and/or patient report) 
10. Intolerance to any of the study drugs 
11. Patients receiving long-term azithromycin 
12. Planned surgery requiring hospital admission within 3 months 
13. Currently enrolled in a pulmonary rehabilitation program 
14. Inability to give informed consent 
15. Pregnant or nursing women or women of childbearing potential not using a medically approved 
means of contraception (i.e., oral contraceptives, intrauterine devices, diaphragm, or subdermal 
implants) 
16. Inability to understand instructions or comply with the study protocol 
17. Participation in another investigational drug clinical trial within 30 days of patient study registration 
 
Medical history can be confirmed by medical records and/or verbal confirmation from patients. However, 
Inclusion criteria 6 & 7 must be verified by a previous PFT report dated within 6 months of screening. 
 
9. Study Duration: 
The anticipated length of this study is 18 months (Figure 3). Months 1 and 2 are for startup, including 
regulatory compliance. We anticipate patient enrollment to take 13 months (i.e., enrollment of 1-2 
patients/week on average). The final two months are for data analysis and manuscript writing. 
 
10. Study Environment and Facilities: 
The study has clinic and office space, data storage and computer facilities, and access to the equipment 
necessary for completing study procedures, including spirometry, body plethysmography, Figure 2., and In 
Check Dial for measuring PIFR. The PFT lab has approximately 1200 square feet of dedicated space, seven 
respiratory therapists available for study procedures, and the equipment shown below to perform the 
required plethysmography testing. Patients will be scheduled for required testing in the PFT lab as needed, 
and the PFT Lab will be reimbursed for services. 
 
 
Figure 2: Vyntus™ BODY Plethysmograph 
 
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11. Summary of Study Visits and Timeline 
 
 
 
Table 4: Procedure Schematic:  
 
     
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Screening Visit/Run-in period 
On the day of screening, patients will have assessments including: 
• If eligible and willing to participate, patients will sign an informed consent 
• Medical history and concurrent medication review 
• Determination of eligibility 
• Patients will be trained on use of DPI with a placebo inhaler (Ellipta, GSK) and the nebulizer using 
nebulized saline. The techniques of nebulizer cleaning and disinfection will be demonstrated. 
• Vital signs (heart rate, respiratory rate, temperature, blood pressure and SpO2) and physical 
examination will be recorded by the study coordinator. 
• Patients will be trained on various questionnaires (CAT, BDI/TDI, SGRQ) by the study coordinator. 
•  Study coordinators will provide extensive training in the use of the daily diary. Participants will 
receive symptom and medication logs to be filled out daily. 
• The baseline peak inspiratory flow rate will be determined with an inspiratory flow meter (In-Check 
DIAL, Clement Clarke International, Harlow UK) using the resistance of a Diskus inhaler (similar to 
that of an Ellipta device). 
• Adjust medications to assure stability 
o Patients will be switched to Anoro Ellipta 1 puff daily. Inhalers will be purchased through UTMC 
pharmacy purchasing team and stored by the study coordinator. The study coordinator will 
dispense the Run-in inhaler. Those receiving inhaled corticosteroids or oral prednisone will be 
allowed to continue them at a stable dose. Patients may use albuterol and/or ipratropium for 
rescue therapy 
o Patients receiving supplemental oxygen will be allowed to participate if their oxygen 
requirements have been stable over 8 weeks 
o Oral theophylline will be discontinued but oral roflumilast will be continued at a stable dose 
 
Baseline Study Visit 2 (within one week of screening/start of Run-in Visit) ± two days*: 
*If a patient has taken study medication within 48 hours of their first Visit 2 pulmonary function test, or rescue 
medication within 6 hours of their first Visit 2 pulmonary function test, the visit will be rescheduled. If a 
patient is unable to come to the study site for Visit 2 due to illness or inclement weather, the visit will be 
rescheduled. The run-in period will be extended for one week. The study coordinator will assess the patients’ 
compliance by phone prior to the run-in extension if the patient is ill or unable to come to the study site. 
Compliance will be assessed in person prior to the run-in extension whenever possible. The patient will be 
instructed to continue the DPI and diary completion until the next visit. This will not be considered a protocol 
deviation. 
 
Pre-Dosing 
• Patients will return one week post their screening visit 
• Medical history and concurrent medications will be reviewed 
• Adverse Events will be reviewed 
• Symptom and medication logs will be reviewed to assure stability of COPD. 
o Participants must show >80% compliance in filling out the daily logs to continue in the study. 
o Patients < than 80% compliant will be considered screen failures. They will resume their 
previous medications, and will be instructed to follow up with their PCP as needed. 
• The following questionnaires will be administered before study drug is administered 
o CAT score 
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o BDI 
o SGRQ 
• Vital signs (heart rate, respiratory rate, temperature, blood pressure and SpO2) will be recorded 
prior to study 
• Pulmonary function will be measured in a body plethysmograph before drug administration 
(baseline) 
• Physical examination and vital signs will be recorded 
• Patients that meet all eligibility criteria will be randomized 
Participants will be randomized 1:1 to receive either active drugs by DPI or nebulizer as a one-time 
administration. We will generate treatment assignments with a pseudo-random-number generator 
with randomly permutated blocks that will ensure balance between the numbers of subjects assigned 
to each treatment. 
 
Treatment Groups 
(Group A) Anoro Ellipta (Umeclidinium/Vilanterol; GSK Research Triangle Park, NC) 1 puff and 
nebulized Revefenacin Placebo (manufactured by The RiteDose Corporation, South Carolina, USA) 
and Formoterol Placebo (sterile normal saline) study drug arm -OR- 
(Group B) Revefenacin 175 µg and formoterol 20 µg by nebulizer (Theravance Biopharma, South 
San Francisco, CA) and 1 puff of placebo DPI study drug arm. 
  
 The nebulizer will always be administered first, and the DPI will be given at the end of the 
nebulizer treatment. Time 0 will be at the end of the DPI treatment. 
 Study treatments will occur within the same time range in the morning (7:00 -11:00am) and 
evening (7:00 - 11:00pm) to minimize diurnal variation. 
 We will make all attempts to conduct the first study visit within 7±2 working days of the 
screening/enrolment visit. 
Post-Dosing 
• Vital signs (heart rate, respiratory rate, temperature, blood pressure and SpO2) will be recorded at 
approximately 1, 2, 4, and 6 hours after drug administration prior to performing the pulmonary 
function measurements. 
• Pulmonary Function Measurements (by staff at the UT Pulmonary Function Laboratory): Every 
attempt will be made to perform repeated pulmonary function testing in a body plethysmograph 
before drug administration and at approximately 1, 2, 4, and 6 hours after each treatment. If 
patients become fatigued, or are unable to finish testing, the RRT will notify the coordinator and 
the reason for stopping prematurely will be clearly documented in the source document. Patients 
will continue in the study. This will not be considered a protocol deviation. 
 
The following parameters will be assessed: 
o FVC 
o FEV1 
o FEV1/FVC 
o FEV3 FEV6 
o FEF25%-75% 
o Residual volume 
o Total lung capacity 
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o Inspiratory capacity 
o Airway resistance 
o Modified Borg Dyspnea Index 
 
• Training 
o Additional Diary training 
 Daily assessment of symptoms (CAT score) 
 Medication logs 
o Study drug/device use training (please see below) 
o Importance of medication compliance training 
o Study visits schedule review and scheduling 
• Participants will continue with assigned treatment and placebo for 12 weeks 
o Morning dose 
 Group A: Anoro Ellipta + Nebulized Revefenacin Placebo and Formoterol Saline Placebo 
 Group B: Placebo DPI + Nebulized Revefenacin + Formoterol 
o Evening dose 
 Group A: Nebulized Formoterol Saline Placebo  
 Group B: Nebulized Formoterol  
 
Phone Visit 1 Week 4 
(Telephone call 4 weeks post first dose ± 2 days) 
• Telephone monitoring by study coordinator to review symptom and medication logs 
• Administer TDI 
• Assess for side effects and rescue medication use 
 
Phone Visit 2 Week 8 
(Telephone call 8 weeks post first dose ± 2 days) 
• Telephone monitoring by study coordinator to review symptom and medication logs 
• Administer TDI 
• Assess for side effects and rescue medication use 
 
Study Visit 3 
(In-person visit 12 weeks post first dose ± 2 days*) 
* If a patient has taken study medication on the morning of their first Visit 3 pulmonary function test, or rescue 
medication within 6 hours of their first Visit 3 pulmonary function test, the visit will be rescheduled. If a patient 
is unable to come to the study site for Visit 3 due to illness or inclement weather the visit will be rescheduled. 
This will not be considered a protocol deviation. 
 
Pre-Dosing 
• Medical history and concurrent medications will be reviewed 
• Adverse Events will be reviewed 
• Diary will be reviewed 
• The following questionnaires will be administered before study drug is administered 
o CAT score 
o TDI 
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o SGRQ 
• Vital signs (heart rate, respiratory rate, temperature, blood pressure and SpO2) will be recorded 
prior to study dosing. 
• Pulmonary function will be measured in a body plethysmograph before drug administration 
(baseline) 
• Physical examination and vital signs will be recorded 
• Medication compliance, collection, and reconciliation 
Post-Dosing 
• Vital signs (heart rate, respiratory rate, temperature, blood pressure and SpO2) will be recorded at 
approximately 1, 2, 4, and 6 hours after drug administration prior to performing the pulmonary 
function measurements 
• Pulmonary Function Measurements (by staff at the UTMC Pulmonary Function Laboratory): Every 
attempt will be made to perform repeated pulmonary function testing in a body plethysmograph 
before drug administration and at approximately 1, 2, 4, and 6 hours after each treatment. If 
patients become fatigued, or are unable to finish testing, the RRT will notify the coordinator and 
the reason for stopping prematurely will be clearly documented in the source document. Patients 
will continue in the study. This will not be considered a protocol deviation. 
The following parameters will be assessed: 
o 
FVC 
o 
FEV1 
o 
FEV1/FVC 
o 
FEV3 FEV6 
o 
FEF25%-75% 
o 
Residual volume 
o 
Total lung capacity 
o 
Inspiratory capacity 
o 
Airway resistance 
o 
Modified Borg Dyspnea Index 
 
End of Study Visits: 
At the end of the study, patients will be given the choice of delivery systems for long-acting bronchodilators 
depending on their ability to use various devices, preference, and insurance coverage under the guidance of 
their treating physicians. Patients who end participation before the 12-week period will be scheduled for early 
termination visit assessments. We will record the reason for dropping out from the study. 
 
12. Reasons for withdrawal/unblinding: 
Patients may be withdrawn if they are non-compliant, require different treatment options to manage their 
COPD, or develop a serious adverse event (SAE) or an acute exacerbation of COPD that necessitates removal 
from the study. All adverse events meeting IRB reporting criteria will be reported to the IRB. Unblinding will be 
permitted for life-threatening complications. 
 
13. Ethical and safety issues: 
Principles of Good Clinical Practice (GCP) will be followed. Patients may withdraw from the study without any 
penalty. An independent Data Safety Monitor will be designated to monitor patient safety. All adverse events 
reported per the IRB and FDA guidelines will be reviewed by the Data Safety Monitor. 
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14. Device Training: 
We will employ device-use training videos developed by National Jewish health for each device used in this 
protocol (including nebulizers). The videos can be viewed at: https://www.nationaljewish.org/treatment- 
programs/medications/asthma-medications/devices/instructional-videos. These videos are also available for 
viewing on YouTube. 
 
After coordinators administer device-use training they will use the “teach-to-goal” method [41] to confirm that 
subjects are using the proper technique, via placebo devices, at the time of enrolment in the study. Study 
coordinators will provide on-site training to participants. The subject will have access to the online training 
videos. We expect that this will make the findings of our study more generalizable to current clinical practice. 
 
15. Study Therapies 
Group A: DPI 
The Anoro Ellipta inhaler (GSK) contains: 
Umeclidinium 62.5 mcg 
Vilanterol 
25 mcg 
 
Patients will receive a single inhalation from the device. A matching inhaler without any active drug will be 
used as placebo. We chose Anoro Ellipta DPI because it is commercially available, has the same class of 
bronchodilators (LAMA/LABA) as revefenacin and formoterol and is commonly used by patients with COPD. 
Furthermore, patients can be easily trained in using the Ellipta device.[42] Moreover, it is equally effective 
compared to other commercially available LAMA/LABA combinations.[43] 
 
Group B: Nebulizer treatment 
Participants will receive nebulizer treatments with revefenacin 175 mcg and formoterol 20 mcg with re-usable 
nebulizers (Pari LC Sprint with Pari Trek S compressors). The Pari-Trek nebulizer and Compressor combination 
delivers fast-efficient aerosol treatments in 5-6 minutes, and has proved effective in other clinical trials, 
including pivotal trials for approval of revefenacin (https://www.rxlist.com/yupelri-drug.htm#indication). The 
two drug solutions are compatible physio-chemically and they will be mixed in the nebulizer and administered 
together. The Placebo Revefenacin being supplied has been manufactured by The RiteDose Corporation, South 
Carolina, USA and contain all revefenacin ingredients, other than the active ingredient. The Formoterol Placebo 
used will be sterile 2.5 ml (0.9 % NaCL) saline vials for inhalation with the nebulizer. Nebulizers will be supplied 
by the study team. 
 
Study coordinators are all familiar with the Ellipta DPI, nebulizer and compressor and have used these devices 
in previous studies. However, they will receive training in the use of the devices and their ability to instruct 
study subjects in proper device technique will be verified. 
 
Blinding 
Treatment assignment will be blinded in this trial. 
 
Packaging, labeling, and re-supply 
All medications will be supplied pre-packaged and labeled and will provide enough medication to treat each 
study participant for 12 weeks. Run-in medication will be relabeled before it is dispensed to ensure that no 
identifiable packaging will allow patients to distinguish between active medication and placebo if enrolled into 
the treatment phase of the study. 
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Storage conditions 
All clinical trial supplies will be stored in a locked, secure cabinet and/or refrigerator and will be kept in their 
original packaging under the recommended storage conditions and may only be dispensed to trial subjects 
according to protocol. 
 
Drug accountability 
Drug supplies will be kept in a secure, limited access storage area under the storage conditions defined by the 
manufacturer. Where necessary, a temperature log will be maintained to make certain that the drug supplies 
are stored at the correct temperature. The study team will receive the investigational drugs delivered by the 
manufacturer. 
 
The unblinded coordinator will maintain records of the product’s delivery to the study site, the inventory at 
the site, the use by each patient, and the return to the manufacturer or alternative disposition of unused 
products. These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and the 
unique code numbers assigned to the investigational products and trial patients. 
 
The unblinded coordinator and/or study coordinator should return the unused and collected investigational 
drugs (including empty boxes) to the manufacturer after the trial. 
 
Upon completion of the trial, the unblinded coordinator and/or study coordinator submits a copy of the 
investigational drug reconciliation log to the manufacturer. 
 
Other Medications: 
Additional maintenance long-acting bronchodilator therapy with other pMDIs, DPIs, or SMIs will not be 
permitted. Patients in either group may employ albuterol pMDIs for rescue. We will permit use of nebulized 
albuterol and or ipratropium only for relief of acute symptoms not relieved by use of short-acting 
bronchodilator pMDIs in either group. We will instruct patients not to switch from use of inhalers to nebulizers 
for maintenance therapy or vice versa. We will instruct patients to inform the investigators if a change in 
therapy becomes necessary. We will also monitor each patient’s treatment by daily diaries, during monthly 
telephone calls and at each clinic visit. All patients will continue to be under the care of their regular treating 
physicians. 
 
16. Pre-Pulmonary Function Testing Restrictions 
Patients will be instructed to stop their run-in or study medication prior to testing for the following time 
intervals: 
 
Albuterol 
 6 hours prior to Baseline/Visit 2, and Visit 3 pulmonary testing 
Ipratropium 
6 hours prior to Baseline/Visit 2, and Visit 3 pulmonary testing 
Run-in DPI 
 48 hours prior to Baseline/Visit 2 pulmonary testing 
Study Drug 
No morning dose of study medication for Visit 3 
 
Caffeine and caffeine containing beverages should not be consumed on the days of treatment visits. 
 
17. Quality assurance procedures: 
We will develop a workable, detailed, protocol and Regulatory Binder for use by the investigators and clinic 
staff. This binder will serve as a reference and training guide for all project procedures and policies. Other 
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quality assurance procedures to be used are: 1) staff training prior to beginning the study on forms, 
procedures, protocol, and randomization 2) at the end of the final study visit (Study Visit 3), subjects will be 
asked which treatment they believe they received during the treatment period. Responses will then be used 
to calculate a “blinding index” and a formal statistical test suggested by Bang and colleagues[44] will be applied 
to assess the degree of blinding. The same tests will be administered to the study personnel. 
 
18. Sample size: 
We anticipate no more than 15% attrition over a 12-week period, leaving at least 60 patients who will 
complete all aspects of the trial.[45] 
 
19. Data analysis: 
The data will be codified according to the data dictionary. Clinical data will be checked for coding errors using 
frequency statistics. Statistical assumptions will be tested before undertaking any inferential analyses. 
Frequency statistics will be conducted on all categorical variables. For each continuous within-subjects 
observation of IC, residual lung volume (baseline, one [1] hour, two [2] hours, four [4] and six [6] hours), the 
distribution of values at each time point will be checked for normality using skewness and kurtosis statistics. 
For the primary outcome of IC, the Area Under the Curve (AUC) for each treatment group across the within- 
subjects observations will be calculated using the trapezoid method. For the secondary outcomes (residual 
volume, etc.), paired-samples t-tests will be used to compare within-subjects observations, given that the 
statistical assumption of normality is met. If normality is violated, Wilcoxon signed rank tests will be used for 
within-subjects comparisons. Statistical significance will be assumed at an alpha value of 0.05 and all analyses 
will be conducted using SPSS Version 25 (Armonk, NY: IBM Corp.). 
 
20. Risks to the Subjects: 
We will conduct the study in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. 
Enrollment will be open to subjects ≥40 years old, of any race, sex, or ethnic background who meet pre- 
defined inclusion and exclusion criteria and are free of contraindications to participate in the trial. These 
methods are designed to determine general health status, ability to understand informed consent and to 
cooperate with study procedures, and presence of medical conditions, habits, or medication usage that would 
otherwise interfere with the study. No vulnerable special populations will be studied, no women who are 
pregnant or are trying to get pregnant will be enrolled, and no children will be enrolled in this project. No 
subpopulation will be targeted or excluded from recruitment. No invasive procedures are planned for the 
purpose of this study. Participants in the study will receive compensation for their time (up to $370), but this 
level of payment is commensurate with the time and effort of participation in the study, and hence is at a level 
that we do not consider to be “coercive.” Otherwise, there are no immediate benefits to patients for 
participating in this study. 
 
Risks from lung function testing: 
Patients will be asked to spend 10-20 minutes in a plethysmograph (box) several times during each of the two 
study visits. Patients may feel claustrophobic in the box, and may experience dizziness, weakness, and/or 
fatigue from repeated testing. 
 
Risk from the study medications: 
The medicines used in this study are “standard,” in that they are routinely used in patients with COPD, have 
undergone years of clinical use and investigation, and have been fully approved by the FDA for use in this 
patient population. However, like all medications, potential side-effects have been noted, including (but not 
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limited to) minor and serious allergic reactions, changes in blood pressure, headache, upper respiratory 
infection, arrhythmia, hyperglycemia, nausea, fatigue, and nervousness. Participants in this study will be 
monitored for side-effects and will be encouraged to report any side effects to study personnel. 
 
Risk from loss of confidentiality: 
Loss of confidentiality is possible because study data will not be collected anonymously. Throughout the 
study, measures to ensure the privacy of information on study subjects will be maintained. All project 
investigators and staff have been certified for training in the use of human subjects in research and have 
received training in HIPAA regulations. Subjects and staff will be informed of the confidentiality of information 
and assured that data will be used only for statistical purposes and group analyses in which the individual 
cannot be identified. 
 
All subjects will have assigned code numbers. All completed forms will be kept in locked files in locked rooms 
to which only project personnel have access. In addition to measures to ensure confidentiality is not breached 
from the use or storage of hard copies (discussed above), electronic files will be available to only key study 
personnel only on the server and designated PCs. Both the computers and the electronic files will be 
username/password protected. PCs will be kept in locked rooms. Server computer security is maintained 24 
hours a day. 
 
21. Anticipated Problems and Pitfalls: 
1) Challenges with recruitment can arise in a clinical study. However, we care for a large population of 
patients with COPD and do not anticipate problems with recruitment or with unexpected side effects or 
complications. 
 
2) There can be imbalances in treatment groups according to disease severity. However, we will ensure that 
study subjects meet eligibility criteria for enrollment and assess the balance of severity among treatment 
groups. 
 
3) Variability in baseline pulmonary function could affect the response. However, we will assess baseline 
values of pulmonary function at the study visit and account for any imbalance in analyses as needed to help 
ensure comparability between the two groups. 
 
22. Anticipated Outcomes and Deliverables: 
The anticipated start date will be January 2, 2023. The first 2 months of the study involves finalizing the 
manual of operations, forms, data entry screens, and other study materials. During this time, IRB approval will 
be obtained, staff trained, and pre-test procedures and refinements carried out. The last patients to complete 
the clinical protocol will do so at the 16 month point of the study so that data entry, editing and analysis will 
be completed within the following 2 months. The anticipated completion date will be July 1, 2024. Scholarly 
output will subsequently appear in several forms, including print (articles published in high impact medical 
journals, abstract and poster presentations at national meetings, policy briefs, and institutional newsletters); 
internet (university and professional organization websites, and various social media venues); and face-to-face 
interactions with various COPD support groups and other meetings of senior citizens. 
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23. Adverse Events and Serious Adverse Events 
Adverse Event Definitions 
We do anticipate that this patient population may have COPD exacerbations during the study that result in 
hospitalizations. We will follow the standard guidelines for the reporting of AEs and SAEs. 
An adverse event (AE) is any untoward medical occurrence that may present itself during the course of a 
research study. An AE can be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the patient’s participation in the research study, regardless of the suspected cause. 
 
Unexpected Adverse Event 
An unanticipated or unexpected adverse event is a medical occurrence whose nature, severity or frequency is 
not consistent with existing information regarding the risk profile of the study procedure. 
 
Serious Adverse Event 
A serious adverse event (SAE) is a medical condition that results in one of the following: 
• 
Death 
• 
Is life threatening 
• 
Requires inpatient hospitalization or prolongs an existing hospitalization 
• 
Creates persistent or significant disability or incapacity 
• 
Results in a congenital anomaly or birth defect 
An important medical event that may not result in death, be life threatening, or require hospitalization may be 
considered a SAE when, based upon appropriate medical judgment, it may require medical or surgical 
intervention to prevent one of the outcomes noted above. 
 
Life threatening: an SAE considered life threatening refers to an adverse event in which the patient was at risk 
of death at the time of the event. It does not refer to an AE which hypothetically might have caused death if it 
were more severe. 
 
Adverse Event Assessment and Documentation 
AEs that are considered possibly, probably or definitely related to the study procedure will be recorded in the 
CRFs. AEs will be assessed starting with onset, and evaluation will continue until resolution is noted, or until 
the investigator determines that the patient’s condition is stable. 
 
All AEs will be characterized by the following: 
• AE name 
• Start and Stop dates 
• Relationship to study procedure 
• Severity 
• Action taken 
• Outcome 
 
Relationship 
The investigators will assess the AEs and using their clinical judgment will assign an attribution to the AE using 
the following categories: 
• Unrelated – The AE is clearly NOT related to the study procedure 
• Unlikely – The AE is doubtfully related to the intervention 
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• Possibly – The AE may be related to the study procedure 
• Probably – The AE is likely related to the study procedure 
• Definitely – The AE is clearly related to the study procedure 
 
Severity 
The severity of the AEs should be graded by the investigator as follows: 
• Mild – Transient discomfort; no prescribed medical intervention/therapy required and does not 
interfere with daily activities. 
• Moderate – Low level of discomfort or concern with mild to moderate limitation in daily activities; 
some assistance may be needed; medical intervention/therapy required. 
• Severe – Discomfort and limitation in daily activities, assistance required; medical intervention/therapy 
required. 
 
Action Taken 
The action taken in response to the AE should be reported using the following categories: 
• None 
• Procedure or physical therapy 
• Withdrawn from study due to AE 
• Hospitalization 
• Prescription drug therapy 
• Non-prescription drug therapy 
• Other (specify) 
 
Outcome 
The clinical outcome of an AE should be characterized as follows: 
• Resolved without sequelae 
• Resolved with sequelae (specify) 
• Ongoing (i.e., continuing at time of study discontinuation) 
• Death 
• Unknown/lost to follow-up 
• Other 
 
Reporting 
All SAEs will be documented in the CRFs. SAEs will be reported to the local IRB per the following guidelines: 
 
Adverse event reports will only be submitted to the local IRB if they are determined by the principal 
investigator to be: Unanticipated, Serious, and Possibly, Probably or Definitely related to a research study 
procedure. 
 
SAEs meeting these criteria (except for deaths) must be reported to the IRB within 5 working days of the study 
team’s notification of occurrence. Deaths that are unanticipated and are possibly, probably or definitely 
related to a research study procedure must be reported to the IRB within 24 hours of notification of 
occurrence. 
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Any relevant follow-up information regarding the SAE should be submitted to the IRB as soon as it becomes 
available and/or upon request. 
 
SAE reports to the IRB must include the following: subject identifier, adverse event or problem description, the 
event relationship to the test article or underlying condition, seriousness assessment, whether the event was 
anticipated or unanticipated, type of report (initial or follow-up), date of injury, whether the intervention was 
stopped, and, if so, whether it was re-started, and whether the event provides new risk information that alters 
the risk-benefit assessment and/or should be added to the informed consent disclosure. 
 
 
24. Patient Recruitment and Informed Consent 
Recruitment 
The study team will recruit from the UTMC pulmonary function lab and other treating physicians within the 
community. Pulmonary staff (IRB approved team members) will inform potential patients of the study. If 
interested, study team members will discuss the study with them in person. If patients are interested but 
cannot be spoken with while on campus, the study team will present them with the IRB approved “Contact 
Form”. If they sign and date the form and provide their phone number and email, the study team will contact 
them via phone or email. 
 
Informed Consent 
Informed consent will be conducted by study team members. The potential subject will be given an IRB 
approved ICF to read. They will be given ample time to read the consent, and all of their questions will be 
answered by the study team prior to signing. After all questions have been answered, the potential subject will 
sign the consent and then a copy will be given to them for their personal records. The original will be filed in 
their research record. 
 
Withdrawal of Consent 
Patients may withdraw from the study at any time. Patients should make every attempt to complete the study 
as specified. Investigators should encourage patient treatment compliance and adherence. All deviations from 
the planned treatment schedule will be documented. 
 
25. Study Management 
The PI and study team has the site resources, time availability, and the patient population needed to complete 
this protocol under FDA, ICH, and GCP guidelines within the defined study timeline. Research that is subject to 
regulation, as defined in 46.102, must be reviewed and approved, by an institutional review board (IRB) that 
operates in accordance with regulation requirements of this policy. Per 21 CFR part 50 Investigator must 
obtain legal informed consent if human participants are being included within research and meet certain 
guidelines. 
 
The PI is ultimately responsible for the conduct of the trial; however, he will delegate authority to appropriate 
members of the research team. The PI will ensure the following: 
 
• 
Study team complies with be GCP and other regulatory requirements. 
• 
The study team allows monitoring and auditing by regulating institutions. 
• 
Ensures person delegated trial responsibilities are qualified and trained appropriately. 
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• 
Ensure that study team members have sufficient time to properly conduct and complete the trial 
within the agreed trial period. 
• 
Ensure that all persons assisting with the trial are adequately informed about the protocol, the 
investigational product, and their trial-related duties and functions. 
• 
Ensure record keeping and record retention in accordance with 21 CFR 50. 
• 
Ensures compliance with, GCP guidelines and other local regulatory requirements. 
• 
Will maintain a list of research team members and delegated duties. 
• 
Assures protocol compliance. 
• 
Reports protocol non-compliance appropriately. 
• 
Obtains IRB approval of the trial. 
• 
Followings regulations and guidelines to protect subject rights, safety, and welfare. 
• 
Controls the accountability of the investigational product(s). 
• 
Ensures accurate case histories and records all observations and other data pertinent to the clinical 
trial on each subject. 
 
26. Protocol Deviations 
A protocol deviation is failure to follow procedures specified in the approved research protocol, which include 
(but are not limited to), deviations from study inclusion/exclusion criteria, or failure to follow criteria for 
subject follow-up, withdrawal, or timely monitoring procedures. Protocol deviations must be reported to the 
IRB by the PI within 5 working days from the day the investigator becomes aware of the event. 
 
Protocol deviation reports to the IRB must include the subject identifier, date of deviation, impact on the 
subject’s safety, and the plan for preventing the deviation in the future (if applicable). 
 
27. Data Quality Assurance 
A quality assurance audit/inspection of this study may be conducted by the overseeing IRB or by regulatory 
authorities. The quality assurance auditor will have access to all study records, the investigator’s trial-related 
files and correspondence, and the informed consent documentation of this clinical trial. 
 
28. Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity of the data 
collected. Source documents are filed at the investigator’s site. Data entered in the eCRFs that are transcribed 
from source documents must be consistent with the source documents or the discrepancies must be 
explained. For eCRFs, all data must be derived from source documents. 
 
Direct Access to Source Data and Documents 
The PI will permit study-related monitoring, audits, IRB review and regulatory inspection, providing direct 
access to source data/documents. 
 
29. Completion of Trial 
When the trial is completed, the PI will inform the IRB and funding institution of the completion in writing. 
 
30. SUMMARY 
Inhalers are generally recommended for maintenance therapy in patients with stable COPD, mainly due to 
their convenience and, otherwise, presumed equivalence to nebulizers in terms of effectiveness; the use of 
nebulizers in this setting is often discouraged. However, recent investigations, especially those that include 
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patient perceptions as an outcome measure, suggest bronchodilator therapy with nebulizers may be more 
effective than inhalers in reducing dyspnea symptoms and improving quality of life in many patients. Clearly, 
well-designed comparative efficacy trials with LABA/LAMA combinations administered by inhalers vs. 
nebulizers are needed to evaluate the role of nebulizers for maintenance therapy in patients with stable 
COPD. The present study seeks to address this important gap in knowledge. 
 
 
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