The Trajectory of Physical Activity Following Pulmonary Rehabilitation
Conditions: COPD, Pulmonary Disease, Chronic Obstructive
Sponsor: Trinity Health Of New England

The Trajectory of Change in Physical 
Activity Following Pulmonary 
Rehabilitation 
NCT02399254 
Protocol & SAP 
SAINT FRANCIS HOSPITAL & MEDICAL CENTER 
 
January 7, 2015 
Authored by: Richard ZuWallack, MD 

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The Trajectory of Physical Activity Following Pulmonary 
Rehabilitation 
 
Principal Investigator for Gaylord Hospital:   Lorraine Trow, MD, Critical Care / 
Pulmonology 
 
Study Coordinator at Gaylord Hospital:  Jessa Ciola, RRT 
 
Principal Investigator for the 5-Center Consortium:  Richard ZuWallack, MD, St. 
Francis Hospital, Hartford, CT, University of CT School of Medicine, Farmington, 
CT 
 
Centers participating in this research study:   St Francis Hospital, Gaylord Hospital, 
Providence VA Hospital, West Haven VA Hospital, Beth Israel Hospital (NYC) 
 
Background and rationale 
Physical activity in COPD patients is reduced, (1) and this inactivity is associated 
with poor outcome, including increased health care utilization and mortality. (2-5) 
Bronchodilators, considered a first line therapy of COPD, have documented effectiveness 
in physiologic function, symptom relief, and exercise capacity enhancement, but 
apparently do not consistently increase in physical activity.  Even pulmonary 
rehabilitation exercise training, with remarkable effectiveness in increasing exercise 
capacity, does not consistently increase physical activity.(6, 7)  There are probably 
multiple reasons behind this apparent lack of efficacy, but two important ones are a poor 
signal-to-noise ratio in accelerometers (used to measure activity) and real problems 
translating increases in physiologic function (such as increased FEV1 or six minute walk 
distance) into increases in physical activity.  Both of the above are major areas of interest 
that need to be addressed to improve our care of COPD. 
This study will follow physical activity following pulmonary rehabilitation 
longitudinally over 48 weeks.  We will use a state-of-the-art accelerometer, the DynaPort 
(https://www.mcroberts.nl/products/movemonitor), to analyze minutes walking per day 

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as the primary outcome, rather than vector magnitude units (VMU) or estimated steps per 
day.  The DynaPort device was rated favorably by PROactive COPD 
(http://www.proactivecopd.com) which tested accelerometers.  Additionally, there is too 
much variability in VMU, and estimated steps per day in slow moving COPD patients are 
inaccurate. Minutes per day of walking activity appears to be a more useful outcome.  
Walking activity from the DynaPort has been demonstrated to be very responsive to 
exercise training in lung transplant patients. (8)  Finally, more information is needed to 
determine the factors that influence the translation of exercise capacity gains realized in 
the rehabilitation center into increased  physical activity in the home and community 
settings. One editorial commented that it takes 3 months to train the muscles and 6 
months to train the brain.(9) We will explore potential factors influencing this important 
outcome, including baseline activity levels, demographic variables, changes in exercise 
capacity, psychological variables, and self-efficacy scores. Finally, we will evaluate the 
rate of change (trajectory) in physical activity over approximately six months after the 
pulmonary rehabilitation intervention. There are limited data suggesting it takes time for 
the translation of increased exercise capacity into increased physical activity to occur. 
(10) If our study corroborates these findings, it would potentially influence our 
therapeutic approach to the physically inactive COPD patient.  
Design: 
This will be predominately a hypothesis-generating study.  Its general design is 
that of a longitudinal study (without a control group) evaluating directly-measured 
physical activity in COPD patients who had participated in pulmonary rehabilitation.  
Activity measurements will be at baseline (before exercise training is started), and at 
approximately 12, 24, 36, and 48 weeks (+/- 3 weeks at each time period) following 
pulmonary rehabilitation.  There will be no direct change, per protocol, in the patient’s 
pharmacological treatment for COPD (controller or rescue inhaler medication) or other 
medical problems; this treatment will be directed by the patient’s health care provider.     
Three distinct types of analysis will be performed:   
1. Evaluation of changes in physical activity before and after pulmonary 
rehabilitation 

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2. Predictors of baseline physical activity 
3. Predictors of change in physical activity following pulmonary rehabilitation.  
This will be an intent-to-treat analysis, providing patients complete 50% or more of the 
pulmonary rehabilitation sessions.  Those dropping out with less than 50% attendance 
will be dropped from the study. 
Dealing with Exacerbations:  It is anticipated that patients will have COPD exacerbations 
over the course of the study.  Since exacerbations themselves affect physical activity, 
activity testing will be postponed for 2 weeks following the clinical end of the 
exacerbation.   We have determined that physical activity returns to close to baseline by 
two weeks after the exacerbation (Ehsan et al, A Longitudinal Study Evaluating the 
Effect of Exacerbations on Physical Activity in Patients with Chronic Obstructive 
Pulmonary Disease. Annals of American Thoracic Society 2013; 10(6):559-64).  If two 
exacerbations occur within the same time block, testing for that period will not be 
performed, and the last observation will be carried forward.  If a patient is hospitalized 
for an exacerbation, that patient will be dropped from the study. 
 
Comment:  We will not be altering the pharmacological management of the patient; this 
study will focus only on the pulmonary rehabilitation component and specifically how it 
affects physical activity.  It is currently almost impossible to carry out a randomized, 
controlled trial of pulmonary rehabilitation, since the intervention is considered a gold 
standard of therapy.  The within-group analysis without a control group would be feasible 
and would not raise ethical issues.  While this approach (without a control group) limits 
the strength of conclusions, the primary intent of this analysis is to explore the rate of 
change in physical activity with pulmonary rehabilitation (realizing that it probably takes 
longer to improve than exercise capacity) and predictors of response to the intervention.  
Hypotheses to be tested: 
Changes in activity following pulmonary rehabiliation 
1. 
Compared with baseline, COPD patients participating in outpatient pulmonary 
rehabilitation will show an increase in directly-measured physical activity 

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(minutes per day of walking activity from the DynaPort) at the 12 ± 3 week 
assessment. (primary hypothesis) 
2. 
Compared with baseline, COPD patients participating in outpatient pulmonary 
rehabilitation will show increases in upright activity, activity intensity, steps per 
day, minutes with METs > 2 (from the DynaPort) after 24 ± 3, 36 ± 3  and 48 ± 3 
weeks 
3. 
Exploratory:  We will analyze the trajectory of physical activity over the 48 
weeks after initiating pulmonary rehabilitation.  
Predictors of baseline physical activity 
4. 
Exploratory: We will analyze predictors of baseline physical activity.  Baseline 
variables tested will include age, gender, body mass index (BMI), six minute walk 
distance, FEV1, self-efficacy (using the PRAISE questionnaire), motivation for 
exercise (using the BREQ-2 instrument, questionnaire), MRC dyspnea, health 
status (using the self-administered Chronic Respiratory Disease (CRQ) 
questionnaire, anxiety and depression (HADS questionnaire, appendix), sleep 
efficiency and awakenings (from DynaPort output), functional performance using 
the Timed Up and Go (TUG) test. 
Predictors of change in physical activity 
5. 
Exploratory:  We will be able to identify responders versus non-responders with 
respect to: 1) the change in activity at 12 weeks, and 2) the trajectory (over 48 
weeks) in these activity measurements; this will include the slopes of change in 
physical activity.  We will then relate baseline variables to responder status.  We 
cannot a priori determine a threshold for physical activity responder status; this 
will have to be done a posteriori when data are available.  We anticipate from the 
post-lung transplant study the responder threshold will be an increase in 10 
minutes walking time per day. Predictor variables are listed above. 
Study patients: 

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Inclusion criteria: 
1. Adults (≥ 40 years) with a primary clinical diagnosis of COPD 
2. A post-bronchodilator FEV1/FVC < 0.70 from spirometry performed within the 
preceding 12 months (no specific FEV1 percent-predicted requirement, although 
we anticipate the FEV1 will average around 45% of predicted, based on previous 
studies of pulmonary rehabilitation) 
3. The patient was referred to pulmonary rehabilitation 
4. The patient is clinically-stable:  no exacerbation in preceding 4 weeks 
5. Modified Medical Research Council (mMRC) dyspnea rating of at least 2 out of 
5. 
Exclusion criteria 
1. Disease severity or co-morbidity that would make the patient be at-risk for 
participation this study 
2. A significant movement disorder, such as hemiplegia, etc.  
3. Inability to read and comprehend the questionnaires, which will be in English 
4. A history of poor wound healing or chronic skin conditions that might predispose 
to local problems from wearing the DynaPort.  (The DynaPort can be worn 
outside a thin garment, such as a tee shirt, and is relatively thin, without 
protruding parts.  However, since the device may be worn overnight, and there is 
a remote risk of pressure problems, this exclusion criterion was added).   
Comments:  It is commonly accepted by pulmonary rehabilitation centers that symptoms 
and functional status limitation are important for referral, not simply FEV1 values.  The 
PI investigators at the various centers will make the clinical decisions as to whether a 
patient referred to that center has a principal diagnosis of COPD, is clinically stable 
(basing this decision on recent exacerbation history), and does not have co-morbidity or 
disease severity or a movement disorder that would make him/her inappropriate for the 
study.  This is the standard procedure of most rehabilitation centers. 

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Sample size estimates 
Sample size estimates are based on Langer et al. Am J Transpl 2012 and using 
http://www.biomath.info/power/ttest.htm.  Patients following lung transplantation were 
randomized to exercise training or standard care.  Walking activity (min/day) from 
baseline to 12 weeks increased from 36 ± 16 to 56 ± 24 in the treatment group.  
Assuming a treatment difference, in minutes, of 18 and a SD of 20 and a within-group 
analysis, an n of ~ 12 would have a power of 0.80 to show this difference.  We expect our 
improvement in walking time with rehabilitation in COPD patients will be less robust.  
Assuming an increase in activity (minutes per day of walking) of 10 minutes would 
require an n of 34 to give a power of 0.80, but an improvement of 8 minutes would 
require 52 patients.  Forty evaluable patients appears to be a reasonable number. 
Number of subjects:  Our goal will be to recruit 40 patients with evaluable data at 12 
weeks.  Assuming 10 dropouts during rehabilitation, we would need to recruit 50. 
Study period:   Recruitment over the 6 sites will be over 10 months (~ 40 weeks). Since 
study follow-up is for 48 weeks per patient, the study will last approximately 84 weeks 
from first patient in to last patient out. 
Activity measurement:  We will use the DynaPort MoveMonitor to assess:  sedentary 
activity, upright activity, walking activity, activity intensity, and steps per day. Activity 
will be measured for 7 consecutive days, 3 days (12 hours per day) minimum.  Patients 
will be asked to wear the devices 24 hours per day, if possible.  
Protocol synopsis:   
1. Patients with COPD entering pulmonary rehabilitation at the study sites will be 
recruited.  Each center will be under its own IRB authority. 
2. Rehabilitation will be given per usual pulmonary rehabilitation center protocol; 
there will be no specific changes in COPD medications, including long acting 
bronchodilators, short-acting bronchodilators, or inhaled corticosteroids.  As is 
typical with pulmonary rehabilitation, these medications will be managed by the 
patient’s health care provider.   

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3. Standardized, written post-rehabilitation home exercise recommendations will be 
given to all patients during rehabilitation and upon completion of the program.  
4. Baseline testing:   
a. Collect information on demographics, baseline testing (see below), list co-
morbidities  
b. First measurement of physical activity (before starting pulmonary 
rehabilitation exercise training), within 6 weeks of beginning pulmonary 
rehabilitation 
c. Outcomes testing 
5. Weeks from study entry: 12, 24, 36, 48: 
a. Timing:  ± 3 weeks, except for the 12 week visit, which will be after the 
end of formal pulmonary rehabilitation, and therefore may occur outside 
of this 3-week window (rationale:  to avoid measuring physical activity 
during pulmonary rehabilitation days) 
b. Evaluate for adverse events, list concurrent medications.   
c. Evaluation for Serious Adverse Events:  Evaluation for serious adverse 
events (SAE) will be made at each study visit if the patient is taking a 
Boehringer Ingelheim drug.  If an SAE is identified on a visit, regardless 
of causal relationship, it will be reported to Boehringer Ingelheim using 
the Serious Adverse Event Report (SAE) in Non Interventional Studies 
(NIS) template within 24 hours or the next business day.  The following 
will be the plan of action for SAE assessment and planning:   
i. Definitions of adverse events 
a. An adverse event (AE) is defined as any untoward 
medical occurrence, including an exacerbation of a 
pre-existing condition, in a patient in a clinical 
investigation who received a pharmaceutical 

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product. The event does not necessarily have to 
have a causal relationship with this treatment. 
b. A serious adverse event (SAE) is defined as any AE 
which results in death, is immediately life-
threatening, results in persistent or significant 
disability / incapacity, requires or prolongs patient 
hospitalisation, is a congenital anomaly / birth 
defect, or is to be deemed serious for any other 
reason if it is an important medical event when 
based upon appropriate medical judgement which 
may jeopardise the patient and may require medical 
or surgical intervention to prevent one of the other 
outcomes listed in the above definitions. 
2. Patients may be hospitalised for administrative or social 
reasons during the study (e.g. days on which infusion takes 
place, long distance from home to site,). These and other 
hospitalisations planned at the beginning of the study do 
not need to be reported as a SAE in case they have been 
reported at screening visit in the source data and have been 
performed as planned. 
ii. The intensity of the AE should be judged based on the following: 
 Mild: Awareness of sign(s) or symptom(s) which is/are easily 
tolerated 
 Moderate: Enough discomfort to cause interference with 
usual activity 
 Severe: Incapacitating or causing inability to work or to 
perform usual activities 
Causal relationship of adverse event:  Medical judgment should be used 
to determine the relationship, considering all relevant factors, including 

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pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant 
diseases and relevant history. Assessment of causal relationship should 
be recorded in the case report forms.  
iii. Yes:  There is a reasonable causal relationship between the 
investigational product administered and the AE.  
iv. No:  There is no reasonable causal relationship between the 
investigational product administered and the AE.  
Worsening of the underlying disease or other pre-existing conditions: 
Worsening of the underlying disease or of other pre-existing conditions 
will be recorded as an (S)AE in the (e)CRF. 
Changes in vital signs, ECG, physical examination, and laboratory test 
results:  Changes in vital signs, ECG, physical examination and 
laboratory test results will be recorded as an (S)AE in the (e)CRF , if 
they are judged clinically relevant by the investigator. 
Responsibilities for SAE reporting:  The Investigators shall report (i.e., 
from signing the informed consent onwards through the trial defined 
follow-up period)  all SAEs and non-serious AEs which are relevant for 
a reported SAE by fax or other secure method using BI SAE Form to 
the BI Unique Entry Point in accordance with timeline specified below. 
v. Within five (5) calendar days upon receipt of initial and follow-up 
SAEs containing at least one fatal or immediately life-threatening 
event;  
vi. Within ten (10) calendar days upon receipt of any other initial and 
follow-up SAEs.  
vii. BIPI Unique Entry Point:  
                                       Boehringer Ingelheim Pharmaceuticals, Inc.  
                                               900 Ridgebury Road Ridgefield, CT  
                                               Fax: 1-203-837-4329  
                                               E-mail: PV_global_casemanagement@boehringer-ingelheim.com 

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For each adverse event, the investigator will provide the onset date, end 
date, intensity, treatment required, outcome, seriousness, and action 
taken with the BI marketed drug. The investigator will determine the 
expectedness of the BI marketed drug to the AEs as defined in the 
Listed or BI Drug Information e.g. Investigator’s Brochure, Summary 
of Product Characteristics (SmPC) or Product Information (PI).  
d. Physical activity measurements, each over 7 days 
e. Outcomes testing 
f. Scripted exercise at home directions (except 48 week visit) 
6. Comments:  Three to 5 days of activity testing is considered adequate to capture a 
particular patient’s activity profile (ERS Statement on Physical Activity, 
submitted for publication).  We will accept a minimum of three days of activity 
measurement for each assessment.  Twelve hours per 24 hour day of activity 
assessment will be considered a day’s measurement.  Although we will ask 
patients to wear the devices day and night, we anticipate many will not wear them 
at night because of inconvenience.  Therefore, a requirement of 12 of a potential 
16 hours (75% wear-time) appears reasonable.  The DynaPort device has an 
algorithm that determines wear time.  If a missing observation occurs over the 
course of the 48-week study (such as from technical problems, two or more 
exacerbations in that time block, etc.), we will carry the last observation forward 
into that missing spot. 
Safety considerations:  Pulmonary rehabilitation will be performed per usual protocol by 
centers with considerable experience in providing this intervention.  The DynaPort device 
is registered with the FDA:  
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfrl/rl.cfm?rid=145003 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfrl/rl.cfm?lid=386697&lpcd=IKK 
We do not believe this has any significant risk associated with it.   Outcomes assessments 
are standard and will be performed in the pulmonary rehabilitation area by trained 
personnel.  

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Table: Measurements during study 
Week 
Visit 
Measurements 
0 
Baseline, 
Pre-Rehab 
Age, gender, BMI, concurrent medications, six minute walk 
distance, FEV1 (may use historical information if within 1 
year), self-efficacy (using the PRAISE questionnaire), 
motivation for exercise (using the BREQ-2 instrument), MRC 
dyspnea, CRQ health status, anxiety and depression (HADS 
questionnaire), sleep efficiency and awakenings (from 
DynaPort output), functional performance (Timed up and Go 
test, TUG), activity assessments from DynaPort 
12 ± 3 
(when 
patient 
has 
completed 
rehab) 
Post-Rehab 
Concurrent medications, six minute walk distance, self-
efficacy (PRAISE questionnaire), motivation for exercise 
(BREQ-2 instrument), MRC dyspnea,  CRQ health status, 
anxiety and depression (HADS), sleep efficiency and 
awakenings (DynaPort output), TUG, activity assessments 
from DynaPort, Scripted exercise at home directions 
24 ± 3 
Short-term 
Follow-up 
Concurrent medications, six minute walk distance, self-
efficacy (PRAISE questionnaire), motivation for exercise 
(BREQ-2 instrument), MRC dyspnea, CRQ health status, 
anxiety and depression (HADS), sleep efficiency and 
awakenings (DynaPort output), TUG, activity assessments 
from DynaPort, Scripted exercise at home directions 
36 ± 3 
Intermediate 
Follow-up 
Concurrent medications, six minute walk distance, self-
efficacy (PRAISE questionnaire), motivation for exercise 
(BREQ-2 instrument), MRC dyspnea, CRQ health status, 
anxiety and depression (HADS), sleep efficiency and 
awakenings (DynaPort output), TUG, activity assessment 
from DynaPort, Scripted exercise at home directions 
48 ± 3 
Late follow-
up 
Concurrent medications, six minute walk distance, self-
efficacy (PRAISE questionnaire), motivation for exercise 
(BREQ-2 instrument), MRC dyspnea, CRQ health status, 
anxiety and depression (HADS), sleep efficiency and 
awakenings (DynaPort output), TUG, activity assessment 
from DynaPort 
 

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Comment:  We fully anticipate the difficulties we will have in getting our study patients 
to return at the proper follow-up dates.  To help in this regard, we have incorporated a 6 
week window (± 3 weeks) at each time measurement.  Even this may not be adequate: if 
an exacerbation intervenes, the test date will have to be postponed.  Further, if patients 
cannot come in for that particular measurement (for instance, they may be away on 
vacation), we will allow the off-protocol data entry at the investigator’s discretion, and 
note it as a protocol violation.  Time points will have error-bars depicting the range of 
times patients came in for testing. 
Data analysis 
The primary variable to be assessed will be changes in daily walking activity (in 
minutes) from baseline to week 12.  The statistical approach for this will be a repeated 
measures analysis of variance using SAS. Covariates may be added, if necessary. We 
anticipate day of week variation (Sundays have less activity) and seasonal variation (less 
activity in winter).  This will be handled by including these variables as covariates in the 
analysis.  We will also analyze the 24 36 and 48 week endpoints compared to baseline 
this way.  Trajectory changes will be first analyzed by graphs relating activity (in 
minutes) at each data collection time.  We will also analyzed slopes of activity, it 
possible.  Responder non-responder analyses will be performed using logistic analysis 
with demographics and baseline disease characteristics as potential predictor variables.   
Factors Affecting Study Duration:   
1. Each patient will be followed for approximately 48 weeks from the beginning of 
pulmonary rehabilitation until the last testing day.   
2. St. Francis Hospital will be the first to seek IRB approval and begin patient 
recruitment. We anticipate IRB approval by approximately mid-February 2015 
and first patient entry shortly after that date. Each study site will be required to 
obtain local IRB approval; we anticipate final approval in all 6 centers within 4 
months of study initiation at St. Francis Hospital.  If St. Francis secures IRB 
approval and begins recruiting by February 15, 2015, the last site will begin 
recruiting by approximately June 15, 2015.   

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3. Each site will be expected to recruit 8-9 patients over 10 months. However, we 
anticipate total recruitment will be somewhat shorter than 10 months. Recruitment 
will be competitive, so patient numbers will probably not be identical across 
centers.  However, we will require four study patients, minimum, per center. 
4. Assuming that the last patient will be enrolled by October 15, 2015 (4 months 
after the last center has secured IRB approval), we should have a data lock and 
analysis by 48 weeks after that date. 
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