A Cluster Randomized, Stepped-Wedge Evaluation of Post Discharge Utilization Among Patients With an Acute Exacerbation of Chronic Obstructive Pulmonary Disorder (COPD)
Phase: NA
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Wake Forest University Health Sciences

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Protocol #:  HIIN-COPD 
 
TITLE: A CLUSTER RANDOMIZED, STEPPED-WEDGE EVALUATION OF POST DISCHARGE 
UTILIZATION AMONG PATIENTS WITH AN ACUTE EXACERBATION OF COPD 
 
Coordinating Site: 
Carolinas Medical Center 
1000 Blythe Boulevard 
Charlotte, NC 28203 
 
Principal Investigator: 
Daniel Howard, MD 
1000 Blythe Boulevard 
Charlotte, NC 28203 
Phone: (704) 355-5375 
Email: Daniel.Howard@carolinashealthcare.org     
 
Co-Principal Investigator: 
Jason Roberge, PhD, MPH  
1540 Garden Terrace 
Charlotte, NC 28203 
Phone: (704) 355-0268 
Email: Jason.Roberge@carolinashealthcare.org     
 
Statistician: 
Jing Zhao, MD, PhD 
1540 Garden Terrace 
Charlotte, NC 28203 
Telephone: (704) 355-1965 
Email: Jing.Zhao@carolinashealthcare.org  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________ 

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The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document whether in 
part or in full to parties not associated with the clinical investigation, or its use for any other 
purpose, without the prior written consent of the Principal Investigator is not permitted. 
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  
Hence, the appearance of product names without these symbols does not imply that these names 
are not protected. 
 
 

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Protocol Approved By: 
 
 
PRINCIPAL INVESTIGATOR: 
 
 
 
EXECUTIVE SPONSORS: 
 
 
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Daniel Howard, MD  
 
 
 
 
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Date  
 
 
 
 
 
 
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PROTOCOL SUMMARY 
Study Title 
HIIN – COPD:  A Cluster Randomized, Stepped-Wedge Evaluation of Post 
Discharge Utilization among Patients with an Acute Exacerbation of COPD 
Study Design 
A cluster randomized, stepped-wedge quality improvement evaluation 
Study 
Objectives 
The primary objective is to evaluate the effectiveness of using a COPD clinical 
pathway compared to usual care among patients with an acute COPD 
exacerbation, on 60-day post discharge utilization (ED, inpatient, and observation 
encounters)  
 
The secondary objectives are to examine the COPD clinical pathway’s effect on 
additional patient outcomes, such as the  
a. CHS Quality, Comfort, and Care 30-day readmission rate. This is a 
readmission rate among patients with an inpatient readmission to the same 
CHS facility as the index encounter. 
b. The patient-centric 30-day readmission rate. This is a readmission rate 
among patients with an inpatient or observation readmission to any CHS 
facility. 
c. The patient-centric 30-day readmission rate where the primary diagnosis of 
the readmission is COPD.  
d. Length of stay 
e. Rate of follow-up visit within 5 days of discharge. 
f. Antibiotic order rate during admission 
g. Steroid order rate during admission 
h. Short acting bronchodilator order rate during admission 
Additional analyses will be to explore: 
 
a. The methodology for identification of COPD exacerbation within the first 
24 hours of hospital admission will be compared to retrospective 
identification through billing codes. 
b. As a sub-analysis, qualitative outcomes will be collected and measured 
with patients, providers, and leaders. These outcomes will be collected and 
evaluated, per a sub-study protocol addendum. 
Study 
Population 
Patients 40 years of age or older hospitalized with an acute exacerbation of COPD 
are included. An acute exacerbation is defined as an encounter where the 
following criteria are met within 24 hours of admission. 
 
• The use of the COPD PowerPlan or 
• A respiratory therapy navigator notification of COPD exacerbation or 
• The use of the respiratory therapy department COPD bronchodilator 
protocol or 

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• A historical diagnosis of COPD or 
A history of COPD in the admitting documentation or 
A COPD diagnosis on the problem list AND 
An order of systemic steroids (prednisone or methylprednisolone) 
 
For the purposes of this project, the evaluable population will include patients who 
meet the same age criteria and have a discharge diagnosis of acute exacerbation of 
COPD 
Study 
Procedures 
During this project, patients who are hospitalized at select CHS sites with COPD 
acute exacerbation symptoms will be treated per the CHS COPD clinical pathway 
(COPD Pathway). The COPD clinical pathway will include four components: (i) 
discrete, evidence-based care steps (ii) patient navigation, (iii) daily data driven 
care gap identification, (iv) monthly leadership huddles.  
 
The evidence based care steps include: (1) verification of COPD diagnosis and 
severity, (2) patient/caregiver education regarding COPD and basic self-
management skills, (3) standard pharmacologic bundle of systemic steroids, 
empiric antibiotics, bronchodilators, (4) pneumococcal and influenza vaccination 
review and completion, (5) smoking cessation advice and therapy when 
appropriate, (6) comprehensive care management assessment, (7) 
recommendations for pulmonary consultation, (8) recommendations for palliative 
care consultation, (9) use of discharge checklist, (10) recommendations for content 
of outpatient follow-up, and will be driven primarily by provider utilization of a 
comprehensive order-set that includes each component and a discharge checklist.   
 
Patient navigation will be provided by the COPD Pathway Coordinator (COPD 
Coordinator) at each site. This role will be filled by an individual (s) who already 
exists on a site’s care team. Because of this, the COPD Coordinator’s site role and 
background may vary by site. The COPD Coordinators will be responsible for 
daily monitoring of care gaps that exist for COPD patients and their respective 
sites and alerting appropriate team member to help close those gaps. The COPD 
Coordinators will receive a daily COPD Gaps list. The COPD Gaps list identifies 
patients who are hospitalized at that time and the associated gaps in receiving the 
evidence based care components.  
 
The intervention occurs at the site level and sites are randomized to the order they 
will receive the intervention in clusters of two.  Two additional facilities will be 
added on a rolling basis in 2 month intervals, until all 8 facilities are active in 
using the COPD pathway. Once added, sites will begin utilizing the COPD 
Pathway in their daily practice.  
 
As a part of the COPD clinical pathway, patients will meet the following discharge 
checklist criteria: 
 
• On a long acting bronchodilator for 24 hours 
• A short acting bronchodilator is scheduled no more frequently than 4 times 
daily for 24 hours 

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• Be off IV steroids for 24 hours prior to discharge  
• A steroid prescription, or have completed a 5-day course while admitted 
• An antibiotic prescribed or have completed a 5-day course while admitted 
• A scheduled appointment with a care provider within 5 days of discharge 
• Received COPD education during discharge 
Statistical 
Analysis 
Analyses is among patients identified as having an acute exacerbation of COPD 
based on final billed coding.  Comparisons of patients hospitalized during the 
intervention and usual care periods will be made using generalized estimating 
equations to control for clustering within hospital and repeated measures within 
hospital.  The primary outcome, 60-day utilization, will be compared between the 
two groups of patients using a logit link in the generalized estimating equations. 
Results will be presented with odds ratios and 95% confidence intervals. 
Sample Size 
Analysis 
8 hospitals will be randomized to intervention in 2 facilities per 2 month 
increments. With the assumption of detecting a change in rates of 60-day non-
elective acute care utilization from 43% in the control period to 33% in the 
intervention period, 59 patients with COPD exacerbation per hospital per two 
months is needed to achieve a power of 0.80 (intra-class correlation coefficients 
(ICC)=0.05 and two-side α=0.05. To account for this varying cluster size, we 
inflated the number of patients by 25% resulting in an average of 74 patients per 
hospital per two months, resulting in a total sample size of 2960 patients among 
the intervention group. 

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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event or Acute Exacerbation 
CHS 
Carolinas Healthcare System 
COPD 
Chronic Obstructive Pulmonary Disease 
EHR 
Electronic Health Record 
ED 
Emergency Department 
PHI 
Private Health Information 
PI 
Principal Investigator 
qid 
4 times per day 
 
 

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TABLE OF CONTENTS 
1. OBJECTIVES ....................................................................... ERROR! BOOKMARK NOT DEFINED. 
1.1. Hypothesis ......................................................................................................................................10 
1.2. Primary Objective .........................................................................................................................10 
1.3. Secondary Objectives ....................................................................................................................10 
2. BACKGROUND ...................................................................................................................................10 
3. RATIONALE ........................................................................................................................................10 
4. SUBJECT AND SITE SELECTION ..................................................................................................11 
4.1. Accrual ............................................................................................................................................11 
4.2. Subjects ...........................................................................................................................................11 
4.3. Participating Sites ..........................................................................................................................12 
4.4. Inclusion/Exclusion Criteria .........................................................................................................12 
4.5. Evaluable Population.....................................................................................................................13 
5. OVERALL DESIGN ............................................................................................................................13 
5.1. Outcome Variables ........................................................................................................................13 
5.2. Trial Design ....................................................................................................................................13 
5.3. Training ..........................................................................................................................................16 
5.4. Data Collection Dates ....................................................................................................................16 
5.5. Continuation of the Intervention ..................................................................................................16 
5.6. Data Collection and Reporting .....................................................................................................16 
6. PROJECT TIMELINE ........................................................................................................................16 
7. INTERVENTION PLAN .....................................................................................................................17 
7.1. COPD Clinical Pathway ................................................................................................................17 
8. STUDY GOVERNANCE .....................................................................................................................18 
9. SAFETY RISKS ....................................................................................................................................19 
9.1. Data Safety Monitoring Plan . ......................................................................................................19 
10. RESEARCH COMPLETION .............................................................................................................19 
11. ETHICAL AND LEGAL ISSUES .....................................................................................................201 
11.1. 
Ethical and Legal Conduct of the Study ...............................................................................201 
11.2. 
Confidentiality ...........................................................................................................................20 
11.3. 
Disclosure of Data .....................................................................................................................20 
12. RETENTION OF RECORDS .............................................................................................................20 
13. PUBLICATION POLICY ....................................................................................................................20 
REFERENCES ......................................................................................................................................22 
APPENDICES .......................................................................................................................................23 
 
 
 

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1. OBJECTIVES 
1.1. Hypothesis 
 
Patients with an acute COPD exacerbation, who receive care at a site using the COPD clinical pathway, 
will have lower 60-day post discharge utilization than patients that receive usual care.  
1.2. Primary Objective 
 
The primary objective is to evaluate the effectiveness of the use of the COPD clinical pathway 
compared to usual care, on 60-day post discharge utilization (ED, inpatient, observation encounters) 
among patients with an acute COPD exacerbation. 
 
1.3. Secondary Objectives 
 
a. The secondary objectives are to examine the COPD clinical pathway’s effect on additional patient 
outcomes, such as the  
i. CHS Quality, Comfort, and Care 30-day readmission rate. This is a readmission rate 
among patients with an inpatient readmission to the same CHS facility as the index 
encounter. 
ii. The patient-centric 30-day readmission rate. This is a readmission rate among patients 
with an inpatient or observation readmission to any CHS facility. 
b. The methodology for identification of COPD exacerbation within the first 24 hours of hospital 
admission will be compared to retrospective identification through billing codes. 
c. Demographics and comorbid conditions will be characterized among the historical population of 
patients at CHS with COPD exacerbation. 
2. BACKGROUND 
Chronic Obstructive Pulmonary Disease (COPD) is a disease characterized by persistent respiratory 
symptoms, incompletely reversible expiratory airflow obstruction, intermittent episodes of acute airway 
and alveolar inflammation termed exacerbations. COPD is hallmarked with periods of symptom stability, 
and periodic acute deteriorations of the patient’s disease condition, called exacerbations. Acute COPD 
exacerbations frequently lead to ED utilization and/or hospitalization in acute care facilities1. Reported 
COPD costs in the U.S. have reached approximately $37 billion annually, with hospitalizations accounting 
for most the estimated costs, and are only expected to continue rising.  Prior to implementation of the CMS 
Hospital Readmission Reduction Program, approximately 20% of patients admitted to a hospital for 
AECOPD were readmitted (all cause) within 30 days. Other types of acute care utilization following 
hospital admission (ED visits, Urgent Care encounters, hospital observation stays have not been studied2.   
Less stringent definitions of care utilization including readmission and ED and/or Urgent Care encounters 
further than 30 days out, can safely be assumed to be even worse.  
 
With the advent of value based care, and the rise of bundled payments for a single episode or cycle of care, 
it has become increasingly important to devise innovative care delivery systems and pathways that will 
both treat patients effectively in the acute setting and prevent readmissions. Further haste driving 

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innovation and work in this disease state, has been Medicare’s identification of COPD as a target for the 
Hospital Readmission Reduction Program. This program penalizes hospitals for 30-day readmissions 
among patients for specific index encounters, such as those with COPD3.  
 
Development and implementation of new acute COPD care models will cost significant investment of time 
and capital. Such investment and the need to have a valid assessment of benefit, necessitate strategic, a 
priori evaluation planning and execution prior to widespread implementation.  
 
Healthcare systems are increasingly adopting disease specific Clinical Pathways (CPW’s). These pathways 
are structured, multidisciplinary care plans, often inclusive of order sets, that detail necessary care steps for 
patients with a specific disease. Despite being present since the 1980’s and fairly ubiquitous in many 
hospitals since the early 2000’s, they have a limited evidence base. A 2011 Cochrane review could not 
draw conclusions on their effects on length of stay and cost, due to variability in study designs. However, 
review of the resulting data did show reduced hospital complications (OR 0.58; 95% CI 0.36-0.94).  
Another review showed that a 3-month integrated disease management intervention (multidisciplinary, 
multi-faceted care) among inpatients was beneficial with 15 patients needing to be treated to eliminate 1 
respiratory related hospital admission4-7. Particularly in the transition to value based care models, there 
remains an obligation for further research to prove effectiveness and cost efficacy for care pathways. 
 
There have been ongoing efforts to define the COPD population based on biologic factors, clinical 
characteristics, and social determinants of health to help identify patients at risk for exacerbations, hospital 
admission, hospital readmission, and mortality.  Some factors associated with increased risk of hospital 
readmission include congestive heart failure, behavioral health issues, medical frailty, increasing age, and 
(simply) prior admission for a COPD exacerbation3,8.  Predictive models and scoring systems have been 
devised, most commonly using dyspnea scores, measurements of expiratory airflow limitation, previous 
hospitalizations, age, and chronic comorbidities; however, use of these tools has not been proven to reduce 
acute healthcare utilization. Attempts at care pathways for delivery of standardized intervention for acute 
COPD exacerbations and complex care interventions for patients with COPD have produced equivocal 
results and there is lack of consensus as to whether such clinical care pathways convincingly improve 
overall patient outcomes. 
 
Even as improvements are made in terms of the understanding of the COPD population, and risk factors for 
readmission, the optimal method to reduce utilization remains questionable. Attempts at care pathways 
nationwide, and other interventions for COPD patients have been undertaken with mixed reports of 
success. The state of research is best summarized by noting that, while several intermediate or process-
oriented outcomes (such as patient self-report of ability to manage symptoms or number of follow-up 
phone calls made to patients) have been impacted by efforts to improve coordination of care, studies to date 
have yet to convincingly illustrate an improvement in utilization rates after any such intervention9-11. 
 
3. RATIONALE 
To better enhance the care of patients with an acute exacerbation of COPD, Carolinas HealthCare System 
(CHS) has designed a COPD clinical pathway, a structured multidisciplinary care plan. The care plan 
utilizes a data system that identifies patients with exacerbation and care gaps in real-time. It includes an 
EMR based order set, patient education, and discharge criteria. A COPD pathway coordinator who works 
to close care gaps and ensure a standardized approach is also part of the care plan. 
 

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At participating CHS hospital, patients who are admitted with a suspected acute COPD exacerbation, will 
enter the COPD clinical pathway. The COPD clinical pathway includes the following key components 
during hospitalization: and an order within 24 hours of being admitted of a short acting bronchodilator, an 
antibiotic, and a steroid, as well as a standardized discharge plan. A patient’s journey through the clinical 
pathway, ends at discharge. The discharge checklist requires that patients:  
 
• Be on a long acting bronchodilator for 24 hours 
• Bo on a short acting bronchodilator is scheduled no more frequently than 4 times daily for 24 hours 
• Be off IV steroids for 24 hours prior to discharge  
• Have a steroid prescription, or have completed a 5-day course while admitted 
• Have an antibiotic prescribed or have completed a 5-day course while admitted 
• Have a scheduled appointment with a care provider within 5 days of discharge 
• Receive COPD education during discharge 
This proposed evaluation is designed to guide CHS strategy and quality improvement for COPD by 
applying research methodology and data analytics to create valid outcomes. Ultimately, as CHS deploys 
resource intensive interventions like this, it is important for the system and its patients to know answers to 
questions such as: Does this process impact readmissions and utilization? 
 
This research project is a pragmatic, randomized quality improvement evaluation which seeks to evaluate 
the effects of standardizing the use of a COPD clinical pathway across various participating facilities 
among patients with an acute exacerbation of COPD.  The outcomes evaluation of this quality 
improvement intervention has been designed to integrate into the routine care and minimize frontline staff 
burden by deploying an evaluation that occurs in a real-world setting with no additional data collection 
outside of usual care.   
 
4. SUBJECT AND SITE SELECTION 
4.1 Accrual 
 
A daily patient list will be generated through an automated process utilizing clinical and patient registration 
information. The list will indicate patients newly hospitalized (hospitalization within the preceding 24-hour 
period) with symptoms of suspected acute COPD exacerbation, at any of the eight facilities. The list 
contains inpatient and observation encounters. The patient list will identify patients at any of the eight 
facilities throughout the project, not just once the facility has implemented the standardized use of the 
COPD clinical pathway. For the purposes of this project, we are not enrolling towards a targeted patient 
accrual. We will enroll patients during a pre-determined data collection period, See Section 6. 
 
4.2 Subjects 
 
An acute exacerbation is defined as an encounter where one the following criteria are met within 24 hours of 
admission. 
 
• The use of the COPD PowerPlan or 
• A respiratory therapy navigator notification of COPD exacerbation or 

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• The use of the respiratory therapy department COPD bronchodilator protocol or 
• A historical diagnosis of COPD or 
A history of COPD in the admitting documentation or 
A COPD diagnosis on the problem list AND 
An order of systemic steroids (prednisone or methylprednisolone) 
 
To identify appropriate records of available clinical data for baseline and historical data collection and 
analysis, we will provision using the following ICD10 code for COPD: J44.1 
 
4.3 Participating Sites 
 
As part of the research design and rollout of this project, randomization will occur at the site level. CORE 
has randomized the facility participation order in advance of project kickoff. Site enrollment will begin with 
two facilities, adding on 2 additional facilities on a rolling basis in 2 month intervals, until all 8 facilities are 
active in using the COPD pathway. Once added, sites will begin utilizing the COPD clinical pathway in 
their daily practice with the target patient population.  
 
The following Carolinas Healthcare System sites will be randomized for participation in this project. 
 
• Carolinas HealthCare System Cleveland 
• Carolinas HealthCare System Kings Mountain 
• Carolinas HealthCare System Lincoln 
• Carolinas HealthCare System NorthEast 
• Carolinas HealthCare System Pineville 
• Carolinas HealthCare System Union 
• Carolinas HealthCare System University 
• Carolinas Medical Center 
 
4.4 Inclusion\Exclusion Criteria 
4.4.1 Inclusion Criteria 
Because this is a site-wide intervention, all patients who have a COPD exacerbation, as determined 
by their clinical care provider will be subject to receiving components of the intervention. Patients 
will be included in the daily Gap List based on the following criteria: 
 
• ≥ 40 years of age at time of admission 
• Identified as having an acute exacerbation of COPD within 24 hours of admission 
 
4.4.2 Exclusion Criteria 
Subjects must not meet any of the following criteria: 
 
• Death during the index encounter 
• Not discharged by the end of the study 
 

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4.5 Evaluable Population 
 
Patients included in the evaluable population for this project, will have their data inform the final outcomes 
assessment. For the purposes of this project, the evaluable population will include patients who meet the 
same age criteria and have a discharge diagnosis of acute exacerbation of COPD: J44.1 
 
5. OVERALL DESIGN 
5.1 Outcome Variables 
5.1.1 Primary Outcome Variable 
The primary outcome variable is 60-day post discharge utilization (ED, inpatient, and observation 
encounters). 
5.1.2 Secondary Outcome Variable(s) 
Secondary outcome variables of the evaluation include: 
 
Examining the COPD clinical pathway’s effect on additional patient outcomes, such as the  
i. 
CHS Quality, Comfort, and Care 30-day readmission rate. This is a readmission rate among 
patients with an inpatient readmission to the same CHS facility as the index encounter. 
j. 
The patient-centric 30-day readmission rate. This is a readmission rate among patients with an 
inpatient or observation readmission to any CHS facility. 
k. 
The patient-centric 30-day readmission rate where the primary diagnosis of the readmission is 
COPD.  
l. 
Length of stay 
m. Rate of follow-up visit within 5 days of discharge. 
n. 
Antibiotic order rate during admission 
o. 
Steroid order rate during admission 
p. 
Short acting bronchodilator order rate during admission 
5.1.3 Additional assessments 
The methodology for identification of COPD exacerbation within the first 24 hours of hospital 
admission will be compared to retrospective identification through billing codes. 
 
As a sub-analysis, qualitative outcomes will be collected and measured with patients, providers, 
and leaders. These outcomes will be collected and evaluated, per a sub-study protocol addendum. 
 
5.2 Trial Design 
5.2.1 Justification for stepped wedge cluster randomized control trial 
The primary aim is to assess the effectiveness of a structured multidisciplinary care plans 
(intervention), compared with standard care (control) on 60-day non-elective acute care utilization 
(ED visits, observation, and inpatient encounters). The COPD clinical pathway will be delivered at 
the level of hospital or cluster, thus minimizing contamination and the risk of selection bias, if 
subjects were randomized at the individual level12. Therefore, the unit of randomization and 

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analysis for this study will be the cluster. Considering logistical constraints and design rigor, the 
intervention will be rolled out sequentially instead of at the same time.  Moreover, substantial and 
differential cluster-effects may exist because of distinct volume and characteristics of patients in 
each hospital. Thus, the stepped wedge design is advantageous compared with other alternative 
designs.  
5.2.2 Randomization and allocation  
The stepped wedge design implies a baseline period, in which no clusters are exposed to the 
intervention12. Then, at the chosen time interval of two months, two hospitals will be randomized 
to cross from the control to intervention (Figure 1). This process continues until all eight hospitals 
have crossed over to the intervention. The order of this cross over process will be randomized. We 
will use block randomization to assign two hospitals at a time to switch from the control to 
intervention using SAS Enterprise Guide version 6.1. Allocation will be communicated only to 
hospital senior leadership initially to prevent contamination. Others including providers at the 
hospital will learn of allocation in the month preceding roll-out. Patients in included hospitals will 
be blinded to the intervention or control period.  
 
 
 
Figure 1. The stepped wedge study design  
 
 
 
 
 
0=control  
1=intervention 
 
 
 
 
5.2.3 Sample size analysis 
Calculations of sample size were based on the primary endpoints of 60-day non-elective acute care 
utilization. With the assumption of detecting a change in rates of 60-day non-elective acute care 
utilization from 43% in the control period to 33% in the intervention period, 59 patients with 
COPD exacerbation per hospital per two months is needed to achieve a power of 0.80 (intra-class 
correlation coefficients (ICC)=0.05 and two-side α=0.05. Holding other parameters constant, the 
larger ICC is, the higher the power we will obtain (Figure 2). With sample sizes per cluster per 
two months ranging from 30 to 158, our preliminary data shows that the coefficient of variation 
(CV) of sample size is approximately 0.5. To account for this varying cluster size, we inflated the 
number of patients by 25% resulting in an average of 74 patients per hospital per two months13, 
resulting in a total sample size of 2960 patients among the intervention group and 5920 patients 
overall inclusive of our control population. The power was calculated by using the PASS 1514. 
 
Figure 2. Alternative Sample Size Estimation 
  
1-Apr 
1-Jun 
1-Aug 
1-Oct 
1-Dec 
Cluster 1 
0 
1 
1 
1 
1 
Cluster 2 
0 
1 
1 
1 
1 
Cluster 3 
0 
0 
1 
1 
1 
Cluster 4 
0 
0 
1 
1 
1 
Cluster 5 
0 
0 
0 
1 
1 
Cluster 6 
0 
0 
0 
1 
1 
Cluster 7 
0 
0 
0 
0 
1 
Cluster 8 
0 
0 
0 
0 
1 

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5.2.4 Statistical analysis 
All data quality monitoring and analysis will be overseen by Dr. Jing Zhao. Distributions of baseline 
characteristics for hospitals and patients will be compared between the intervention or control periods to 
assess effectiveness of the randomization, and statistical or clinical differences will be adjusted in 
sensitivity analyses. All analyses for treatment and control periods comparisons will use an intention-to-
treat approach and results will be reported used the CONSORT extension to cluster randomized trials.  
 
5.2.5 Primary aim 
The primary outcome for this study is 60-day non-elective acute care utilization. Characteristics of the 
hospitals and individuals will be summarized by levels of randomization steps, hospitals and individuals. 
The count, rates and 95% confidence intervals of 60-day non-elective acute care utilization in the -control 
period will be presented and compared with that in the -treatment period. The primary analysis will be 
conducted using generalized estimating equations with fixed effects for intervention, time (steps), and 
intervention multiply by the time, accounting for the cluster randomized trial design with a random cluster 
(hospitals) effect. We will estimate and report the intra class correlation coefficients for all outcome 
measures to assess assumptions for sample size analyses and for future investigations using similar designs 
and outcomes. The primary analyses will follow the intention to treat principle with an additional per 
protocol analysis including by using denominator in those who had pathway ordered as well as 
intervention periods when truly occurred. The secondary analyses will include within cluster comparisons 
of intervention and control periods (not adjusting for any confounding effect of time), as well as 
comparisons of a series of (unbalanced) quasi-parallel cluster trials between those enrolled and unenrolled 
clusters at each intervention enrollment period. The same analyses plan will also be applied to secondary 
outcomes. 
59
57
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51
48
45
93
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70
167
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125
0
20
40
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120
140
160
180
0.05
0.1
0.15
0.2
0.25
0.3
Sample size per hospital per two months 
Intra-class correlation coefficients (ICC) 
Figure 2. Alternative Sample Size Estimation 
(power=0.80, α=0.05)
D = -0.1
D = -0.08
D = -0.06

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5.2.6 Missing data 
All the related available electronic data will be pulled without missing any subjects. Thus, the missing of 
outcome variables are less likely to occur. However, the missing information on covariables is unavoidable. 
Sensitivity analyses are recommended for trials with missing data. We will compare baseline characteristics 
such as age, gender, and health insurance status between patients with complete follow-up data to those 
with missing data by intervention period to assess potential biases that may exist in the complete case 
analysis. We will conduct sensitivity analyses for the primary and secondary outcomes using several 
methods which have different missing data assumptions: (1) complete case analyses which assumes missing 
completely at random; (2) multiple imputation using M=10 imputations, which assumes missing at random; 
and (3) assigning poor scores and good scores for missing values differentially by treatment group, which 
aligns with non-ignorable missingness (the data missingness is related to the actual value).  
 
 
5.3 Training 
 
Beginning two to three weeks prior to first patient enrolment at the respective facility, the COPD pathway 
coordinator and those responsible for discharge will begin training on the materials supporting the pathway 
as well as use of the pathway itself. This will include communication touchpoints between the coordinator, 
discharge facilitator as well as the individuals responsible for the clinical path. Specifically, there will be 
education on the COPD protocol, Education Checklist, the COPD clinical pathway and order set as well as 
the criteria and fulfillment options required for discharge.  
 
5.4 Data Collection Dates 
 
The implementation of the COPD clinical pathway will begin on 6/1/17 at the first two facilities. 
 
5.5 Continuation of the Intervention 
 
Participating sites will likely continue treating patients diagnosed with an acute COPD exacerbation per the 
COPD clinical pathway after the study period has ended. This is outside the purview of the evaluation 
protocol and will be decided by clinical and administrative leaders at the respective sites. 
 
5.6 Data Collection and Reporting 
 
A daily list of patients with an acute exacerbation of COPD will be generated. Each morning at 06:00 the 
list is automatically emailed via secure transmission to the appropriate COPD pathway coordinator at each 
participating facility or stored on a secured server. Patient demographics, comorbid conditions and 
utilization will be obtained from the electronic medical record and billing systems. A monthly executive 
summary will be produced showing patient volume and related implementation metrics such as: 
1. Rate of use of the COPD PowerPlan 
2. Rate of use of the respiratory therapy department COPD bronchodilator protocol 
3. Average length of stay 
4. Rate of follow-up visit within 5 days of discharge. 
5. Antibiotic order rate during admission 
6. Steroid order rate during admission 
7. Short acting bronchodilator order rate during admission 
8. LAMA, LAMA/LABA, LABA/ICS order rate at discharge 

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6. PROJECT TIMELINE 
 
 
7. INTERVENTION PLAN 
7.1. COPD CLINICAL PATHWAY 
The pathway includes the following components. 
• A data system that identifies patients with exacerbation and care gaps in real-time 
• A COPD pathway coordinator who works to close care gaps and ensure standardized approach. 
• A standardized care pathway inclusive of an EMR based order set, patient education, and discharge 
criteria. 
7.1.1. EMR Based Order Set 
The order set includes an order within 24 hours of being admitted of 
• A bronchodilator albuterol, ipratropium, ipratropium-albuterol) 
• An antibiotic (amoxicillin-clavulanate, doxycycline, azithromycin, ampicillin-sulbactum) 
• A steroid (prednisone, methylprednisolone) 
7.1.2. Patient Education 
Education will be provided by the COPD pathway coordinator and will be aligned to the 
treatment. The COPD pathway coordinator will use a set of standardized teaching tools and 
checklists in the process. Some components of the education include: 
• Action plan (Living with COPD) 
• Home medication review (steroids, antibiotics, etc.)  
• Respiratory equipment - technique, what to use and when, tips 
• 
Smoking cessation  
7.1.3. Discharge Criteria 
At the time of discharge, the patient should have each of the following (unless otherwise stated): 

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• Stability on a long acting bronchodilator (e.g., spiriva, serevent) 
• Not requiring a short-acting bronchodilator more than qid (e.g., albuterol, ipratropium, 
ipratropium-albuterol) 
• Be on an oral steroid for 24 hours prior to discharge (e.g., prednisone, methylprednisolone) 
• A steroid prescribed, supplied, or have completed a 5-day course while admitted 
• An antibiotic prescribed, supplied, or have completed a 5-day course while admitted 
• A scheduled appointment with a care provider within 5 days of discharge 
• 
Received COPD education prior to discharge 
7.1.4. Patient Identification and Care Gaps 
Patients are identified as described in the ‘Subjects’ section. Care gaps that are monitored daily 
include the initiation of the COPD PowerPlan and the Respiratory therapy department COPD 
bronchodilator protocol. The PowerPlan includes order sets for a bronchodilator, an antibiotic, 
and a steroid. 
7.1.5. COPD Pathway Coordinator 
Once a patient is identified, their clinical path will be guided by the pathway coordinator. These 
individuals will monitor the use of the COPD clinical pathway and assure that all milestones 
within the patient experience are addressed including assuring that discharge needs are met. The 
Pathway Coordinator will use the COPD Pathway Program which will inform the flowsheet used 
to track and record the patients clinical path. The COPD Pathway Coordinator will be 
responsible for reporting any pathway gaps to both the discharge facilitator and the clinician 
involved in the patient’s care.   
8. STUDY GOVERNANCE 
This quality improvement trial will be conducted at Carolinas HealthCare System.  It will be run jointly by 
the Center for Outcomes Research and Evaluation (CORE) and the Pulmonology Department. Daniel 
Howard, MD, (Pulmonologist) will serve as the Principal Investigator and Jason Roberge as the Co-
Principal Investigator with oversight from the Executive Committee (EC).  The EC will consist of leaders 
across the System involved in the trial, quality improvement, and implementation (Table 1).  The EC will 
have the overall responsibility of trial oversight and direction.  The EC will support dissemination of 
project findings and next steps.  The EC will receive monthly progress reports and will meet periodically 
for status updates from the team and to set direction.  When appropriate, ad hoc committee meetings will 
be scheduled to discuss pressing concerns. 
 
Table 1. Executive Committee 
Daniel Howard 
Pulmonology Department 
Jason Roberge 
Center for Outcomes Research and Evaluation 
Amy Clary 
Clinical Services 
Scott Furney 
CHS Executive Leadership/Internal Medicine 
Mary N. Hall 
CHS Executive Leadership 
James Hunter 
CHS Executive Leadership 
Scott Rissmiller 
CHS Executive Leadership 
 

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9. SAFETY RISKS 
This project presents no more than minimal risk to patients who participate in the COPD clinical pathway. 
The deployment of the COPD clinical pathway at participating sites, utilizes care components that are 
already leveraged in CHS facilities. While based on evidence and present in some facilities, these elements 
of care are not consistently applied across sites and COPD patients.  
 
There is always the risk of disclosure of a patient’s private health information (PHI) or medical 
information. However, the processes identified in this protocol to enable the execution of this project, do 
not increase inherent risk of disclosure. Carolinas HealthCare System utilizes several hard and soft safety 
controls in the protection of patient information and medical records. Security controls include, but are not 
limited to, multiple system firewalls, access restrictions to patient records and information, locked offices 
and buildings housing research and patient data, and multiple layers of username and password protected 
computer and system access. The project team will ensure that appropriate handling of patient PHI follows 
standard CHS procedure. In the event of PHI disclosure, the appropriate departments will be informed per 
legislation and privacy regulations. 
9.1. Data and Safety Monitoring Plan 
The Co-PIs are responsible for the ethical and compliant conduct of this project in accordance with 
local, state, and federal laws and regulations. Ongoing supervision of the study progress and conduct 
will be facilitated through at least monthly meetings with key stakeholders and the PIs. These monthly 
meetings will address data updates, milestones, and concerns. Because this project presents no more 
than minimal risk to patients, per the FDA Guidance for Clinical Sponsors: Establishment and 
Operations of Clinical Trial Data Monitoring Committees, this study does not require oversight by a 
Data and Safety Monitoring Board or Committee.  
10. RESEARCH COMPLETION 
The Principal Investigator has the right to close the project at any site and at any time. 
For any closure, the following applies: 
• Closures should occur only after consultation between involved parties. 
• All affected institutions must be informed as applicable, according to local law.   
• In case of a partial study or site closure, patients still participating in the COPD clinical pathway, or 
those who are considered in follow-up, must be taken care of in an ethical manner. 
 
The study will be considered complete when one or more of the following conditions is met: 
• 
The enrollment period has ended, and the data collection period is complete. 
• 
The IRB or Principal Investigator discontinues the study. 
• 
The Principal Investigator defines an administrative or clinical cut-off date. 
Upon study completion, a final report will be presented to the Executive Committee and all key 
stakeholders. The final report will detail all findings including primary, secondary and exploratory 
outcomes. The team will also prepare a manuscript for publication  
 

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11. ETHICAL AND LEGAL ISSUES 
11.1. 
Ethical and Legal Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation of this 
study, are designed to ensure that the Investigators abide by Good Clinical Practice (GCP) guidelines and 
under the guiding principles detailed in the Declaration of Helsinki.  The study will also be carried out in 
keeping with the applicable local laws and regulation(s). 
 
Documented approval from appropriate agencies (e.g. IRB) will be obtained before the start of the study, 
per GCP, local laws, regulations, and organizations.  
 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study conduct; 
the Investigators may not modify or alter the procedures described in this protocol. 
 
Modifications to the study protocol will not be implemented without consulting the Principal Investigator 
and the IRB, as applicable.  The Principal Investigator must assure that all study personnel, including co-
investigators and other study staff members, adhere to the study protocol and all applicable regulations and 
guidelines regarding research both during and after study completion. 
 
The Principal Investigator will be responsible for assuring that all the required data will be collected and 
properly documented. 
 
11.2 Confidentiality 
 
All records identifying the subject will be kept confidential and, to the extent permitted by the applicable 
laws and/or regulations, will not be made publicly available. 
 
11.3 Disclosure of Data 
 
The Principal Investigator, his or her associates and co-workers, and the appropriate regulatory agencies 
may use the information and data included in this protocol as necessary for the conduct of the study.  
Information contained in this study, and data and results from the study are confidential and may not be 
disclosed without the written permission of the Principal Investigator.  
 
12. RETENTION OF RECORDS 
Essential documentation including all IRB correspondence, will be retained for at least 2 years after the 
investigation is completed. Documentation will be readily available upon request. 
 
13. PUBLICATION POLICY 
The Principal Investigator or designee must send any draft manuscript, abstract, or conference presentation 
to members of the project Executive Committee for feedback and transparency, prior to submission of the 
final version. The Principal Investigator will be responsible for all relevant aspects regarding data reporting 
and publication.  

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The Principal Investigator or designee will ensure that the information and results regarding the study will 
be made publicly available on the internet at www.clinicaltrials.gov. 
 
 

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REFERENCES 
 
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Anderson, J. Greg Sanders, Jessica K. Nichols, Cindy C. Blackburn, Mark T. Dransfield. Results of a Medicare 
Bundled Payments for Care Improvement Initiative for Chronic Obstructive Pulmonary Disease Readmissions. 
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Tina Shah VGP, Megan Huisingh-Scheetz, Steven R. White. COPD Readmissions: Addressing COPD in 
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effects of clinical pathways on professional practice, patient outcomes, length of stay, and hospital costs: 
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Rutten-van Mölken, Niels H Chavannes. Cochrane corner: is integrated disease management for patients with 
COPD effective? Thorax 2014;69:1053-5. 
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Kris Vanhaecht WS, Jan Peers, Cathy Lodewijckx, Svin Deneckere, Fabrizio Leigheb, Marc Decramer, 
Massimiliano Panella. The impact of care pathways for exacerbation of Chronic Obstructive Pulmonary 
Disease: rationale and design of a cluster randomized controlled trial. Trials 2010;11. 
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C Lodewijckx WS, M Panella, S Deneckere, F Leigheb, M Decramer, K Vanhaecht. Impact of care 
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Echevarria C, Steer J, Heslop-Marshall K, et al. The PEARL score predicts 90-day readmission or death 
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Saimma Majothi KJ, Nicola R Heneghan, Malcolm J Price, Richard D Riley, Alice M Turner, Susan E 
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management for Patients with COPD Who Have Recently Been Discharged from Hospital: A Systematic 
Review and Meta-analysis. International Journal of Chronic Obstructive Pulmonary Disease 2015;10:853-67. 
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Marie Lavesen SL, Addie J. Frederiksen, Bjarne Ø. Lindhardt, Dorthe Overgaard. Nurse-initiated 
Telephone Follow-up on Patients with Chronic Obstructive Pulmonary Disease Improves Patient 
Empowerment, but Cannot Prevent Readmissions. Danish Medical Journal 2016;63:1-5. 
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Elena Titova ØS, Signe Berit Bentsen, Synnøve Sunde, Sigurd Steinshamn, Anne Hildur Henriksen. 
Does an Integrated Care Intervention for COPD Patients Have Long-Term Effects on Quality of Life and 
Patient Activation? A Prospective, Open, Controlled Single-Center Intervention Study. PLoS ONE 2017;12. 
12. 
Hemming K, Haines TP, Chilton PJ, Girling AJ, Lilford RJ. The stepped wedge cluster randomised trial: 
rationale, design, analysis, and reporting. BMJ : British Medical Journal 2015;350. 
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Sandra M Eldridge DA, Sally Kerry. Sample size for cluster randomized trials: effect of coefficient of 
variation of cluster size and analysis method. International Journal of Epidemiology 2006;35:1292-300. 
14. 
NCSS L. PASS 15. Kaysville, Utah, USA2017. 
 
 

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APPENDICES 
Appendix A: CHS COPD Clinical Pathway 
 
 
 
 

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