Clinical trial NCT03219866
Conditions: COPD COPD Exacerbation
Keywords: Nebulizer Inhaler
Sponsor: Wake Forest University Health Sciences
Start date: 2017-10-03; Completion date: 2020-04-01
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This will be a non-blinded feasibility (pilot) study comparing triple therapy nebulizer vs dry powdered inhalers (DPI) for care transitions in Chronic obstructive pulmonary disease (COPD) exacerbation patients.

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
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.

Detailed description:
Drugs used to treat Chronic obstructive pulmonary disease (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 is charged 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 nonblinded 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. The study will consist of 3 outpatient visits (Transitional Care Visit \[314 days after discharge\], Visit #2 \[30 +/5 days after discharge\], and Visit #3 \[90 +/5 days after discharge\]). Visit #2 and #3 are for study purposes, the Transitional Care Visit is standard of care. We hypothesize and aim to demonstrate 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.

Arms: arm 1: Subjects will receive a long-acting B2-agonist (LABA; Brovana, twice daily), corticosteroid (ICS; Pulmicort, twice daily), and a short-acting anti-cholinergic (SAMA; Atrovent, three times a day). arm 2: Subjects will receive a LABA/ICS (Advair Diskus, twice daily) plus a long-acting anticholinergic (LAMA; Spiriva Handihaler, once daily).
Interventions: intervention 1: Nebulizers intervention 2: Dry Powder Inhaler intervention 3: Brovana intervention 4: Pulmicort intervention 5: Atrovent intervention 6: Advair Diskus intervention 7: Spiriva HandiHaler
Intervention descriptions: intervention 1: Patients treated and discharged on nebulized bronchodilators intervention 2: Patients treated and discharged on Dry Powder Inhalers intervention 3: Subjects will receive a long-acting B2-agonist(LABA; Brovana, twice daily) intervention 4: Subjects will receive a corticosteroid (ICS; Pulmicort, twice daily) intervention 5: Subjects will receive a short-acting anti-cholinergic (SAMA; Atrovent, three times a day) intervention 6: Subjects will receive a LABA/ICS (Advair Diskus, twice daily) intervention 7: Subjects will receive a long-acting anticholinergic (LAMA-Spiriva Handihaler, once daily)

Protocol documents:
Prot_SAP_001.pdf: 
Nebulizer vs Dry Powdered inhalers for COPD 
 
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Nebulizer versus Dry Powdered Inhalers for COPD 
 
 
IRB00042362 
NCT03219866 
3/14/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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, 


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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  


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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 


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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 


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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 


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 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 


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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 


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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 
 
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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 
 
 


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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 


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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 
 

ICF_000.pdf: 
Page 1 of 10
Version: 12-4-2018
Section of Pulmonary, Critical Care, Allergy and Immunological Diseases 
PRELIMINARY STUDY FOR COMPARISON OF TRIPLE THERAPY NEBULIZER 
VERSUS DRY POWDERED INHALER FOR CARE TRANSITIONS IN COPD
Informed Consent Form to Participate in Research
Jill A Ohar, MD, FCCP, Principal Investigator
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you have been hospitalized for Chronic Obstructive Pulmonary Disease (COPD) 
exacerbation (flare). Your participation is voluntary. Please take your time in making your 
decision as to whether or not you wish to participate. Ask your study doctor or the study staff to 
explain any words or information contained in this informed consent document that you do not 
understand. You may also discuss the study with your friends and family.
WHY IS THIS STUDY BEING DONE?
The purpose of the study is to compare two drug delivery devices for the treatment of COPD: 
nebulized therapies versus Dry Powered Inhalers (DPI). For the purpose of this study, 
medications delivered via nebulizer are: Brovana, Pulmicort and Atrovent, and medications 
delivered via DPI are: Spiriva and Advair. Both drug delivery devices and all medications are 
approved for use by the U.S. Food and Drug Administration (FDA). As part of this study, we 
will note and record different lung measurements, patient preference, unscheduled doctor’s 
office visits, emergency room visits and hospital re-admission rates.  
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
This study wil1 enroll 100 people at this research site.
WHAT IS INVOLVED IN THE STUDY?
You will be randomized into one of two drug delivery devices as described below. 
Randomization means that you are put into a group by chance. It is like flipping a coin. You will 
have an equal chance of being placed in either group. You will receive either:

Nebulizer Group (Brovana 15mcg twice per day via inhaled nebulizer, Pulmicort 0.5mg 
twice per day via inhaled nebulizer and Atrovent 0.5mg 3 times per day via inhaled 
nebulizer ) 
or

Dry Powered Inhaler Group (Spiriva 18mcg once per day via inhalation and Advair 
250/50 twice per day via inhalation) 
You will be expected to use the assigned drug delivery device as directed until the End of Study 
visit (approximately 90 days after hospital discharge).  Once the study is completed you will 
resume your prior home respiratory medication regimen, or be prescribed an appropriate COPD 
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management regimen.   
The study will consist of enrollment during hospitalization and 3 outpatient visits:
Enrollment:  You will be identified, qualified, consented and enrolled by the respiratory 
therapy navigator (RTN).You will receive your assigned drug delivery device (nebulizer 
or inhaler) and medications free of charge prior to hospital discharge. The RTN will teach 
you how to take the medications with the assigned drug delivery device.  
Visit 1: You will return for a standard of care post hospital discharge visit 3 to 14 days 
after you are discharged from the hospital. As part of that visit you will be evaluated by 
both a physician and a respiratory therapist. In addition to the standard of care procedures 
performed at this visit, the following will be collected for the study: lung volume 
measurements, questionnaires and evaluation your drug delivery preference.  The RTN 
will also determine and record if you have 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 lung volume measurement, questionnaires and 
evaluation of your drug delivery preference. The RTN will also determine and record if 
you have had an unscheduled physician appointment, urgent care, ER or inpatient visit 
for COPD or any other condition since the last visit.  Study medications will be refilled at 
this time.
Visit 3:  The end of study visit (90+/- 10 days) will include lung volume measurements, 
questionnaires, evaluation of your drug delivery preference and collection of unused 
medications and the drug delivery devices. The RTN will also determine and record if 
you have had an unscheduled physician appointment, urgent care, ER or inpatient visit 
for COPD or any other condition since the last visit. If you were randomized to the 
nebulizer arm, you will need to return the study nebulizer machine that was dispensed at 
the start of the study.
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Enrollment
Transitional care visit   
(3-14 days after 
leaving hospital)
30+/-5 day visit
End of study visit
(90+/- 10 days)
•Obtain 
informed 
consent
•Questionnaires 
about your   
breathing and 
living with a 
breathing 
condition 
•Randomization 
to drug delivery 
device 
(nebulizer or 
inhaler)
•Medication 
administration 
training 
•Measure how fast you 
take a deep breath
•Measure lung volumes 
•Questionnaires about 
your breathing and 
living with a breathing 
condition 
•Ask your  preference 
of nebulizers or inhalers 
•Navigator will ask you 
about all: 
-Unscheduled MD visits
-Urgent Care visits
-Emergency Room 
visits
-Hospital admissions 
for any causes & COPD
•Measure how fast you 
take a deep breath 
•Questionnaires about 
your breathing and living 
with a breathing 
condition
•Ask your  preference of 
nebulizers or inhalers 
•Refill medications
•Navigator will ask you 
about all:  
-Unscheduled MD visits
-Urgent Care visits
-Emergency Room visits
-Hospital admissions for 
any causes & COPD
•Measure how fast you 
take a deep breath
•Measure lung volumes
•Questionnaires about 
your breathing and 
living with a breathing 
condition 
•Ask your  preference of 
nebulizers or inhalers 
•Collect medications  
and equipment
•Navigator will ask you 
about all:
-Unscheduled MD visits
-Urgent Care visits
-Emergency Room 
visits
-Hospital admissions for 
any causes & COPD
HOW LONG WILL I BE IN THE STUDY?
You will be in the study for about 100 days.
You can stop participating at any time. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences.  If all medications are discontinued, you are at risk of having increased 
COPD symptoms and a possible COPD exacerbation. 
WHAT ARE THE RISKS OF THE STUDY?
Being in this study involves some risk to you. You should discuss the risk of being in this study 
with the study staff. Risks and side effects related to the study include:  One drug delivery device 
may be more beneficial to a specific group of people.  Therefore, you could experience an 
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increase in COPD symptoms or exacerbations.  The medications you will be randomized to as in 
this study are considered the standard of care for treatment of COPD. You will likely have been 
or are currently on some, if not all, of the three medications in an arm of this study. Medication 
adverse reactions for medications in either the nebulizer arm or dry powder inhaler arm are 
included in the table below:
Study 
Arm
Medication
Medication 
Class
Adverse Reactions
Aformoterol 
(Brovana)
Long-acting
B2-agnoist
Pain, chest pain, back pain, diarrhea, sinus 
infection, leg cramps, shortness of breath, 
rash, flu syndrome, peripheral edema (leg 
swelling), pulmonary/chest congestion
Budesonide 
(Pulmicort)
Inhaled 
corticosteroid
Respiratory infection (thrust, fungal 
infection), rhinitis (runny/stuffy nose), 
coughing, otitis media (ear infection), viral 
infection, , gastroenteritis (stomach flu), 
vomiting, diarrhea, abdominal pain, ear 
pain, epistaxis (bloody nose), conjunctivitis 
(pink eye), rash
Nebulizer 
Arm
Ipratropium 
(Atrovent)
Short-acting
anti-cholinergic
Tachycardia (fast heart rate), palpitations, 
eye pain, eye dilation, urinary retention, 
urinary tract infection, urticaria (hives)
Fluticasone 
propionate and 
salmeterol 
(Advair)
Long-acting
B2-agnoist/ 
Inhaled 
corticosteroid
Pneumonia, oral candidiasis (thrush), thoat 
irritation, dysphonia (hoarse voice), viral 
respiratory infections, headache, 
musculoskeletal pain
Dry 
Powder 
Inhaler 
Arm
Tiotripium 
bromide (Spiriva)
Long-acting
anti-cholinergic
Upper respiratory tract infection, dry mouth, 
sinusitis, pharyngitis (sore throat), non-
specific chest pain, urinary tract infection, 
dyspepsia (indigestion), rhinitis 
(runny/stuffy nose)
    
In addition, there is a slight risk of a breach of confidentiality.  We will do our best to protect 
your confidential information.  There also may be other side effects that we cannot predict. You 
should tell the research staff about all the medications, vitamins and supplements you take and 
any medical conditions you have. This may help avoid side effects, interactions and other risks.
Taking part in this research study may involve providing information that you consider 
confidential or private.  Efforts, such as coding research records, keeping research records secure 
and allowing only authorized people to have access to research records, will be made to keep 
your information safe.
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Since there is no possible benefit from participating in this protocol for a pregnant woman, we 
will exclude pregnant women. Subjects will be excluded if female and are not post-menopausal 
for at least one year. 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.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
You are not expected to receive any direct benefit from taking part in this research study. We 
hope the information learned from this study will benefit other people in the future.  
WHAT OTHER CHOICES ARE THERE?
You do not have to be in this study to receive treatment. You should talk to your doctor about all 
the choices you have. Instead of being in this study, you have these options:  Continue your 
current respiratory medications or change to new medications. You could be treated with study 
treatments/drugs even if you do not take part in the study.
WHAT ARE THE COSTS?
All study costs, including any study medications and procedures related directly to the study, will 
be paid for by the study. Costs for your regular medical care, which are not related to this study, 
will be your own responsibility. 
Your first visit is standard of care after hospitalization and it will be billed to you or your 
insurance company.  The 30 day and 90 day visits are for research only and will be paid for by 
the study.  Medications will be provided to you, by the study, for the length of time you are 
enrolled in the study.  The drug delivery device will be provided to you, by the study, for the 
length of time you are enrolled in the study. 
WILL YOUR RESEARCH RECORDS BE CONFIDENTIAL?
The results of this research study may be presented at scientific or medical meetings or published 
in scientific journals.  Your identity and/or your personal health information will not be disclosed 
unless it is authorized by you, required by law, or necessary to protect the safety of yourself or 
others.  There is always some risk that even de-identified information might be re-identified. 
Participant information may be provided to Federal and other regulatory agencies as required.  
The Food and Drug Administration (FDA), for example, may inspect research records and learn 
your identity if this study falls within its jurisdiction.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a research study.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
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who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
WILL YOU BE PAID FOR PARTICIPATING?
You will receive a $15.00 Walmart card at the transitional care visit that occurs within 14 days of 
hospital discharge, $50 if you complete study visit 2 and $50 after you complete study visit 3, for 
a total of $115.00 to cover expenses incurred by you as a result of the study such as gasoline 
and/or a meal.  If you withdraw for any reason from the study before completion you will not be 
paid for any visits that are not completed.
To receive payment, you must provide your social security number, name and address so that we 
can comply with IRS (Internal Revenue Service) reporting requirements.  When payments are 
reported to the IRS we do not let them know what the payment is for, only that you have been 
paid.  If you do not wish to provide this information you can still take part in this study but you 
will not be paid.
Additionally, if you were randomized to the nebulizer arm, you will need to return the study 
nebulizer machine that was dispensed at the start of the study in order to receive the final $50 
check after the End of Study visit.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by Sunovion Pharmaceuticals Inc. The sponsor is providing money 
or other support to Wake Forest University Health Sciences to help conduct this study. The 
researchers do not, however, hold a direct financial interest in the sponsor or the product being 
studied.
Dr. Jill Ohar, the Principle Investigator, however is on the advisory board for Sunovion, the makers of 
Brovana, and the sponsor of the study and receives consulting fees from the company.
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this policy 
the reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. The Wake Forest University School of Medicine, and 
the North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these 
medical services or to provide any other compensation for such injury or illness. Additional 
information may be obtained from the Medical Center’s Director of Risk and Insurance 
Management, at
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If you are injured, the sponsor may require information such as your name, social security 
number, and date of birth in order to pay for your care.  This is because the sponsor is required 
by law to report any payments made to cover the care of any persons who are members of a 
government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call 
WHAT ABOUT MY HEALTH INFORMATION?
In this research study, any new information we collect from you and information we get from 
your medical records or other facilities about your health or behaviors is considered Protected 
Health Information. The information we will collect for this research study includes:  medical 
history, questionnaires, lung test results, hospitalizations, doctor visits and patient preference. 
If this research study involves the diagnosis or treatment of a medical condition, then Protected 
Health Information collected from you during this study will be placed in your medical record, 
and may be used to help treat you, arrange payment for your care, or assist with Medical Center 
operations. 
We will make every effort to keep your Protected Health Information private. We will store 
records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer. 
Your personal health information and information that identifies you (“your health information”) 
may be given to others during and after the study. This is for reasons such as to carry out the 
study, to determine the results of the study, to make sure the study is being done correctly, to 
provide required reports and to get approval for new products.  
Some of the people, agencies and businesses that may receive and use your health information 
are the research sponsor; representatives of the sponsor assisting with the research; investigators 
at other sites who are assisting with the research; central laboratories, reading centers or analysis 
centers; the Institutional Review Board; representatives of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital; representatives from government agencies such as 
the Food and Drug Administration (FDA), the Department of Health and Human Services 
(DHHS) and similar agencies in other countries.
Some of these people, agencies and businesses may further disclose your health information. If 
disclosed by them, your health information may no longer be covered by federal or state privacy 
regulations.  Your health information may be disclosed if required by law. Your health 
information may be used to create information that does not directly identify you. This 
information may be used by other researchers. You will not be directly identified in any 
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publication or presentation that may result from this study unless there are photographs or 
recorded media which are identifiable.
If required by law or court order, we might also have to share your Protected Health Information 
with a judge, law enforcement officer, government agencies, or others. If your Protected Health 
Information is shared with any of these groups it may no longer be protected by federal or state 
privacy rules.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for an indeterminate period of time. This authorization does not 
expire. Any research information entered into your medical record will be kept for as long as 
your medical record is kept by the Medical Center. You will not be able to obtain a copy of your 
Protected Health Information in the research records until all activities in the study are 
completely finished. 
You can tell Jill A Ohar that you want to take away your permission to use and share your 
Protected Health Information at any time by sending a letter to this address:
 
However, if you take away permission to use your Protected Health Information you will not be 
able to be in the study any longer. We will stop collecting any more information about you, but 
any information we have already collected can still be used for the purposes of the research 
study.
By signing this form you give us permission to use your Protected Health Information for this 
study.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this Web site at any time. 
Laboratory test results and other medical reports created as a result of your participation in the 
research study may be entered into the computer systems of Wake Forest University Health 
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Sciences and North Carolina Baptist Hospital. These will be kept secure, with access to this 
information limited to individuals with proper authority, but who may not be directly involved 
with this research study
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. The investigators also have the right to stop your participation in the study 
at any time. This could be because it is in your best medical interest, your condition worsened, 
new information becomes available, you had an unexpected reaction, you failed to follow 
instructions, or because the entire study has been stopped. 
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, 
.
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB 
.
You will be given a copy of this signed consent form. 
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SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.   By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
Subject Name (Printed):_____________________________
Subject Signature: _________________________________ Date: ________Time:_______ am pm 
Person Obtaining Consent (Printed):_____________________________
Person Obtaining Consent:___________________________ Date:_________ Time:________ am pm
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