Increasing Adherence to Pulmonary Rehabilitation After COPD Related Hospitalizations
Phase: NA
Conditions: COPD Exacerbation
Sponsor: Mayo Clinic

 
 
Increasing Adherence to 
Pulmonary Rehabilitation after 
COPD related Hospitalizations 
 
NCT#03865329  
 
March 3, 2020 

  
 
 
 
 
 
 
 
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General Study Information 
 
Principal Investigator:       Roberto Benzo, MD 
 
 
 
 
 
 
 
 
Study Title:    Increasing Adherence to Pulmonary Rehabilitation after COPD related 
Hospitalizations 
 
Protocol version number and date: Version 4, March 3, 2020    
 
Research Question and Aims 
 
Hypothesis:  Pulmonary Rehabilitation (PR) is a critical part of chronic obstructive pulmonary disease (COPD) 
treatment, reducing breathlessness, increasing health-related quality of life (QOL), and decreasing healthcare 
utilization.  However, only a small portion of patients with COPD complete PR, mostly due to access issues or 
frailty. In this application we propose to test the effectiveness of a home-based PR program developed in our 
previous NIH awards that aims to improve program adherence, QOL, daily physical activity, and healthcare 
utilization. 
 
Aims, purpose, or objectives: Aim 1: To refine the current program of home PR (crafted through NIH grant 
R44HL11416/IRB 14-009016 for out patients) via a pilot test of subjects with COPD after a disease-related 
hospitalization and further refinement based on a qualitative feedback of patient caregivers and coaches by (a) 
completing a pilot study of 10-15 subjects and refining the home-based PR program developed in our previous 
applications to be used in subject with COPD after a hospitalization; and (b) analyzing the experience of 
subjects, caregivers, and coaches through a formal qualitative study and refining the intervention in year 1. The 
refined home-based PR program will be tested in a well-powered phase 2 randomized, clinical trial of 150 
patients that will be started in the R61 period and finalized in the R33 period. 
Aim 2: To start a phase 2 randomized, clinical trial (recruit 30/150) testing the feasibility and study accrual of 
a refined home-based PR delivered after a COPD related hospitalization compared to a control group of patients 
referred to conventional PR (center-based) in year 2. 
 
Background: Despite proven benefits, the proportion of people with COPD who receive Pulmonary 
Rehabilitation (PR) is very small. The current model of a center-based PR program fails to address the needs of 
many patients with COPD. The most common patient barrier to attendance is travel to center-based programs, 
particularly for frail patients with more severe COPD who need transportation assistance. Home-based, 
unsupervised PR has been proposed as an alternative model to hospital-based programs and has been found to 
be safe and effective. In particular PR post-hospitalization has been reported as the most effective intervention 
to prevent a hospital readmission; however, the reality is that many times this is not a feasible intervention as 
only 4% of eligible individuals are able to adhere to PR after a hospital admission (for multiple reasons).While 
COPD is responsible for nearly 700,000 hospitalizations annually, many of these hospitalizations, which 
account for a large proportion of the annual direct medical costs of COPD, are potentially preventable 
readmissions. 
Study Design and Methods 
 
Methods: 

  
 
 
 
 
 
 
 
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 Figure 1 
 
Phase 1 (R61):  A cohort of 10-15 patients will be recruited after a COPD-related hospitalization (COPD 
exacerbation or pneumonia) to use the home PR program system plus telephonic coaching for twelve weeks, 
and provide feedback through a qualitative study to refine the PR program system to be acceptable for the post-
hospitalization period. Patients will be recruited until themes saturation (no more new feedback from patients).  
 
We will use a natural language processing program to query the electronic medical records of Mayo Clinic 
Rochester to identify all patients presenting with COPD-related illness.  In addition we will screen the patients 
admitted to the Chest Service (Domitilla 6B) of Saint Mary’s Hospital.  The study coordinator will receive the 
list of participants (with research authorization already processed through the natural language program) and 
will meet the patient in the hospital before they are discharged.  
 
 During the consent process, the patient will have the opportunity to try the proposed home-based PR system in 
the hospital room, aiding in their confidence in their ability to use the system and the ease of the exercises. The 
study team will provide a step by step demonstration of the exercises (following the exercises on the computer 
tablet).  The participant will be asked to rate their confidence to use the technology presented and their 
confidence (self-efficacy) to perform the home rehabilitation routine on a scale from 0 (no confidence) to 10 

  
 
 
 
 
 
 
 
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(great confidence). A rating of five or greater will be deemed an acceptable confidence level to participate in the 
study.   
Each participant will be asked to define a particular place and time they can perform the home-based PR. The 
physical and mental environment is critical for the successful adoption of new behavior (PR). Participants will 
learn about the weekly calls with the coach to discuss their rehabilitation and monitored measures (steps, level 
of shortness of breath, well-being, and fatigue). They will then go over the daily answers to well-being 
questions (mood, breathlessness, and energy, as tested in the pilot study and shown in Fig.2; see participant 
software application section below). After performing the PR routine (to ensure safety and understanding) and 
reviewing the use of the monitors, a plan for a PR coach call, a week to 10 days after discharge. The participant 
will use the criterion activity monitor (Actigraph, Fig. 3) that will determine the baseline physical activity 
during the first week immediately after discharge to define a baseline physical activity. The coordinator will 
discuss the in-home activities with the participant to identify possible exercise-related fall hazards in the home 
environment. 
 
               
      
 
Figure 2                                                                                           Figure 3             Figure 4 
 
Participants are expected to engage in the home-based PR at least six days a week. The Garmin Vívofit™ 
activity monitor (Fig. 4) is to be worn at all times (battery lasts one year) to capture daily steps and the 
metabolic equivalent of tasks (METs) per day. The PR routine begins with a slow breathing awareness exercise, 
“pursed lips breathing,” followed by upper-extremity exercises (Fig. 2), then two walks (in the home or outside) 
for 6 minutes, and finishing with another slow and mindful pursed-lips breathing exercise. The exercise 
protocol lasts about 20 minutes, which is the amount of daily dedicated exercise time associated with a risk 
reduction in hospitalization and improved QOL22,23 and is recommended by current PR guidelines.13 The 
proposed protocol is also currently being used by the PI of this proposal in a prospective COPD trial (R01 
CA163293) in addition to the work cited in the preliminary data (R44 HL114162). The PR coach will contact 
by phone or mail the primary care, or referring, provider before initiating the PR program to introduce the 
provider to the study, as well as to coordinate and develop a strategy in case of a COPD exacerbation (a 
common cause of PR abandonment).  
The proposed home-based PR system (Fig.1) consists of three commercial devices and two software 
applications. The devices are a Garmin Vívofit™ (AM), a Nonin 3150 WristOx2® Pulse Oximeter (PO), and a 
7” 
Android™ tablet with 3G/4G cellular service (Verizon). The AM and PO wirelessly communicate with the 
tablet 

  
 
 
 
 
 
 
 
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via Bluetooth. During the upper extremity exercise routine and walks, the PO measures the participants’ heart 
rate (HR) and oxygen saturation (SpO2). Near the end of the day, the tablets periodically sound a musical alarm 
and display a short health status questionnaire (Fig. 2) asking participants to rate their well-being,24 ease of 
breathing, and energy level. At night, the tablets securely transmit the device data and well-being questionnaire 
answers to a remote Web server, which securely stores the data and generates reports. Health coaches call the 
participants weekly to discuss their progress in PR and SM (see below). 
Participant software application (tablet): When the participant turns on the Android™ tablet, the application 
logs in, and the participant accesses to the main screen (Fig. 5). To initiate one of these activities, the user 
selects the corresponding action from the “To-Do” column. Selecting “Exercise” from the “To-Do” column 
initiates a video guiding the user through the PR exercises (Fig. 6). Similarly, selecting “Walk” from the “To-
Do” column starts a 6-minute countdown once the application detects that the participant has initiated 
walking. Before displaying the exercise and walking videos the application verifies that the participant is 
wearing the AM and PO to assure measure and compliance (during exercise an increase in heart rate is 
expected). When the participant finishes the selected activity, it appears in the “Done” column. The application 
provides instructions before and between each activity. Patients are asked to follow the videos in all PR sessions 
to maintain a minimal and equal “dose” of PR for all participants. The oximeter data during exercise is used as a 
measure of adherence and exercise time. 
      
 
Figure 5 
 
 
 
 
 
     Figure 6 
 
 
 
The “my journey” screen (Fig.7) plots historical data, allowing participants to see trends as in the pilot study. 
 

  
 
 
 
 
 
 
 
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Figure 7 
 
From this screen, users can view daily steps, average heart rate, SpO2, and questionnaire answers. The user also 
can select the historical window (e.g., last week, last month, last quarter). 
 
 
 
 
 
 
 
Coaching PR Calls (weeks 1-12) content for PR 
feedback plus SM: After the hospital and consenting visit, coaching calls will occur weekly for  twelve weeks 
following this protocol: (1) Listen to the participant’s journey. (2) Provide feedback of the PR process at home 
based on the feedback from the coach application. Sessions will generate dialogue by listening to “change 
participant’s comments on anticipated activities. (3) If problems arise, resist the urge to attempt to solve the 
participant’s problems and barriers. (4) Listen carefully and kindly (ambivalence from the participant in 
changing their behavior). (5) Discuss how behaviors connect to the participant’s values and strengths. (6) 
Collaborate in setting goal(s) for the following week. A goal can be anything the patient wants to discuss even 
beyond PR (like smoking cessation, vaccinations, weight loss, etc.) (7) Discuss the process of action planning: 
elicit the participant’s preferences. (8) Elicit the participant’s choice; do not assign goals, and use the 
participant’s language to describe the goal. (9) Assess confidence for goal completion, reaffirm commitment to 
the action plan, and express optimism. (10) Thank the participant and plan the next call. 
(11) All calls will be recorded to ensure fidelity and compliance with the protocol and MI principles (10% of 
all calls will be reviewed). 
Health Coach Software Application: The health coach software application provides three types of reports. 
The overview report (Fig. 8) allows health coaches to succinctly ascertain the status of their participants and 
flag anyone who may be experiencing problems. The health coach may select a participant 
from the overview to display the trend report (Fig. 9). The trend report allows the health coach to review the 
participant’s progress between weekly health coaching sessions.  Finally, the health coach may select a day 
from the trend report to display a detailed report (figure 10). 

  
 
 
 
 
 
 
 
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Figure 8 
 
 
 
 
 
 
Figure 9 
 
 
Figure 10 
 
 
While participant monitoring does not occur in real time, any significant physiologic abnormaility measured 
during rehabilitation and transmitted to the server (02 saturation less than 80% or heart reate grater than 140 or 
less than 40 beats per minute) prompts a message to the coach to call the particpant to investigate the event.  
The PI also is alerted within 24 hours by tet message if a physiologic abnormality is measured to ensure the 
appropratie response.  In R44HL114162-03 Home-Based Health Management of COPD Patients, the remote 
rehabilitation and health coaching system has been pilot tested together and found feasible, actionable,and 
acceptable.  After the pilot is completed, a qualitatitve study will be done to identify areas of deficits to be 
changed and then adapted for the the second phase of the study, a randomized control trial. 

  
 
 
 
 
 
 
 
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Phase 2 (R61):  Mayo Clinic Rochester and Jacksonville Fl will participate in this Phase.  Phase 2 will take part 
in year 2 of the study.  After the study has been refined in Phase 1, thirty (30) participants (of the planned 150 
subjects) will be recruited and randomized to one of two to the home-based PR or referred to conventional PR 
(standard of care).   After the 30 subjects are enrolled, the study staff will review the feasibility, informing the 
team about accrual and outcome completion rate (questionnaires and activity monitors).   This will allow the 
study team to forcast a complete and informative study for the R33.   
The particpants randomized to control/conventional care will be offered mileage reimbursement to and from a 
pulmonary rehab center.  The miliage rate used will be the current IRS standard rate (57.5 cents per mile in 
2020).  The study will pay mileage up to a total of $500.  Study staff will use MapQuest to determine the miles 
from participants residence to the rehab center.  The participants will be asked to sign an Authorization to 
Release Protected Health Information-Research in order to obtain Pulmonary Rehabiliation Records. Mileage 
will be paid monthly when possible, or when in reciept of the medical records confirming attendence.   
 
 
Phase 3 (R33): Mayo Clinic Rochester and Jacksonville Fl will participate in this Phase.   After review of the 
first 30 participants, the remaining 120 patients with a COPD-related hospitalization (exacerbation or 
pneumonia) will be randomzied at hospital discharge to the home-based PR or usual care (referral to 
conventional center-based PR).  Inclusion, exclusion criteria and recruitment will be identical to the Phase 1 and 
2 of the study. Randomization will be completed online through a centralized program Research Electronic Data 
Capture (REDCap).   
The participants randomized to home-based PR will follow the same procedures in the R61 phase, plus any 
changes suggested by the qualitative study.  Any changes will involve a protocol modification and submitted to 
the IRB for review. 
 
Questionnaires and Activity Monitor:  All participants will be asked to complete questionnaires and wear a 
small activity monitor (Actigraph) at Baseline and Months 3,6 and 12.   The participants will be supplied with 
postage paid envelopes to return the questionnaires and activity monitor.   
 
Questionnaires:  Questionnaires include the Medical Research Council (MRC), Chronic Respiratory 
Questionnaire (CRQ), EureoQol-5D (EQ5D), Patient Health Questionnaire- 9 question (PHQ9), General 
Anxiety Disorder – 2 question (GAD2), Interpersonal Support Evaluation List (ISEL),  Self-Management 
Ability Scale (SMAS30), Linear Analog Scale Assessment (LASA) , Meaning in Life Questionnaire (MIL) and 
the Working Alliance Inventory (WAI).  All questionnaires with the exception of the WAI will be administered 
at baseline and 3, 6 and 12 Month.  The WAI questionnaire will be administered when the participant has 
completed the Health Coaching Period.  For participants randomized to the Intervention arm, the WAI will be 
administered at 3 months.  Participants randomized to the Control/Wait arm will receive the WAI at 6 months. 
The Charlson Cormobidity Index (CCI) will be included in the baseline questionnaire packet.  The CCI will 
assist in summarizing the enrolled subjects in statistical models. 
 
The PHQ9 will be reviewed by study staff within 24 hours of receiving the questionnaire in the mail.  The study 
staff will score the PHQ9 and a total score >14 (15 and above) and Item 9 is a zero will prompt a review of 
medical records for current mental health treatment (in consultation or pharmaceutically) of depression.  If the 
patient is not being treated for mental health issues a licensed health care provider will contact the patient and 
offer a referral or other treatment suggestions.    If anything other than “not at all” on Item 9 “Thoughts that you 

  
 
 
 
 
 
 
 
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would be better off dead or of hurting yourself in some way? The participant will be called by a licensed health 
care provider. 
 
Health Care Utilization:  The Study Coordinator will contact all participants at Months 3,6 and 12 via telephone 
to determine health care utilization, the participants will be asked how many times they have gone to the 
doctor/Emergency Room/Hospital for breathing problems.  In addition, the particpants will be asked if they 
have taken antibiotics or prednisone for breathing related illnesses since the last time the Study Coordinator 
called them. 
 
Conventional PR group: Referral to Conventional PR (retention strategies) 
We plan to optimize the possibility of patients referred to conventional PR to attend by generating a dialogue 
about the importance of PR, facilitating the referral and then follow up with a call. This optimization initiative 
includes targeting the most prevalent problems that explain the current poor utilization of the traditional 
hospital-based PR after a hospitalization: (1) lack of a referral or strong recommendation from a physician (we 
plan to do a dedicated referral to the [patient indicating the nearest PR program and contact information 
including the proper referral order), and (2) inadequate follow-up or facilitation of enrollment after referral (we 
will communicate with the individuals two weeks after discharge to encourage PR program adherence). 
Finally, we acknowledge that many patients/caregivers will clearly express being unable to attend conventional 
PR and realize then that the control arm receive no active intervention. The latter is a significant problem in 
behavioral interventions that cannot be blinded. To palliate that problem and given that the project targets daily 
physical activity, we will provide every individual in the conventional PR group a Garmin Vivofit (Fig. 3), an 
activity monitor that has a large display and is easy to use so that they can monitor steps every day. We have 
ample experience on the use of this monitor in current pour proposal. This is the same monitor that individuals 
in the Home PR receive for daily use. The study does not cover standard of care treatment.  Home PR group: 
Proceedings will be as in the pilot study plus refinement (see R61, Phase 1 and 2). 
 
Recording of calls and qualitative interviews:  All health coaching calls and the qualitative interviews will be 
recorded.  The health coaching calls are recorded and the voice file saved on a secure research drive that only 
study team has access too.  The files are saved under the participants subject number and the week of the call.  
The calls are randomily selected to be reviewed by the PI Dr. Benzo and the Fidelity Officer, Dr. Matt Clark. 
Dr.’s Benzo and Clark will score the health coach using the MITI worksheet (attached, Appendix 1).  The 
voicefiles will be deleted off of the research drive at the end of the study. 
 
Resources:   
The Mindful Breathing Lab has a dedicated staff assigned to the PI, Dr. Benzo.  The Mindful Breathing Lab has 
space located on the 8th floor of Stabile and an exam room on Gonda 18 South.  Mayo Clinic Rochester will be 
part of all phases of the study. 
Margaret Johnson is Co-Investigator located in Jacksonville, FL.  Margaret Johnson is a Pulmonologist and has 
vast experience treating COPD patients. Dr. Johnson has a study coordinator dedicated to her COPD studies.  
Mayo Clinic Florida will take part in Phase 2 and Phase 3.  
 
 
 
Subject Information 
 

  
 
 
 
 
 
 
 
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Target accrual is the proposed total number of subjects to be included in this study at Mayo Clinic. A “Subject” 
may include medical records, images, or specimens generated at Mayo Clinic and/or received from external 
sources.    
 
Target accrual:  
Study 1 (R61):  15 participants 
Study 2 (R33):  150 participants 
 
 
Subject population (children, adults, groups):  Men and Woman 40 years of age or older, who have been 
hospitalized with a COPD related illness. 
 
Inclusion Criteria 
• COPD related hospitalization and eligible for PR 
• Age 40+ 
• Confidence (score > 5 in a self-efficacy question (1-10 scale): how confident you feel to use this system 
on a daily basis) 
 
Exclusion Criteria 
• Inability to walk (orthopedic-neurologic problems or confined to bed) 
 
 
Research Activity 
 
Check all that apply and complete the appropriate sections as instructed.  
  
1. 
  Drug & Device:  Drugs for which an investigational new drug application is not required. Device for 
which (i) an investigational device exemption application is not required; or the medical device is 
cleared/approved for marketing and being used in accordance with its cleared/approved labeling. (Specify in 
the Methods section) 
 
2. 
  Blood:  Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture.  
 
3. 
  Biological specimens other than blood:  Prospective collection of human biological specimens by 
noninvasive means that may include: urine, sweat, saliva, buccal scraping, oral/anal/vaginal swab, sputum, 
hair and nail clippings, etc. 
 
4. 
  Tests & Procedures:  Collection of data through noninvasive tests and procedures routinely employed 
in clinical practice that may include: MRI, surface EEG, echo, ultrasound, moderate exercise, muscular 
strength & flexibility testing, biometrics, cognition testing, eye exam, etc.  (Specify in the Methods section) 
 
5. 
  Data (medical record, images, or specimens):  Research involving use of existing and/or prospectively 
collected data. 
 

  
 
 
 
 
 
 
 
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6. 
  Digital Record:  Collection of electronic data from voice, video, digital, or image recording. (Specify in 
the Methods section) 
 
7. 
  Survey, Interview, Focus Group:  Research on individual or group characteristics or behavior, survey, 
interview, oral history, focus group, program evaluation, etc.  (Specify in the Methods section) 
 
Review of medical records, images, specimens – Category 5 
 
For review of existing data: provide a date range or an end date for when the data was generated. The end date 
can be the date this application was submitted to the IRB.  Example: 01/01/1999 to 12/31/2015 or all records 
through mm/dd/yyyy.  
Date Range: 
 
Check all that apply (data includes medical records, images, specimens).  
 
  (5a)  Only data that exists before the IRB submission date will be collected.   
 
 
  (5b)  The study involves data that exist at the time of IRB submission and data that will be generated after 
IRB submission. Include this activity in the Methods section.  
Examples 
• The study plans to conduct a retrospective chart review and ask subjects to complete a questionnaire.  
• The study plans to include subjects previously diagnosed with a specific disease and add newly 
diagnosed subjects in the future.  
 
  (5c)  The study will use data that have been collected under another IRB protocol. Include in the Methods 
section and enter the IRB number from which the research material will be obtained. When appropriate, note 
when subjects have provided consent for future use of their data and/or specimens as described in this protocol.  
 
Enter one IRB number per line, add more lines as needed 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 
  (5d)  This study will obtain data generated from other sources. Examples may include receiving data from 
participating sites or an external collaborator, accessing an external database or registry, etc.  Explain the source 
and how the data will be used in the Methods section.  
 
  (6)  Video audio recording: Describe the plan to maintain subject privacy and data confidentiality, 
transcription, store or destroy, etc.  
 

  
 
 
 
 
 
 
 
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Health Coaching calls are recorded for fidelity analysis.  Calls will be randomly selected and reviewed by the 
PI, Dr. Roberto Benzo and Motivational Interviewing expert, Dr. Matt Clark.  The calls are reviewed to ensure 
that the health coach is adhering to the principles of Motivational Interviewing and the protocol.  Feedback will 
be provided to the coach.  The recorded files are stored on a secure research drive within the Mayo firewall and 
only accessible by the study staff.  At the completion of the study and the final analysis, the files will be deleted.   
 
 
HIPAA Identifiers and Protected Health Information (PHI) 
 
Protected health information is medical data that can be linked to the subject directly or through a combination 
of indirect identifiers.  
 
Recording identifiers (including a code) during the conduct of the study allows you to return to the medical 
record or data source to delete duplicate subjects, check a missing or questionable entry, add new data points, 
etc. De-identified data is medical information that has been stripped of all HIPAA identifiers so that it cannot be 
linked back to the subject. De-identified data is rarely used in the conduct of a research study involving a chart 
review.   
 
Review the list of subject identifiers below and, if applicable, check the box next to each HIPAA identifier 
being recorded at the time of data collection or abstraction.  Identifiers apply to any subject enrolled in the 
study including Mayo Clinic staff, patients and their relatives and household members.  
 
Internal refers to the subject’s identifier that will be recorded at Mayo Clinic by the study staff. 
External refers to the subject’s identifier that will be shared outside of Mayo Clinic. 
 
Check all that apply: 
INTERNAL 
EXTERNAL 
Name 
x 
 
Mayo Clinic medical record or patient registration number, lab accession, 
specimen or radiologic image number  
x 
 
Subject ID, subject code or any other person-specific unique identifying 
number, characteristic or code that can link the subject to their medical data   
x 
 
Dates: All elements of dates [month, day, and year] directly related to an 
individual, their birth date, date of death, date of diagnosis, etc.   
Note: Recording a year only is not a unique identifier.  
x 
 
Social Security number 
 
 
Medical device identifiers and serial numbers 
 
 
Biometric identifiers, including finger and voice prints, full face photographic 
images and any comparable images 
x 
 
Web Universal Resource Locators (URLs), Internet Protocol (IP) address 
numbers, email address 
 
 
Street address, city, county, precinct, zip code, and their equivalent geocodes 
x 
 
Phone or fax numbers 
x 
 
Account, member, certificate or professional license numbers, health 
beneficiary numbers 
 
 

  
 
 
 
 
 
 
 
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Vehicle identifiers and serial numbers, including license plate numbers 
 
 
Check ‘None’ when none of the identifiers listed above will be recorded, 
maintained, or shared during the conduct of this study.  (exempt category 
4) 
 None 
 None 
 
 
Data Analysis 
 
 
Power analyses may not be appropriate if this is a feasibility or pilot study, but end-point analysis plans are 
always appropriate even if only exploratory. Provide all information requested below, or provide justification if 
not including all of the information.  
 
Power Statement:  The primary endpoint of this study will be the rate of adherence compared between the two 
groups. Secondary endpoints include rates of COPD related hospitalization or death, activity levels as measured 
by the average number of steps per day, and the CRQ scales of dyspnea, fatigue, emotional function, physical, 
mastery, and the total score. Differences between groups will be compared with Fisher’s exact tests for 
proportions and ttests for continuous endpoints. These analyses will be supplemented with logistic regression 
models and linear models to compare groups after adjusting for confounding factors. 
 
Data Analysis Plan: One hundred and forty-four patients will be entered on this study (72 per arm). After 
adjusting for multiple comparisons, this sample size will provide at least 80% power to detect a difference in the 
rates of adherence of  6% in the control group to 50% in the intervention group. This sample size will also 
provide at least 80% power for detecting a 50% reduction in hospitalization/death rates (from 50% in the 
control group at 6 months to 25% in the intervention group at 6 months), a difference of 1000 steps at 3 months 
(assuming a standard deviation [SD] of 2,000 steps), and a 0.5 difference in CRQ summary scores at 3 months 
(assuming an SD of 1.0). The sample size will be increased to 150 (75 per arm) to account for a 5% drop out 
rate. 
 
 
 
 
Statistical Analysis and Power 
The primary endpoint of this study will be the rate of adherence compared between the two groups. Secondary 
endpoints include rates of COPD related hospitalization or death, activity levels as measured by the average 
number of steps per day, and the CRQ scales of dyspnea, fatigue, emotional function, physical, mastery, and the 
total score. Differences between groups will be compared with Fisher’s exact tests for proportions and ttests 
for continuous endpoints. These analyses will be supplemented with logistic regression models and linear 
models to compare groups after adjusting for confounding factors. 
One hundred and forty-four patients will be entered on this study (72 per arm). After adjusting for multiple 
comparisons, this sample size will provide at least 80% power to detect a difference in the rates of adherence of  
26% in the control group to 50% in the intervention group. This sample size will also provide at least 80% 
power for detecting a 50% reduction in hospitalization/death rates (from 50% in the control group at 6  

  
 
 
 
 
 
 
 
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months to 25% in the intervention group at 6 months), a difference of 1000 steps at 3 months (assuming a  
standard deviation [SD] of 2,000 steps), and a 0.5 difference in CRQ summary scores at 3 months (assuming an 
SD of 1.0). The sample size will be increased to 150 (75 per arm) to account for a 5% drop out rate. 
Outcomes for the Phase 2 Randomized study 
Aim 3a: Adherence will be our primary outcome 
Overview: The reported adherence for PR after a hospitalization is 4% and in the best case scenario (free PR 
and free transportation like in the UK) is 10%. From our preliminary data, now in press (Respiratory Care), we 
found an adherence of >80% to the proposed system in outpatients with COPD. We hypothesize the adherence 
to a complete home-based PR program by post-hospitalized patients will be around 50%, and the adherence to 
the conventional hospital-based PR program to be 25% (due to our strong efforts to encourage people attend) 
will consider a complete PR when 75% of the expected PR visits are completed. We will compute the degree of 
completion of conventional PR from our electronic health record (EHR). The home-based PR compliance will 
be assessed by the entries of the PR coach in REDCap. 
Aim 3b: CRQ Physical and Emotional Summary scores post PR 
To determine the effect size of the home-based PR system with health coaching on physical and emotional 
QOL, we will analyze the CRQ physical and emotional summary scores. The CRQ Physical Summary score 
includes dyspnea (symptom #1 in COPD) and fatigue (symptom #2 in COPD) domains; the CRQ Emotion 
Summary score, includes the emotion (independent factor for admissions and poor quality of life) and mastery 
(self-management) domains of the CRQ.25 The CRQ is a 20-question inventory assessing the areas of dyspnea, 
fatigue, emotion, and feelings of mastery. The fatigue, emotion, and mastery subscales ask patients to rate how 
often in the last two weeks they have been afflicted with a particular feeling or experience on a scale of 1 to 7, 
with higher ratings indicating less symptom impairment. The CRQ has shown to be valid and has high internal 
consistency reliability.25 Test-retest reliability is adequate in all subscales, but is particularly high in the 
subscales of fatigue (r=0.90), emotion (r=0.93), and mastery (r=0.91).25 The minimal clinically important 
difference for this instrument of 0.5 points is universally recognized.13 The CRQ will be measured at baseline, 
and 3, and 6 months post-hospital discharge.  
Aim 3 c: Daily Physical activity post PR 
Physical activity is the strongest predictor of survival in COPD and is independently related to 
hospitalization.26,27 Physical activity will be measured by the ActiGraph™ wGT3X-BT activity monitor (Fig. 
8), which has been validated and used to assess physical activity in COPD populations.27-29 The ActiGraph 
activity monitor has tri-axial accelerometers and will be worn on the wrist for seven days at baseline and at 3, 
and 6 months post-hospital discharge at the pre-specified time points (Figure 17) and will measure steps and 
minutes spent in sedentary, light, and moderate activity.30,31 The main daily physical activity outcome is the 
number of daily steps (most common, generalizable and simple). Secondary, but important, measures to be 
analyzed are activity counts, minutes per day spent in daily physical activities of at least moderate intensity, and 
sedentary time (<2METs metabolic equivalents).32We will also measure sleep time and sleep efficiency with 
this monitor. 
Aim 3d: COPD-related hospital readmission (COPD exacerbation or pneumonia as discharge 
diagnosis) at one month, three months and six months. They will be assessed by the EHR and also by Care 
Utilization Calls (a safety measure in case individuals are rehospitalized outside the Mayo system). The calls 
will occur every three months (to avoid recall bias), will use a scripted protocol as in a previous application, and 
will be conducted by a coordinator blinded to the intervention. Emergency Department (ED) visits and 
hospitalizations (all cause) will also be recorded. 
Aim 4: CE analysis EuroQol Five Dimensions questionnaire 

  
 
 
 
 
 
 
 
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The EuroQol Five Dimensions questionnaire (EQ-5D) is a standardized instrument for measuring generic health 
status. The health status measured with EQ-5D is used for estimating preference weight for that health status, 
then, by combining the weight with time, a quality-adjusted life year (QALY) can be computed. QALYs gained 
its used as an outcome in the cost-utility analysis, which is a type of economic evaluation that compares the 
benefit and cost of healthcare programs or interventions. EQ-5D is one of the most commonly used generic 
health status measurements, and its good validity and reliability have been reported in various health conditions. 
It will be the tool to be used in the proposed cost-effectiveness analysis (CEA). 
Secondary Outcomes 
Self-Efficacy: The Mastery domain of the CRQ will be used to assess self-efficacy. The CRQ questions 
assessing self-efficacy are “In the last two weeks, how much of the time did you feel very confident and sure 
that you could deal with your illness?” and “How often during the last two weeks did you feel you had complete 
control of your breathing problems? 
Baseline Demographics and comorbidities: Baseline demographics to be collected include age, mMRC, 
FEV1, highest grade completed in school, marital status, gender, structural and functional social support,33 
race, steroid (prednisone) use in the three months before the study, comorbid conditions (Charlson 
Comorbidity Index), smoking status, and previous hospitalizations and ED visits. 
Analyses 
There are three distinct quantitative study hypotheses (inform different aspects of the process). 
Hypothesis 3a (Aim 3a) states that adherence will be higher in subject referred to home PR, will be tested with 
Fisher’s exact test supplemented with logistic regression adjusting for dyspnea MRC, age, social support, 
comorbidities, and FEV1. Exploratory analyses will be performed to examine how the number of rehab sessions 
impacts hospitalization/ED rates, CRQ dyspnea score, CRQ emotional score, and number of daily steps. 
Hypothesis 3b (Aim 3b): participants on home-based PR will have higher physical (dyspnea fatigue) and, higher 
emotional CRQ summary scores at month three than participants who were referred to conventional  
PR. Tested with t-tests supplemented with linear regression models adjusting for baseline scores and dyspnea 
MRC, age, social support, comorbidities and FEV1. 
Hypothesis 3 c (aim 3c): participants on home-based PR will have more daily PA than participants referred to 
conventional PR at month three. This will be measured by daily steps and minutes spent in sedentary, light, and 
moderate activity measured by the ActiGraph.30,31 This study has two activity monitors, the ActiGraph, a gold 
standard activity monitor used for outcome measures (7-day wearing) at baseline, 3, and 6 months; and the 
Garmin Vivofit PR activity monitor, which will be used daily, but will NOT be used as an outcome measure, 
rather for PR and health coaching and participant awareness of physical activity (participant will keep this 
activity monitor). Tested with Wilcoxon tests supplemented with linear regression models adjusting for baseline 
values and dyspnea MRC, age, social support, comorbidities and FEV1. 
Hypothesis 3d (Aim 3d): individuals in the home-based PR program will have lower readmissions and ER visits 
compared to individual referred to conventional PR. Tested with Fisher’s exact test supplemented with logistic 
regression models adjusted for hospitalizations in the previous year, age, dyspnea, and comorbidities. 
For the continuous study outcomes, changes from baseline to three months will be compared between the 
study arms using two-sample, two-sided t-tests with 5% type I error rates. Changes in QOL, number of steps, 
and length of stay will be compared between the two treatment sequences using two-sample two-sided t-tests. 
No adjustments will be made for multiple testing. Means, SDs, medians, ranges, and frequency distributions 
will be reported and plotted over time by study arm. Linear models will be used to assess the impact of  
treatment arm on three-month outcomes after adjusting for the corresponding baseline measure and other 
variables related to the outcome (age, degree of breathlessness at baseline using the mMRC dyspnea, and 

  
 
 
 
 
 
 
 
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FEV1). Repeated measures mixed models will be used to estimate the intervention effect over the 6 months of 
the study (this will measure trajectory and maintenance of benefits / behavior change). Intent-to-treat analyses 
will also be performed to determine the sensitivity of the results to dropouts and missing values. In the intent to- 
treat analyses, if a month three measure is missing for any reason, it will be described as not changing from 
baseline. Healthcare utilization (number of ED visits, hospitalizations, and length of stay) between baseline and 
three months will be treated (analyzed) as both binary (for incidence rates) and continuous (for the number of 
events). The binary endpoints will all be compared between groups using Fisher’s exact test. Logistic regression 
models will also be fit to look for differences in these outcomes by arm after adjusting for age, mMRC, FEV1, 
baseline levels of anxiety, depression, and fear, and baseline healthcare utilization, (before starting the study) 
particularly hospitalizations in the previous year. 
Descriptive summaries of the changes between baseline, three, six, and nine months will be used to assess the 
effect of the home based intervention on the control arm and the residual beneficial effect on the intervention 
arm. These results will be only descriptive and exploratory. No formal hypothesis testing will be done. All data 
will be stored in REDCap and analyzed using SAS (Cary, NC). 
Per-Protocol Analysis (Dose Response):We will conduct an exploratory analysis to assess the effect of dose of 
PR sessions on study outcomes. This analysis will control for potential confounders of dose. 
Assessment of Bias: Potential bias due to loss to follow-up will be assessed using a time to event analysis for 
the association of patient characteristics with time to dropout; results will be reported and used to evaluate the 
robustness of the study findings. We will also conduct sensitivity analyses in which missing data for dropouts 
are imputed under plausible missing-not-at-random assumptions. 
Missing data: A common affliction with randomized clinical trial field experiments is noncompliance with both 
treatment and missing study participation data. To estimate the overall treatment effect for the entire sample, an 
"intention to treat" analysis will be conducted, using our above likelihood-based analysis method for repeated 
measures, including data on all subjects who were randomized to the study group. This allows us to use all 
available data, rather than delete participants with missing values from the analysis of treatment effects.34  
Aim 4: Cost-Effectiveness Analysis 
This aims to estimate the value of implementing Home PR compared to subjects referred to conventional PR. 
The CEA, will estimate the ratio of the average change of cost per patient divided by the average change in 
QALYs per patient for health coaching compared to delivering standard care. QALYs will be based on the EQ- 
5D-3L35 using a preference-based value set derived from a sample of the US population. QALYs will be 
calculated by multiplying the utilities by a number of time participants spent in a particular health state. 
Transitions between health states will be linearly interpolated. The perspective for the CEA is that of the 
healthcare provider. 
For both arms, all resource utilization at the health centers for the one-year period following index 
hospitalization discharge will be collected. Estimated costs will be standardized using a bottom-up approach. 
Professional services defined by Current Procedure Terminology code will be valued using national 
reimbursement amounts from the Medicare fee schedules. Billed charges for hospital services will be valued 
using department specific cost-to-charge ratios based on the hospital’s annual Medicare cost report. All costs 
will be inflated to a common year using the Gross Domestic Product implicit price deflators. 
Multivariate regression models will be employed to control for differences between study groups. Due to the 
highly skewed nature of healthcare costs, a generalized linear model incorporating a gamma distribution and 
log-link function will be used. The cost-effectiveness of the home PR intervention will be determined using the 
threshold of $50,000/QALY. The 95% CI of the cost-effectiveness ratio will be calculated using nonparametric 
bootstrapping. 

  
 
 
 
 
 
 
 
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Healthcare utilization occurring at facilities outside of our network will not be captured. Sensitivity analysis of 
the cost-effectiveness will be performed based on residency status (local, regional, and distant). 
Limitations: We acknowledge that comparing to completed regular PR would be ideal, however, given that the 
completion rate post-hospitalization is so low, accruing for such a study would be unrealistic. We strongly 
believe that the proposed design truly represents “a real world” study and the result from it would be applicable 
to the practicing clinicians and regulatory agencies and payers to further support alternative ways of PR (if our 
hypothesis is confirmed: increased adherence, decreased readmission and patients’ critical outcomes like 
daily physical activity and quality of living).We will put a dedicated effort to motivate individual to attend 
conventional PR if they are randomized to arm. 
We will not know if the improvement in adherence is because of the home-based PR or health coaching. 
However, given that, only 4% complete conventional PR after a hospitalization, a meaningful improvement in 
adherence would not require much effort from the patients the home-based PR program. 
 
R61 milestones (two years) 
Year 1 
1. Finalization of the protocol and the informed consent document 
2. Development of the manual of operations and case report forms 
3. Establishment of a Data and Safety Monitoring Board 
4. Institutional Review Board approval of the trial 
5. Pilot cohort of 10-15 patients to refine the intervention already developed for outpatients 
6. Qualitative study and application of the necessary changes to the proposed Home PR 
Year 2 
Begin enrollment into the clinical trial to allow for an evaluation by the end of the R61 phase of early 
enrollment and the probability of completing the trial on time and budget. Target for year two will be to 
recruit 30 of 150 subjects planned for the whole study. 
R33 milestones 
Meeting the projected recruitment for all study participants, including women and minorities (50 subjects per 
year). 
1. Year 3 – 80/151 subjects recruited, 
2. Year 4 – 130/151 subject recruited; 
3. Year 5 – 151 of 151 subjects recruited, Database lock and analysis, Submission of the primary manuscript(s) 
to peer-reviewed scientific journal(s) and dissemination of results including the submission of study results to 
ClinicalTrials.gov within 12 months of the primary completion date. 
4. All years milestones – Report of monitoring protocol implementation and collection of data related 
to primary and secondary endpoints and adverse events. 
 
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