Preliminary Study for Comparison of Triple Therapy Nebulizer Versus Dry Powdered Inhaler for Care Transitions in COPD
Phase: PHASE4
Conditions: COPD, COPD Exacerbation
Sponsor: Wake Forest University Health Sciences

Nebulizer vs Dry Powdered inhalers for COPD 
 
1 
 
Revision date 2/24/17 
 
Nebulizer versus Dry Powdered Inhalers for COPD 
 
 
IRB00042362 
NCT03219866 
3/14/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Nebulizer vs Dry Powdered inhalers for COPD 
 
2 
 
Revision date 2/24/17 
 
Investigator: 
Jill A Ohar, MD, FCCP 
Professor of Internal Medicine 
Section of Pulmonary, Critical Care, Allergy, and Immunological Diseases 
Wake Forest University School of Medicine 
Winston-Salem, NC 
 
Title:   
Preliminary study for comparison of triple therapy nebulizer versus dry powdered inhaler 
for care transitions in COPD 
Abstract:  
 
Drugs used to treat COPD are available primarily in hand held inhaler devices that deliver dry 
powder (DPI), a soft mist or a metered dose of spray (MDI). The frail, arthritic elderly are often 
prescribed DPI rather than MDI or soft mist devices, because they require less coordination.  
DPIs however require the ability to inhale against a resistance with a peak inspiratory force (PIF) 
more negative than -60 L/min to break the dry powder into respirable particles.  Preliminary data 
suggests that suboptimal PIF’s are common during an acute exacerbation of COPD, affecting 
48% of hospitalized patients, thus placing them at risk for treatment failure and possibly hospital 
readmission.   Use of nebulizers to administer respiratory medications may avoid the hazards of 
insufficient dosing that can result from use of DPI however they are cumbersome, expensive and 
the variety of drugs available in a nebulizer format is limited. We hypothesize that patients 
treated in hospital and discharged on respiratory medications administered by nebulizers will 
exhibit better symptom control and lower COPD and all cause hospital readmission rates 
compared with patients treated with respiratory medications delivered by DPI. We aim to 
demonstrate that 1) patients treated and discharged on nebulized bronchodilators will have fewer 
readmissions to hospital at 30 and 90 days compared to the group utilizing DPI 2) that the 
nebulizer group will demonstrate a longer duration of time till hospital readmission for COPD 
and all cause readmission compared to the group utilizing DPI and 3) the nebulizer group will 
demonstrate better symptom control compared to the group utilizing DPI. This non-blinded 
feasibility (pilot) study will enroll 100 patients hospitalized for an exacerbation of COPD who 
are > 40 years of age, have a clinical diagnosis of COPD defined by FEV1/FVC or FEV1/SVC < 
70% on bedside or previous baseline spirometry and FEV1/FVC or FEV1/SVC < 70% on clinic 
visit < 2 weeks from hospital discharge and have smoked > 10 pack years.  The study will 
consist of 3 outpatient visits (Transitional Care Visit [3-14 days], Visit #2 [30 +/- 5 days], and 
Visit #3 [90 +/- 5 days after discharge]). Visit #2 and #3 are for study purposes, the Transitional 
Care Visit is standard of care. Study endpoints will include 30- and 90-day hospital readmission, 

Nebulizer vs Dry Powdered inhalers for COPD 
 
3 
 
Revision date 2/24/17 
 
time until COPD and all-cause readmission, number of unscheduled clinic or ER visits, and 
mortality. COPD Assessment Test (CAT), Modified Medical Research Council (mMRC) 
dyspnea score, Saint George Respiratory Questionnaire (SGRQ), and patient preference will be 
assessed during each outpatient visit. The Montreal Cognitive Assessment (MOCA) test and 
spirometry variables will be measured at the bedside during hospitalization and at Visit #3 after 
hospital discharge. 
 
Background: 
COPD (Chronic obstructive pulmonary disease) is a disorder that is estimated to affect 6% of 
adults1 and is largely caused by cigarette smoking.2  Patients with COPD have a disproportionate 
prevalence of comorbidities compared with smokers without COPD, with arthritis being the most 
common of the co-morbidities.3  Because COPD is more common in the elderly with a 
prevalence of 12% in individuals 65 years of age and older1, many COPD patients may also 
suffer dementia and other disorders of cognition that may affect their disease management.  
COPD is characterized by acute exacerbations or flares of the disease that account for 50-75% of 
the annual $50 billion cost of COPD in the US.4  Many drugs used to treat COPD have also been 
shown to decrease exacerbation frequency,5-8 thus reducing costs.  These drugs are most 
effective when used in combination9,10 and are available primarily in hand held devices that 
include  dry powder inhalers (DPI), a soft mist and metered dose inhalers (MDI). The frail, 
arthritic elderly are often prescribed DPI rather than MDI or soft mist devices, because they 
require less coordination.  DPIs however require the ability to inhale against a resistance with a 
force more negative than -60 L/min to break the dry powder into respirable particles and deliver 
them to the site of action in the lower respiratory tract.11  In addition to an adequate peak 
inspiratory flow rate (PIFR), also required for reliable delivery of a DPI is an initial inhalational 
blast and suitable inhalational duration.  Preliminary data suggests that suboptimal PIFs are 
common during an acute exacerbation of COPD affecting 48% of hospitalized patients. This 
places patients at risk for treatment failure and possibly leads to hospital readmissions, a 
significant socioeconomic burden.12 Use of nebulizers to administer respiratory medications may 
avoid the hazards of insufficient medication delivery that can result from use of DPI in a 
population characterized by suboptimal PIFs, frailty, and arthritis.  
 
Hypothesis and aims:  
We hypothesize that patients treated in hospital and discharged on respiratory medications 
administered by nebulizers will exhibit better quality of life (QoL), symptom control and lower 
COPD and all cause hospital readmission rates compared with patients treated with respiratory 
medications delivered by DPI 
 
We aim to demonstrate that: 
1) patients treated and discharged on nebulized bronchodilators will have fewer 
readmissions to hospital at 30 and 90 days compared to the group utilizing DPI  

Nebulizer vs Dry Powdered inhalers for COPD 
 
4 
 
Revision date 2/24/17 
 
 
2) the nebulizer group will demonstrate a longer duration of time until hospital readmission 
for COPD and all cause readmission compared to the group utilizing DPI 
 
3) the nebulizer group will demonstrate better QoL (measured by the SGRQ – Saint George 
Respiratory Questionnaire) and symptom control (as measured by the CAT & mMRC) 
compared to the group utilizing DPI. 
 
 
Study Design 
This will be a non-blinded feasibility (pilot) study and therefore it is not formerly powered.  The 
study will consist of enrollment during hospitalization and 3 outpatient visits.   
Enrollment: Patients will be identified, qualified, enrolled and consented by the respiratory 
therapy navigator (RTN) such that they will receive study medication prior to hospital discharge.  
Once hospitalized patients are stable for transition to long term COPD medications (triple 
therapy) the patients will be randomized in 1:1 ratio to 1 of 2 arms, a nebulizer arm or a DPI arm. 
Before discharge the following assessments will be performed; Montreal cognitive assessment 
test (MOCA) and SGRQ.   
Visit 1: Patients will return for their standard of care post hospital discharge visit 3- 14 days after 
date of discharge.  As part of that visit they will be evaluated by both a physician and a 
respiratory therapist.  The following tests are part of that visit: PIF, spirometry, mMRC and 
CAT.  The respiratory therapist study coordinator will also check patient preference for nebulizer 
vs. DPI using a Likert scale and administer the SGRQ. The study coordinator will also determine 
and record if the patient has had an unscheduled physician appointment, urgent care, ER or 
inpatient visits for COPD or any other condition since discharge.  
Visit 2:  The 30+/-5 day visit will include PIF, spirometry, mMRC, CAT and patient preference 
for nebulizer vs. DPI.  The study coordinator will also determine and record if the patient has had 
an unscheduled physician appointment, urgent care, ER or inpatient visit for COPD or any other 
condition since the last visit. 
Visit 3:  The end of study visit (90+/- 10 days) will include PIF, spirometry, mMRC, CAT, 
patient preference for nebulizer vs. DPI, MOCA, SGRQ and collection of unused study drugs 
and equipment. The study coordinator will also determine and record if the patient has had an 
unscheduled physician appointment, urgent care, ER or inpatient visit for COPD or any other 
condition since the last visit. 
Patients (n=100) will be randomized to therapy groups regardless of PIF. The patients will be 
counselled and educated regarding their assigned medications and delivery devices (nebulizers 
vs. DPIs) and disease state management during hospitalization and at outpatient visits by the 

Nebulizer vs Dry Powdered inhalers for COPD 
 
5 
 
Revision date 2/24/17 
 
RTN according to the current standard of care. Patients will be randomized by the Investigational 
Drug Service pharmacy. The patients will be discharged on therapy and given all meds and 
equipment needed for the first 30 days of the study.  All COPD controller medications and 
nebulizer equipment will be made available to the patient free of charge for the duration of the 
study (90 days). All medications will be provided by the funding pharmaceutical agency to 
eliminate bias.  Inhalational medication costs can vary widely (from 10 to $1000/month) 
dependent upon the preferred product of the insurer thus allowing the insurer to influence the 
medication or delivery device and therefore possibly introduce bias in this protocol. 
Treatment Arms: 
Nebulizer Arm:  Subjects will receive a long-acting B2-agnoist (LABA; Brovana, twice daily), 
corticosteroid (ICS; Pulmicort, twice daily) and a short-acting anti-cholinergic (SAMA; 
Atrovent, three times a day). 
DPI Arm:  Subjects will receive a LABA/ICS (Advair Diskus, twice daily) plus a long-acting 
anticholinergic (LAMA-Spiriva Handihaler, once daily). 
 
 
Eligibility: 
Patients hospitalized for an exacerbation of COPD will be eligible if all of the following criterial 
are met: 
Inclusion: 
 > 40 years of age 
 Clinical diagnosis of COPD 
 Smoking history > 10 pack years 
 Lung Function- FEV1/FVC or FEV1/SVC < 70% on bedside spirometry or previous 
baseline and FEV1/FVC or FEV1/SVC < 70% on clinic visit < 2 weeks from 
discontinuation 
 Able to give informed consent 
 
Patients will be excluded for any of the following reasons: 
Exclusion: 
 Dementia 
 
to active cancer with an anticipated survival of < 6 months  
 
End stage cardiovascular disease with an ejection fraction of < 20% 
 
Inability to attend outpatient visits 
 
Active Schizophrenia (actively hallucinating, combative) 
Pregnancy; subjects will be excluded if female and are not post-menopausal for at least one year. 
Since there is no possible benefit from participating in this protocol for a pregnant woman, we 

Nebulizer vs Dry Powdered inhalers for COPD 
 
6 
 
Revision date 2/24/17 
 
will exclude pregnant women. If a subject is found to be pregnant during the 90-day study 
period, they will be excluded from the study and their data not used for study purposes. 
Study Endpoints: 
 Number of patients readmitted within 30 days of hospital D/C 
 Number of days until COPD or all cause hospital readmission 
 Number of patients readmitted within 90  days of hospital D/C 
 PIF measured with in check device set on DPI (Advair Diskus) at the bedside during 
hospitalization and at every study visit  
 COPD Assessment Test (CAT) during each visit 
 Modified Medical Research Council (mMRC) 
 Mortality 
 Number of Unscheduled clinic or ER visits  
 Patient preference for nebulizer or DPIs 
 Spirometry variables measured at the bedside during hospitalization, visit #1 (<14 days) 
and visit #3 (90 +/- days) after hospital discharge 
 Patient reported readmissions at outside hospital, or outpatient/ED treatment for 
AECOPD 
 QoL measured by SGRQ 
Demographic data: 
 Name/Study ID number 
 DOB/Age 
 Smoking status (current/former) 
 Pack year 
 Wood stove exposure (years)  
 Gender 
 BMI  
 Charlson Comorbidity Index 
 Cognitive function measured by the Montreal Cognitive assessment (MoCA) measured at 
randomization and on first & last post discharge clinic visit  
 Presence or absence of chronic respiratory failure defined as needing supplemental O2 
and required flow rates 
 Date of index admission 
 Date of index discharge 
 LOS for index admit 
 Days on mechanical ventilation for index admit 
 Days on NIV for COPD (not for Obstructive Sleep Apnea) for index admit 
 ICU days for index admit 

Nebulizer vs Dry Powdered inhalers for COPD 
 
7 
 
Revision date 2/24/17 
 
 Dates of readmission (all cause and COPD) 
 D/C date for readmission 
 # of readmission/90 days 
 
Data capture will be done exclusively within Wake Forest’s REDCap database. Please see 
attachments for database schemata and collection forms. There is an additional form within 
REDCap to collect readmission or adverse events that are obtained at a subject visit, or if a 
patient contacts a study member via telephone number provided. 
 
Statistical methods:   
This research project is primarily a feasibility project.  The sample size will be 50 participants in 
each treatment group. We expect that we will be able to follow 90% or more of the participants 
for 90 days. With this sample size we will be able to estimate the retention percentage in each 
group with a standard error of 4%. We will be able to estimate the percentages of the 
dichotomous outcomes with a standard error of 7% and for continuous outcomes with a standard 
error of 0.15 times its standard deviation. 
We will compare summary statistics of the outcome variables to get a preliminary estimate of the 
possible effect sizes to be expected in a larger trial. The percent of patients readmitted within 30 
and 90 days of hospital discharge, 90-day mortality, and other dichotomous outcomes will be 
compared between the two groups using Fisher’s Exact test. The number of days until 
readmission and until death will be compared by Kaplan-Meier curves and tested using the log-
rank test. The number of unscheduled clinic or ER visits will be compared using Poisson 
Regression.  Continuous outcome measures when there is no baseline value will be compared 
and tested using the two sample t-test. When a baseline value of the outcome is available, 
analysis of covariance using the baseline value as covariate will be used. Spirometry variables 
measured at baseline and post randomized visits 1 and 3 will be analyzed by repeated measures 
analysis of covariance with the baseline value being a covariate. A statistician from the Wake 
Forest University Department of Biostatisticial Sciences (Tim Morgan, Ph.D; no conflicts of 
interest) will analyze and perform statistical tests for this study. Jill Ohar, the P.I., will be 
excluded from data collection and will not have access to REDCap database. 
  
Subject Recruitment Methods 
Patients will be identified, consented, and enrolled by the respiratory therapy navigator (RTN) 
during the usual course of care they provide to inpatients that are admitted for a COPD 
exacerbation and utilize the attached informed consent form. The RTN, in the usual course of 
care, assesses the patient, and per protocol/standing order, prescribes chronic/long-term 
inhalation therapies, which may include nebulizers or dry powder inhalers (DPI).  Once 
hospitalized patients are stable for transition to long term COPD medications, the patients will be 

Nebulizer vs Dry Powdered inhalers for COPD 
 
8 
 
Revision date 2/24/17 
 
randomized in 1:1 ratio to 1 of 2 arms, a nebulizer arm or a DPI arm by the investigational drug 
service pharmacy. The patients will receive medication education as part of usual care provided 
to COPD exacerbation patients prior to hospital discharge. Inclusion criteria include a clinical 
diagnosis of COPD, age >/= 40 years, smoking history >/= 10 pack years, spirometry findings 
consistent with COPD and ability to give informed consent. Patients will be excluded for 
dementia, active cancer or schizophrenia, end stage cardiovascular disease, or inability to attend 
outpatient clinic visits. No recruitment flyers or advertisements will be utilized. No penalty or 
loss of benefits will occur as a result of either not participating or withdrawing at any time. 
Vulnerable or special classes of subjects will not be included in this study.  Patients who are 
cognitively or psychologically impaired will be excluded based on study exclusion criteria 
(dementia, schizophrenia, and by inability to attend clinic visit). Patients will also be enrolled 
during hospitalization and the RTN will be aware, during usual daily care of any possible 
impairment and will not enroll those with possible impairment or vulnerable to coercion. The 
RTN will utilize medical records in their standard practice to identify COPDE exacerbation 
patients admitted to the hospital and follow them throughout the hospitalization. The RTN will 
identify and screen patients based on the study inclusion and exclusion criteria during standard of 
practice evaluation. A limited waiver of HIPAA is requested to utilize PHI to identify potential 
subjects who will be approached for participation in the study. The RTN will access and use only 
the minimum amount of PHI necessary to review eligibility criteria. This includes, but is not 
limited to patient’s past medical history and evaluation of their COPD diagnosis (e.g. smoking 
pack years, prior pulmonary function testing results). Confidentiality and privacy will be 
protected prior to ascertaining desire to participate by only accessing the minimal amount of 
information required to screen patients for eligibility. This is expected to be information that is 
accessed in the usual care delivered by the RTN to the screening population. No information 
regarding screening will be collected by the RTN, unless enrolled and randomized, and therefore 
will not need to be destroyed if a patient declines participation in the study. 
 
Informed Consent 
 
Signed informed consent will be obtained from each subject.  Informed consent will be obtained 
by the RTN, or another member of the study team if the RTN is unavailable to obtain consent. 
Informed consent will be obtained while the subject is still admitted to the hospital. The subject 
will therefore be able to be randomized to a treatment arm and receive education regarding the 
medication delivery device, as is part of the usual care provided to this patient population prior to 
hospital discharge. 
 
Confidentiality and Privacy 
 
Confidentiality will be protected by collecting only information needed to assess study 
outcomes, minimizing to the fullest extent possible the collection of any information that could 

Nebulizer vs Dry Powdered inhalers for COPD 
 
9 
 
Revision date 2/24/17 
 
directly identify subjects, and maintaining all study information in a secure manner.  To help 
ensure subject privacy and confidentiality, only a unique study identifier will appear on the data 
collection form.  Any collected patient identifying information corresponding to the unique study 
identifier will be maintained on a linkage file, store separately from the data.  The linkage file 
will be kept secure, with access limited to designated study personnel.  Following data collection 
subject identifying information will be destroyed three years after closure of the study by 
deletion of electronic files and shredding of any paper files, consistent with data validation and 
study design, producing an anonymous analytical data set.  Data access will be limited to study 
staff.  Data and records will be kept locked and secured in a REDCap Database, with any 
computer data password protected.  No reference to any individual participant will appear in 
reports, presentations, or publications that may arise from the study. 
 
Research sponsor will have access to finalized study data, but not individual subject records. All 
accessible data will be de-identified and not contain PHI. 
 
Data and Safety Monitoring 
 
The principal investigator will be responsible for the overall monitoring of the data and safety of 
study participants.  The principal investigator will be assisted by other members of the study 
staff. The principal investigator or study coordinator will report all events or risks to the IRB in a 
timely manner. 
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol 
changes will be promptly reported by the principal investigator or designated member of the 
research team to the IRB and sponsor or appropriate government agency if appropriate. 

Nebulizer vs Dry Powdered inhalers for COPD 
 
10 
 
Revision date 2/24/17 
 
Figure 1. Study Schemata 
Randomization prior to discharge 
 
 
 
Enrollment 
Transitional care visit   
(3-14 days post D/C) 
30+/-5 day visit 
End of study visit 
(90+/- 10 days) 
Demographics 
PIF 
CCI 
MOCA 
SGRQ 
 
•PIF 
•Spirometry 
 
•mMRC 
•CAT 
•SGRQ 
•Patient preference 
 
 
 
 
 
•Navigator to ask 
patient about all:  
Unscheduled MD visits 
Urgent Care visits 
Emergency Room visits 
Hospital admittance for 
all causes & COPD 
•PIF 
 
 
•mMRC 
 
•CAT 
•SGRQ 
•Patient preference 
 
 
 
 
•Navigator to ask patient 
about all:   
Unscheduled MD visits 
Urgent Care visits 
Emergency Room visits 
Hospital admittance for 
all causes & COPD 
•PIF 
•Spirometry 
•MOCA 
•mMRC 
•CAT 
•SGRQ 
•Patient preference 
•Clinical Outcomes 
•Collect study 
medication and 
equipment 
•Navigator to ask 
patient about all: 
Unscheduled MD visits 
Urgent Care visits 
Emergency Room visits 
Hospital admittance for 
all causes & COPD 
 
CCI: Charleson Comorbidity index 
MOCA:  Montreal Cognitive Assessment 
SGRQ: Saint George Respiratory Questionnaire 
mMRC: Modified Medical Research Council Dyspnea Scale 
CAT: COPD Assessment Test 
PIF: Peak Inspiratory Flow 
 
 

Nebulizer vs Dry Powdered inhalers for COPD 
 
11 
 
Revision date 2/24/17 
 
References 
 
1. 
Chronic obstructive pulmonary disease among adults--United States, 2011. MMWR Morb 
Mortal Wkly Rep. 2012;61(46):938-943. 
 
2. 
From the Global Strategy for the Diagnosis, Management, and Prevention of COPD, 
Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2015; 
http://www.goldcopd.org. Accessed March 8, 2015. 
 
3. 
Pleasants RA, Ohar JA, Croft JB, Liu Y, Kraft M, Mannino DM, et al. Chronic 
obstructive pulmonary disease and asthma-patient characteristics and health impairment. 
COPD. 2014;11(3):256-266. 
 
4. 
Guarascio AJ, Ray SM, Finch CK, Self TH. The clinical and economic burden of chronic 
obstructive pulmonary disease in the USA. Clinicoecon Outcomes Res. 2013;5:235-245. 
 
5. 
Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al. A 4-year trial of 
tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543-
1554. 
 
6. 
Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ. 
Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised 
clinical trials. Lancet. 2009;374(9691):685-694. 
 
7. 
Ferguson GT, Anzueto A, Fei R, Emmett A, Knobil K, Kalberg C. Effect of fluticasone 
propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD 
exacerbations. Respir Med. 2008;102(8):1099-1108. 
 
8. 
Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J, et al. Once-
daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of 
exacerbations of COPD: two replicate double-blind, parallel-group, randomised 
controlled trials. Lancet Respir Med. 2013;1(3):210-223. 
 
9. 
Cazzola M, Page CP, Calzetta L, Matera MG. Pharmacology and therapeutics of 
bronchodilators. Pharmacol Rev. 2012;64(3):450-504. 
 
10. 
Cazzola M, Molimard M. The scientific rationale for combining long-acting beta2-
agonists and muscarinic antagonists in COPD. Pulm Pharmacol Ther. 2010;23(4):257-
267. 
 
11. 
Mahler DA, Waterman LA, Gifford AH. Prevalence and COPD phenotype for a 
suboptimal peak inspiratory flow rate against the simulated resistance of the Diskus(R) 
dry powder inhaler. J Aerosol Med Pulm Drug Deliv. 2013;26(3):174-179. 
 
12. 
Loh CH, Lovings T, Ohar JA . Low Inspiratory Flow Rates Predict COPD and All Cause 
Readmissions. ATS Abstract;2016;In press.Appendix 

Nebulizer vs Dry Powdered inhalers for COPD 
 
12 
 
Revision date 2/24/17 
 
Attachments: 
1. REDCap data collection form schemata 
2. Copies of Questionnaires/Surveys  
a. MOCA 
b.  CAT 
c. MMRC 
d. SGRQ 
e. Patient Preference 
3. Consent form