The NIH Exercise Therapy for Advanced Lung Disease Trials: Response and Adaptation to Aerobic Exercise in Patients With Interstitial Lung Disease
Phase: NA
Conditions: Interstitial Lung Disease, Idiopathic Pulmonary Fibrosis, Interstitial Pneumonitis, Desquamative Interstitial Pneumonia
Sponsor: National Institutes of Health Clinical Center (CC)

14.-CC-0027- Version 13
1
Leighton Chan 07.12.2021
CLINICAL RESEARCH PROJECT
Protocol #14-CC-0027
 
 
Date:
July 12, 2021
To:
General Medicine IRB1
Protocol Title:
The NIH Exercise Therapy for Advanced Lung Disease Trials:
Response and Adaptation to Aerobic Exercise in Patients with
Interstitial Lung Disease
Principal Investigator:  
Leighton Chan, MD, MPH (E) *
Chief, NIH Clinical Center, Rehabilitation Medicine Department
301.496.4733
chanle@cc.nih.gov
Building 10 Room 1-1469
Estimated Duration of Study: 36-60 Months
Estimated Completion Date of Study:  December 2021
Subjects of study:
Number
Sex
Age range
                                             
  
    60
M&F              
21-80 years
60 subjects with Interstitial Lung Disease without Pulmonary Hypertension.  Enrollment will remain open 
until 30 subjects in the Aerobic Exercise Training (AET) group and 30 subjects in the Control (CON) 
have completed the study. 
Project involves ionizing radiation?
No
Offsite project?                                                               Yes
Multi-Institutional project?
Yes, NIH (medical and research testing, and 
exercise and educational training), Inova Fairfax 
Hospital (exercise and educational training),
DSMB involvement?
No
Tech Transfer: CRADA, MTA
No
Identifying Words:  
Exercise, Interstitial Lung Disease, Pulmonary
                          
Rehabilitation

14.-CC-0027- Version 13
2
Leighton Chan 07.12.2021
Table of Contents
Précis………………………………………………………………………………. Page 06
Key Personnel……………………………………………………………………... Page 07
Background…………………………………………………………....................... Page 10
Preliminary Results………………………………………………………….  Page 13
Informational Gaps…………………………………………………………. Page 18
Research Objectives……………………………………………………………….. Page 18
Specific Aims……………………………………………………………………… Page 19
Study Design and Methodology………………………..………………………….. Page 20
Overview of the Research Paradigm………………………………………. Page 22
Methods……………………………………………………………….…… Page 23
Electrocardiogram………………………………………… Page 23        
Blood Draw………………………………………….…….. Page 23
Pregnancy Testing…………………………………………. Page 23
Echocardiogram…………………………………………… Page 23
Pulmonary Function Test………………………………….. Page 25
Six Minute Walk and Fatigability Tests…………………… Page 26
Treadmill Cardiopulmonary Exercise Test…….…………
Page 27
Pulmonary Gas Exchange………….……………………… Page 27
Heart Rate Measurements…………………………………. Page 28
Near Infrared Spectroscopy………………………………... Page 28
Bioelectrical Impedance Plethysmography…………………Page 28
Arterial Occlusion Muscle Oxygenation Capacity Test…… Page 28
Health Related Quality of Life Questionnaires……………. Page 29
Educational Sessions…………………………………….… Page 30
Exercise Training………………………………………….. Page 30
Participant Inclusion and Exclusion Criteria……………………………………… Page 31
Inclusion Criteria………………………………………………………….. Page 31
Exclusion Criteria ……………………………..………………………..... Page 32
Monitoring Subjects………………………………………………………………
Page 33
Unanticipated Problems, Adverse Events, and Protocol Deviation…………….....  Page 33
Study Analysis………   ………………………………………………………….
Page 34
Sample Size Calculations……………………………………………….............. Page 35
Human Subject Research Protections……………………………………………… Page 36
Subject Selection…………………………………………………………………….Page 36
Rationale……….……………………………………………………………………Page 36
Recruitment………………………………………………………………..... Page 37
Exclusions…………………………………………………………………… Page 39
Benefits and Risks/Discomforts…………………………………………….. Page 39

14.-CC-0027- Version 13
3
Leighton Chan 07.12.2021
Informed Consent…………….…………………………………………….. Page 41
Data Safety and Monitoring Plan…………………………………………………. Page 42
Conflicts of Interest………………………………………………………………..  Page 43
Subject Compensation……………………………………………………............
Page 43
Data Management Plan……………………………………………………………  Page 43
References………………………………………………………………………..
Page 44
List of Abbreviations……………………………………………………………..
Page 48

14.-CC-0027- Version 13
4
Leighton Chan 07.12.2021
Précis
We propose a randomized controlled trial (RCT) to determine the safety and efficacy of aerobic 
exercise for patients who have interstitial lung disease (ILD) uncomplicated by pulmonary 
hypertension. Aerobic exercise training (AET) based rehabilitation has become a standard of care 
for patients with pulmonary diseases such as COPD. In an uncontrolled study, we have observed 
more efficient cardiorespiratory function, increased physical work capacity, and improved health 
related quality of life (HRQoL), following AET, in patients who have ILD without pulmonary 
hypertension. We have also observed in a RCT, similar findings in patients who have pulmonary 
hypertension complicated by ILD of various etiologies. Serious adverse events resulting from AET 
were not observed in these studies. Our work to date has established plausibility for the efficacy 
of AET and its safety for patients with ILD. A RCT is now needed to determine the efficacy of 
AET as a medically prescribed and supervised intervention in patients who have ILD. Our research 
team is uniquely qualified to undertake this research and is one of the few teams possessing the 
experience and background necessary for contributing to this novel, understudied, yet critical field 
of rehabilitation research.   
Subjects will be over the age of 21 years and living within a reasonable travel distance from the 
greater Washington D.C. area.  All tests will be conducted at the NIH Clinical Center and subjects 
will receive AET or a control regimen of patient education at either Inova Fairfax Hospital or the 
NIH Clinical Center. The staffs at both sites are well experienced in providing exercise therapy for 
patients with ILD. 
There will be two primary treatment conditions. Patients with ILD will be randomized to either an 
intervention consisting of AET plus patient education (AET+) or a control condition that includes 
patient education only (CON).  AET will consist of a 10-week regimen of supervised treadmill 
walking three times a week.  The duration of the exercise sessions will progress from 30 minutes 
to 45 minutes per session over the 10 weeks as tolerated.  The intensity of the exercise will be 
between 70 and 80% of the patient’s heart rate reserve. Those randomized to control will not 
engage in AET. There will, however, be a secondary study: a crossover design in which subjects 
in the CON group will subsequently complete the AET regimen.  
The primary outcome measure for our trial will be 6-minute walk test distance (6MWD).  
Secondary outcome variables will include treadmill cardiorespiratory exercise test (tCPET) results 
with, pulmonary gas exchange, central circulatory function, and muscle oxygenation. A number 
of questionnaires will also be completed including: St. George’s Respiratory Questionnaire, 
Fatigue Severity Scale, SF-36v2 Health Survey, Human Activity Profile, Profile of Mood States, 
and King’s Brief Interstitial Lung Disease Health Status Questionnaire. All of this data will be 
obtained before and after the AET+ and CON regimens and in both of the secondary studies. 
AET is generally safe, inexpensive, and can easily be made available and accessible to almost 
everyone. It requires no approval by regulatory agencies and is thus available as a medically 
prescribed and supervised intervention almost immediately following confirmation of its safety 
and efficacy. Six-minute walk distance is associated with improved HRQoL in patients with ILD 
and in specific subsets. Effective use of AET as a rehabilitative intervention could have a high 
degree of impact on personal and public health outcomes in this advanced lung disease subset.

14.-CC-0027- Version 13
5
Leighton Chan 07.12.2021
Background
Interstitial lung disease (ILD) is the result of over 200 etiological pathways arising from several 
different insults to the lung parenchyma: inhaled substances, drug side effects, connective tissue 
disease, infection, and malignancy.1 The disease can also be of idiopathic origin. If prolonged, the 
resulting inflammation causes permanent and progressive fibrotic reorganization of the 
parenchyma and small airways, which reduces the distensibility of the lung and impedes O2 and 
CO2 exchange. 
In addition to diminished longevity, patients with ILD experience low physical work capacity 
(PWC).2  The distance walked on a 6-minute walk test (6MWT) is the most frequently used 
measure of PWC in patients with chronic lung diseases including both chronic obstructive 
pulmonary disease (COPD) and pulmonary hypertension (PH).  6MWT distance is almost always 
reduced in patients who have ILD due to significant exertional dyspnea or increased fatigability. 
Du Bois and associates3 reported that in the subset of patients who have idiopathic pulmonary 
fibrosis (IPF), a 26-meter reduction in 6MWT distance over a 24 week period predicted decreased 
survival at 1-year and a 24-week decline of 50-meters or more predicted a 4-fold increase in the 
risk of death at 1-year.  
Aerobic exercise training (AET) is well known to improve cardiorespiratory fitness and physical 
work capacity in the general population,4 including those who have illnesses that severely limit 
cardiorespiratory function.5  Benefits, including decreased mortality,6,7 have been documented in 
conditions such as coronary heart disease,8,9 cerebrovascular disease,10 peripheral vascular 
disease,11 COPD,12 diabetes mellitus,13 and kidney disease.14 There is also some evidence that AET 
may be beneficial for patients who have autoimmune, collagen vascular diseases15-17 in which ILD 
is often a secondary co-morbidity. However, despite its potential benefits, there are only a few 
small studies conducted, which examine the influence of AET in patients who have ILD. 
Four retrospective and three prospective studies have suggested that outpatient AET may increase 
6MWT distance,18-22 reduce exertional dyspnea,19,21-24 and improve overall HRQoL19-21,23,24 in 
patients with ILD. Two20,21 of the three prospective studies were small, randomized trials but only 
118 subjects were included in the interventional and control arms of all three of these studies 
combined. Similar findings were observed in a retrospective study of patients with ILD admitted 
for specialized inpatient AET rehabilitation25 and in a prospective study of outpatient AET in 
subjects referred for lung transplantation.26 
In our ongoing study of patients with PAH,5 patients were randomized to either a group receiving 
AET plus education (AET+) or education only (CON). We observed improved 6MWT distance 
and HRQoL following a 10-week, medically supervised, outpatient AET rehabilitation program.  
Significant improvements were not observed in the CON group over baseline. Many of these 
patients had PAH secondary to ILD.  We therefore initiated a parallel study in patients who have 
ILD without PAH. This study serves as preliminary work for the proposed RCT.
In this on-going preliminary study, we are using a prospective cohort design in which 
cardiorespiratory function, physical performance, and HRQoL comparisons are made for data 
obtained before and after 10 weeks of AET compared to base line.  Subjects are free of ischemic 
heart disease; cor pulmonale; dilated, hypertrophic or non-idiopathic cardiomyopathy, and had 
normal ejection fraction and pulmonary capillary wedge pressure. None of the subjects have 
hepatic or renal failure; metastatic cancer with a life expectancy less than 6 months; history of 
disabling stroke; any severe psychiatric condition; active tobacco or substance use; uncontrolled 

14.-CC-0027- Version 13
6
Leighton Chan 07.12.2021
diabetes mellitus; any form of mitochondrial disease; pregnancy; or antiretroviral therapy.  
Additionally, subjects’ medical regimens are required to be stable for at least three months prior 
to participation in the study.  Subjects in the study are sedentary and have not participated in a 
routine aerobic exercise or pulmonary rehabilitation program that includes aerobic exercise for at 
least six months prior to their enrollment. All subjects receive a physical examination by a 
Rehabilitation Medicine Department physician prior to enrollment to verify the medical 
appropriateness of their participation, meeting the inclusion criteria, and the absence of exclusion 
criteria.  The study is being carried out in the RMD and at Inova Fairfax Hospital Pulmonary 
Rehabilitation Center. . NIH  Institutional Review Board will be the relying IRB for both sites. 
(NIH: 08-CC-0133; Inova: 08.129;) will be obtained before any recruitment of subjects or other 
study activity occurs.   
At enrollment, blood samples are obtained and subjects undergo baseline research testing, which 
includes tCPET, 6MWT, muscle oxygenation tests, measurement of cardiac output and 
questionnaires to assess their perception of fatigue, daily physical activity, and general HRQoL. 
Subjects then participate in 10-weeks of AET with face to face supervision for each session in an 
outpatient pulmonary rehabilitation center. Following AET, all of the research tests and 
questionnaires completed at baseline are repeated, and post-AET values of the outcome variables 
are compared and assessed for significant differences. 
Cardiorespiratory function is measured by pulmonary gas analysis during tCPET to volitional 
exhaustion at baseline and after AET. Subjects whose arterial hemoglobin desaturates rapidly 
during tCPET are tested under a hyperoxic condition in which FIO2 is maintained at 40%. The 
principal pulmonary gas exchange measures include oxygen consumption (VO2) at volitional 
exhaustion, peak respiratory exchange ratio (RER), end tidal partial pressure of CO2 and O2 
(PETCO2 and PETO2), expired minute ventilation (Ve), tidal volume (Vt) and breathing frequency 
(ƒ).  We also use iterative methods of evaluating cardiorespiratory function including identification 
of the time taken to attain the anaerobic threshold (AT-time), time duration of tCPET to volitional 
exhaustion (tCPET-time), and determination of the time required to achieve one half of the peak 
VO2 (VO2-halftime). Heart rate is determined from continuous electrocardiography. Cardiac 
output (Qt) and stroke volume (Vs) are measured by bioimpedance cardiography.  Measures of 
muscle oxygen extraction capacity include peak arteriovenous O2 difference (a-vO2peak) and 
hemoglobin saturation indices obtained by continuous wave near infrared spectroscopy. 
Measures of PWC are peak work rate (WR) and 6MWT distance. Peak WR is calculated from 
treadmill speed and percent grade at peak exercise tCPET, and body weight. The 6MWT is 
performed on an 80-meter circular track according to the guidelines of the American Thoracic 
Society.27 
Several questionnaires are used to examine patient reported health-related quality of life, including 
the SF-36 Version 2 (SF-36v2), Profile of Mood State (POMS), Fatigue Severity Scale (FSS) and 
Human Activity Profile (HAP).  The SF-36v2 and POMS are multidimensional instruments that 
provide measures of fatigue severity and physical functioning in the overall context of health 
related quality of life. Specifically, fatigue severity is determined from the Vitality domain of the 
SF-36v2 and the Fatigue-Inertia scale from POMS, while physical activity is evaluated using the 
Physical Functioning domain of the SF-36v2 and the Vigor-Activity scales of POMS. One-
dimensional instruments, including the FSS and HAP, are also used to capture patient-reported 
fatigue severity and physical activity. 

14.-CC-0027- Version 13
7
Leighton Chan 07.12.2021
All subjects participate in an AET program comprised of treadmill walking for 30-45 minutes per 
session, 3 sessions per week, for 10 weeks.  A minimum of 24 out of the 30 possible AET sessions 
is required to maintain participation in the protocol.  Treadmill speed and grade are continuously 
adjusted to keep subjects’ heart rates as close as possible to a target zone corresponding to 70-80% 
of subjects’ heart rate reserves, determined from tCPET.  The target zone is determined using the 
method of Karvonen28 in which the resting heart rate is subtracted from the peak heart rate and 
multiplied by 0.70 and 0.80. Each of these fractions is then added to the resting heart rate to 
establish the target heart rate training zone.  At the beginning of each AET session, subjects 
participate in a 5-10 minute warm-up period where treadmill speed and inclination is gradually 
increased until subjects reach their target heart rate zone.  The session timer begins once the target 
heart rate zone is reached.  
Subjects unable to reach or sustain their training zones due to exertional dyspnea or lower 
extremity fatigue are allowed to exercise at symptom-limited intensities as needed. However, these 
subjects are instructed to increase their walking intensity to the prescribed heart rate training zone 
as soon as they were able.  In the event that subjects are unable to sustain exercise, even at a 
modified intensity, brief rest breaks are permitted as needed. However, the duration of the rest 
breaks is not allowed to exceed one half of the duration of the preceding exercise bout.  Upon 
returning from a rest break, the session timer does not resume until the subjects have once again 
attained their respective target heart rate zones.  All subjects requiring supplemental oxygen during 
training are given an adequate flow rate to keep subjects’ SpO2 ≥ 85%. 
Preliminary Results
Thirteen patients with ILD (Table 1) were studied. Participants had a variety of underlying causes 
of their ILD, but all were either New York Heart Association Functional Classification 
(NYHA)/WHO Functional Class II or III and 38% required supplemental O2. Overall attendance 
of the exercise sessions averaged 90% (Table 2). Five subjects spent less than 70% of the targeted 
30-45 minutes in their training heart rate zone, while 8 subjects spent 70% or more of the time in 
the zone (Table 2). No serious adverse events were reported during the aerobic exercise training 
intervention. No significant changes in subjects’ body weight (81.5 ± 16.4 vs. 81.1 ± 17.1 kg, p = 
0.200) or gastrocnemius skin fold (23 ± 11 vs. 21 ± 11 mm, p = 0.239) were observed during the 
study period.
Table 1. Baseline Characteristics of Study Patients
Characteristics
All Patients (n=13)
Age, mean (SD), years
57.0 (9.1)
Female, n (%)
9 (69)
Race/ethnicity, No. (%)
    White
11 (85)
    African American
2 (15)
BMI, mean (SD), kg/m2
28.6 (4.8)
Supplemental O2 Use, No. (%)
5 (38)
Diagnosis

14.-CC-0027- Version 13
8
Leighton Chan 07.12.2021
    Nonspecific interstitial pneumonitis
6 (46)
    Idiopathic pulmonary fibrosis
3 (23)
    Systemic sclerosis 
2 (15)
    Desquamative interstitial pneumonia
1 (8)
    Sjögren's syndrome 
1 (8)
NYHA/WHO Functional Classification, No. (%)
    Class II
6 (46)
    Class III
7 (54)
Pulmonary Function Test, mean (SD)
    Forced Vital Capacity (FVC), % predicted
52.9 (18.0)
    Forced Exhaled Volume in 1-s (FEV1), % predicted
57.0 (20.3)
    Ratio FEV1/FVC, % predicted
83.4 (3.6)
The overall cardiorespiratory response during tCPET was improved as evidenced by significant 
increases in AT-time and tCPET-time (Figure 1) after aerobic exercise training.  Physical work 
capacity increased significantly with a 12% increase (~ 52 meters) in 6MWD and 32% increase 
(39 watts) in peak work rate observed after training (Figure 1). Moreover, in the trained condition, 
work rate was higher at any given level of VO2 (Figure 2), than in the untrained condition, 
underscoring an increase in work efficiency.
Table 2. Aerobic Exercise Training Summary of Subjects Completing a Minimum of 24 Sessions
Subject
Total 
Sessions
Total Exercise 
Time (min)
Time in Training Zone 
(% of total exercise time)
Average 
HR 
(% HRR) 
Supplemental Oxygen 
Use (L/min)
1
25
943
97
72
-
2
30
1159
97
71
6
3
27
1065
44
68
6
4
26
1020
73
70
6-15
5
25
976
85
72
-
6
25
975
96
71
3-6
7
28
1074
68
70
10-15
8
25
975
44
68
2-4
9
27
1027
11
67
6-15
10
27
1065
89
71
-
11
29
1036
82
70
-
12
28
1095
92
72
3-5
13
26
1042
38
69
2-12
Mean 
27
1035
70
70
7
SD
1.6
59.0
27.7
1.7
1.5

14.-CC-0027- Version 13
9
Leighton Chan 07.12.2021
*
*
*
*
Figure 1  Test duration (tCPET), time to anaerobic threshold (AT-time), peak work rate (WR) and 6-minute walk test distance (6MWD) in the 
untrained (white bars) and trained (black bars) patients with ILD. tCPET was 163 ± 130 seconds (p = 0.001) and AT-time was 145 ± 15 seconds 
(p < 0.001) longer in the trained than in the untrained state.  Peak work rate was 43 ± 37 watts (p = 0.002) higher and 6MWD was 52 ± 48 meters 
(p = 0.001) farther in the trained versus the untrained state. Error bars equal one standard deviation unit.
Figure 2  Work rate-VO2 slope in the untrained (white circles) and trained (black squares) conditions. Regression equation was y=13.838x-
132.54; R2 = 08813 for the untrained condition (dotted line) and y=16.274x-151.86; R2=09343 for the trained (solid line) condition.  Slope was 
significantly higher (p=0.002) in the trained (14.89±4.94 than in the untrained (11.86±4.87) condition.  

14.-CC-0027- Version 13
10
Leighton Chan 07.12.2021
A statistically significant increase in peak VO2 was observed after training, but the increase was 
deemed to be too small to be clinically relevant.22,23,43-46  Resting HR and Qt were significantly 
reduced in the trained condition, however no other differences in resting cardiorespiratory function 
were observed (Table 3). While values for peak Qt, stroke volume, and heart rate were similar; a-
vO2 was 16% higher in the trained condition which was statistically significant. Additionally, the 
change in amplitudes for [deoxy-Hb/Mb] and [diff-Hb/Mb] were increased without a significant 
increase in [tot-Hb/Mb] amplitude after training (Figure 3); these findings suggested the 
improvement in muscle oxygenation was accomplished by an increase in cellular O2 extraction 
capacity rather than by increased O2 to the muscle cells. 
Table 3. Cardiorespiratory Measures 
Outcome Measures
Pre-training
Post-training
Difference
P value
Resting Values
     VO2, ml/kg/min
5.4 (2.4)
5.2 (2.3)
- 0.2
0.384
     VCO2, ml/kg/min
4.3 (1.3)
4.0 (1.6)
- 0.3
0.234
     ƒ, breaths/min
31 (8.4)
31 (9.5)
0
0.463
     Ve, l/min
15.3 (4.0)
14.7 (5.2)
- 0.6
0.323
     Vt, ml/min
2.1 (0.6)
2.3 (0.8)
+ 0.2
0.172
     RER
0.88 (0.21)
0.80 (0.23)
- 0.08
0.463
     a-vO2, vol%
6.1 (2.7)
6.6 (2.8)
+ 0.5
0.091
     PETO2, mmHg
154.8 (61.7)
149.4 (54.6)
- 5.4
0.197
     PETCO2, mmHg
38.0 (5.7)
38.9 (6.7)
+ 0.9
0.125
     HR, beats/min
103 (13.1)
95 (11.3)
- 8
0.024
     Vs, ml
72.0 (13.8)
67.9 (16.0)
- 4.1
0.136
     Qt, l/min
7.3 (1.7)
6.4 (1.6)
- 0.9
0.027
     HCT, %
40.5 (2.8)
40.7 (3.0)
+ 0.2
0.308
Peak Values
     VO2, ml/kg/min
17.4 (5.5)
18.2 (5.0)
+ 0.8
0.048
     VCO2, ml/kg/min
19.5 (4.7)
19.8 (4.7)
+ 0.3
0.293
     ƒ, breaths/min 
53 (11.0)
52 (9.3)
- 1
0.359
     Ve, l/min
55.1 (15.13)
54.0 (16.1)
- 1.1
0.192
     Vt, ml/min
1029 (361.2)
1055 (419.4)
+ 26
0.242
     RER
1.17 (0.23)
1.11 (0.17)
- 0.06
0.037
     a-vO2 difference, %
9.2 (2.2)
10.7 (2.9)
+ 1.5
0.049a
     PETO2, mmHg
160 (58.4)
158 6.1)
- 2
0.08a
     PETCO2, mmHg
41 (9.6)
43 (9.7)
+ 2
0.055
     HR, beats/min
148 (18.0)
144 (14.2)
- 4
0.086
     Vs, ml
105 (20.1)
99 (21.8)
- 6
0.179
     Qt, l/min
15.7 (3.8)
14.5 (4.0)
- 1.2
0.177
Abbreviations: tCPET, treadmill cardiopulmonary exercise test; VO2, minute oxygen consumption;  VCO2, 
minute carbon dioxide expiration;  ƒ, breathing frequency; Ve, minute ventilation; Vt, tidal volume; RER, 
respiratory exchange ratio; a-vO2, arteriovenous oxygen difference; PETO2, end-tidal partial pressure of 
oxygen; PETCO2, end-tidal partial pressure of carbon dioxide; HR, heart rate; Vs, stroke volume; Qt, cardiac 
output; HCT, hematocrit.
a Wilcoxon Signed Ranks Test

14.-CC-0027- Version 13
11
Leighton Chan 07.12.2021
Figure 3  Muscle oxygenation capacity in the untrained and trained conditions.  Bars represent concentration changes for oxygenated ([oxy-
Hb/Mb]), deoxygenated ([deoxy-Hb/Mb]), total ([Tot-Hb/Mb]) and difference (diff-Hb/Mb) in hemoglobin/myoglobin. White bars represent the 
untrained condition and black bars represent the trained condition.  [deoxy-Hb/Mb] (p = 0.037) and [diff-Hb/Mb] (p = 0.027) were significantly 
greater in the trained versus the untrained state.  Error bars represent one standard deviation unit.
Significant improvements were seen in 5 out of 8 subsections on the SF-36v2, specifically in the 
vitality and physical functioning domain, as well as the overall physical and mental component 
scores (Figure 4).  Specific improvements in the fatigue-inertia and vigor-activity domains of the 
Profile of Mood States, Fatigue Severity Scale scores, and the Average Activity Scale of the 
Human Activity Profile were also noted (Figure 4).
*
*

14.-CC-0027- Version 13
12
Leighton Chan 07.12.2021
Figure 4  Item and composite scores for the SF-36v2 (A), Fatigue severity Scale (FSS; B), Profile of Mood States (POMS; C) and Health 
Activity Profile (HAP; D).  The horizontal line in A and B represents the normative values. White bars represent values for the untrained 
condition and black bars represent values for the trained conditions.  Improvements in the trained versus untrained state were observed in overall 
physical and mental health (SF36v2), fatigue severity (FSS), mood states associated with fatigue-inertia and vigor-activity (POMS) and 
Maximum (MAS) and Average (AAS) Activity Scales of the HAP. Bars represent 1 standard deviation unit.
*Indicates a significant difference between untrained and trained conditions (p < 0.05).

14.-CC-0027- Version 13
13
Leighton Chan 07.12.2021
Informational Gaps
Outcomes of our preliminary study suggest the value of aerobic training for increasing 
cardiorespiratory capacity, diminishing fatigue severity, and improving the capacity for 
performing physical activities in patients with ILD.  Increased cardiorespiratory function appears 
to mediate improvements in PWC, fatigue severity, and physical activity. However the 
cardiorespiratory adaptation results are somewhat atypical. In many conditions, peak VO2 is 15-
20% higher after training.29 This occurs as a result of increases in both central circulatory O2 
delivery and peripheral O2 extraction.4  In our study of patients with ILD, peak VO2 increased only 
by 4.6% after AET despite a 16.3% increase in peak a-vO2. An increase in peak Qt was not 
observed. Resting right ventricular function was within normal ranges, Qt increased during 
exercise, and patients did not become symptomatic of congestive heart failure. Therefore the 
mechanisms limiting the improvement in peak VO2 were likely impaired pulmonary gas exchange 
and restricted lung function, which are hallmarks of the ILD clinical course.
The mechanistic link to improvement provides relatively strong evidence for a substantial benefit 
of AET.  However, some of the measurements, such as those made at volitional exhaustion, 6MWT 
distance and questionnaire responses could have been to some degree influenced by motivational 
factors and familiarity with the testing procedures. Therefore, a RCT is needed before the 
mechanistic and clinical effects of AET can be determined with confidence. We are proposing a 
small, phase 2 RCT to establish the safety and efficacy of AET in patients with ILD.
Research Objectives:
The objectives of the work proposed are, in patients who have ILD, to:
1. Determine the safety and tolerability of exercise training in patients with ILD to determine 
appropriate pulmonary rehabilitation exercise guidelines.
2. Examine responses and adaptations to exercise at quantifiable target intensities that 
correspond to energy expenditure requirements.
3. Understand changes in the symptom limited exercise test results, using training-specific 
testing modalities.
4. Examine the effects of exercise training on physical activity functioning.  
5. Determine the relationships between patient’s ability to achieve and maintain an aerobic 
steady state and to sustain physical activity.
6. Determine the effect of aerobic exercise training on psychosocial and behavioral 
functioning and other HRQOL components.
7. Based on the progression in training volume, delineate the time course of improvement in 
work capacity across an aerobic exercise training program.
8. Explore the relationships among measures of aerobic metabolic function and potential 
mechanistic factors that may limit oxidative metabolism.
9. Examine the relationships among indices of aerobic metabolic function and the 
mechanisms by which aerobic exercise training improves oxidative metabolism.
To accomplish these objectives, we will perform a RCT comparing a 10-week, interventional 
regimen of AET plus patient education (AET+) to a control condition of patient education only 
(CON) that does not include AET.  A secondary study will also be conducted using a single  
“crossover” design in which the patients randomized to the control arm of the main study will 
receive AET after they are finished the 10-week education only regimen. 

14.-CC-0027- Version 13
14
Leighton Chan 07.12.2021
Our Specific Aims are:   
1. “Determination of the Influence of AET+ on PWC in Patients with ILD”. 
Specific Hypothesis:  AET+ will improve measures of PWC, including our main outcome 
variable 6MWT distance, and peak WR, as well as performance and perceived fatigability 
over controls. 
“Sub-study On Crossover:” After completing the education-only regimen and 
subsequently completing the AET regimen, improvements similar to AET+ will be 
observed in 6MWT distance, peak WR, and fatigability.
2. “Characterization of the Cardiorespiratory Adaptation to AET in Patients with ILD.”
Specific Hypothesis: After AET+, significant increases in AT-time and muscle 
oxygenation will be observed over control. 
“Sub-study On Crossover:” After completing the education-only regimen and 
subsequently completing the AET regimen, improvements similar to AET+ will be 
observed in AT-time and muscle oxygenation capacity.
3. Determination of the Influence of AET on Patient-reported Measures of Fatigue, Physical 
Activity, and Other HRQoL Domains in Patients with ILD.”
Specific Hypothesis: After AET+, patients will report decreased fatigue severity measured 
by the Fatigue Severity Scale, increased physical activity measured by the Human Activity 
Profile, and improvement in other HRQoL domains measured by the St. Georges 
Respiratory Questionnaire and SF-36v2 over control.
“Sub-study On Crossover:” After completing the education-only regimen and 
subsequently completing the AET regimen, improvements similar to AET+ will be 
observed in fatigue severity, physical activity and other HRQoL domains.  
4. “One-year Follow Up on Hospitalization, Lung transplant, and Mortality.”
This is a descriptive analysis to examine health outcomes of frequency, length and severity 
of hospitalizations, acceptance onto a lung transplant waiting list, and mortality occurring 
over the year after completion of the main study. 

14.-CC-0027- Version 13
15
Leighton Chan 07.12.2021
Study Design and Methods
Overview of the Research Paradigm
     ----------------------------------------------------------------------------------------------
Inclusion
Baseline Tests
Block Randomization
    Exercise +          Education
Education
only
Patient education and 
aerobic exercise 
training (AET+)
Patient education only and 
no aerobic exercise 
training (CON)
AET+ Finished
Repeat Tests
Control group (CON) crosses over to 
exercise training 
Patients originally assigned to the 
control group finished
Repeat Tests
1-year Follow-up 
Patients will be contacted monthly for 1 year following 
completion of exercise training to determine continued 
exercise habits, the amount of re-hospitalizations, 
acceptance to a lung transplant waiting list, and 
mortality rate.
1. Echocardiogram 
2. Pulmonary Function Test
3. Health Related Quality of Life  
     Questionnaires
-
SGRQ
-
FSS
-
HAP
-
SF36V2
-
POMS
-
K-BILD
4.  Six Minute Walk Test
5.  Arterial Occlusion Muscle  
      Oxygenation Capacity Test
6.  tCPET  
-
Pulmonary Gas 
Exchange Analysis
-
Heart Rate Measurement
-
Near Infrared 
Spectroscopy
-
Bioelectrical Impendence 
Plethysmography 
 *Pregnancy test for applicable 
patients

14.-CC-0027- Version 13
16
Leighton Chan 07.12.2021
To qualify for participation, subjects will undergo physical evaluation by a credentialed member 
of the Rehabilitation Medicine Department’s medical staff to determine if they meet the inclusion 
and exclusion criteria.  At this time, subjects must answer “no” to the question “do you currently 
participate, or within the past six months have you regularly participated, in a structured exercise 
program greater than 30 minutes a day for 3 or more days a week.”  Subjects answering “no” to 
this question, and meeting other inclusion/exclusion criteria will then undergo an EKG and 
Doppler echocardiography to rule out pulmonary hypertension and right and left ventricular 
dysfunction. In addition, they will have pulmonary function testing with DLCO to rule out COPD 
and to assess lung diffusion capacity. Subjects will also undergo a blood draw for two tests:  Nt 
ProBNP and Complete Blood Cell Count with Differential.  Qualified participants will then receive 
the baseline research test battery, which includes 6MWT, tCPET with cardiac output and muscle 
oxygenation measurements, and questionnaires to measure patient-reported fatigue severity, 
physical activity, and other HRQoL domains. 
After completion of the baseline research test battery, subjects will be randomized to one of two 
groups. The randomization design will be a 2x2 block randomization in which subjects will be 
randomized in pairs.  The first subject will be assigned to either a control group that receives 10-
weeks of patient education lectures (1 day per week, 1 hour each lecture) with no AET or an 
intervention group participating in AET, 3 days per week for 10 weeks, in addition to the 
educational lectures (AET+). The second subject of the pair will be assigned to the opposite group. 
After completion of the AET+ or control regimens, subjects will undergo the follow up research 
test battery.  The follow up battery consists of echocardiogram, pulmonary function test, arterial 
occlusion muscle oxygenation test, 6MWT, tCPET, and questionnaires identical to those included 
in the battery at baseline. Subjects in the control group will subsequently participate in a 10-week 
AET regimen identical to AET+ except without the educational lectures, since participation in the 
lectures was completed as the control condition. A second identical, follow up test battery will be 
completed by this group after the crossover AET regimen is completed. After completion of their 
AET+, subjects will be contacted monthly with regard to continued exercise habits, the frequency, 
length, and severity of hospitalizations, or acceptance to a lung transplant waiting list. Mortality 
will also be assessed at this time.
Specific Aim 1:  “Determination of the Influence of AET+ on PWC in Patients with ILD”. 
The main outcome variable for this project is 6MWT distance, which is the most frequently used 
measured of physical performance for evaluating patients with ILD and other advanced lung 
diseases. A minimal clinically important difference (MCID) for 6MWT distance has been 
determined to be approximately 30 meters in ILD 2. Additional measures of PWC used in this study 
are peak WR on the tCPET, and performance and perceived fatigability as measured by a 
modification of the method used by Schnelle and coworkers in an older cohort. We will measure 
all 4 of these variables at baseline and after the AET+ and control regimens, as well as after the 
crossover regimen. We hypothesize that:
1.1.  An increase in 6MWT distance of at least 30 meters longer than control will be observed 
after AET+.
1.2.  A significant increase in peak WR will be observed after AET+ compared to control.
1.3.  A significant decrease in performance fatigability will be observed after AET+ compared 
to control.
1.4.  A significant decrease in perceived fatigability will be observed after AET+ compared to 
control.

14.-CC-0027- Version 13
17
Leighton Chan 07.12.2021
1.5  In the Sub-study on Crossover we hypothesize that AET will result in improvements over 
baseline in all of the variables of interest including 6MWT, peak WR, and performance and 
perceived fatigability that are similar to AET+.
Specific Aim 2:  “Characterization of the Cardiorespiratory Adaptation to AET in Patients with 
ILD.”  Measures of cardiorespiratory capacity are often influenced by subjective factors such as 
motivation and confidence. Our measures of cardiorespiratory capacity in this project are AT-time, 
and muscle oxygenation capacity. Neither of these physiological measures is influenced by 
subjective factors. We will measure AT-time during tCPET and muscle oxygenation by arterial 
occlusion testing at baseline and after the AET+ and control regimens. We will also measure Qt, 
peak VO2, PETO2 and PETCO2 during tCPETs at baseline and after the AET+ and control 
regimens. We will measure all of the variables again after the group initially completing the control 
regimen completes the crossover AET regime. We hypothesize:
2.1.  After the AET+ regimen, AT-time will be significantly prolonged over controls.
2.2   After AET+, a significant increase in muscle oxygenation capacity will be observed over 
controls.
2.3   Qt, peak VO2, PETCO2 and PETO2 will remain unchanged following both AET+ and 
control regimens.
2.4  In the Sub-study on Crossover we hypothesize that AET will result in improvements over 
baseline in all of the variables of interest including AT-time and muscle oxygenation that 
are similar to AET+.  We also hypothesize that Qt, peak VO2, PETO2 a PETCO2 will 
remain unchanged over baseline after AET.
Specific Aim 3:  “Determination of the Influence of AET on Patient-reported Measures of Fatigue, 
Physical Activity, and Other HRQoL Domains in Patients with ILD.” We will use the Fatigue 
Severity Scale (FSS) to assess fatigue severity, Human Activity Profile (HAP) to assess 
participation in physical activities, SF-36v2 to assess general HRQoL, Profile of Mood States 
(POMS) to assess changes in mood, and Kings Brief Interstitial Lung Disease Health Status 
Questionnaire (K-BILD) to assess HRQoL specific to ILD.  We will also use the St. Georges 
Respiratory questionnaire to assess HRQoL specific to IPF. Subjects will answer the 
questionnaires before and after the AET+ and control regimens. Subjects in the group receiving 
the control regimen will again answer the questionnaires after completing the crossover AET 
regimen.  We hypothesize 
3.1. After AET+, fatigue severity will be diminished over control.
3.2. After AET+, participation in physical activity will be increased over control.
3.3. After AET+, overall mood will be increased over control.
3.4  After AET, general HRQoL and HRQoL specific to ILD and IPF will all be improved over 
control.
3.5 In the Sub-study on Crossover we hypothesize that AET will result in improvements over 
baseline in all of the variables of interest including fatigue severity, physical activity, mood 
state, and HRQoL that are similar to AET+.
Specific Aim 4:  “One-year Follow Up on Hospitalization, Lung transplant, and Mortality.” In this 
follow up sub-study, patients will be contacted monthly for one year after completing AET+ 
regarding frequency and type of exercise subjects have continued; number and nature of 
hospitalizations; days spent in the hospital; and the severity of their condition causing 
hospitalization. Subjects’ acceptance onto transplants lists and patient mortality will also be 
determined. We will examine potential associations among these variables and our variables of 
interest to determine plausibility of relationships between study outcomes and clinical endpoints. 

14.-CC-0027- Version 13
18
Leighton Chan 07.12.2021
Two corollary hypotheses will be examined: i) poor clinical outcomes are associated with the 
severity of cardiorespiratory impairment, and ii) AET-induced improvements in these outcomes 
are associated with improvements in cardiorespiratory capacity 
Methods
Medical Tests:  
The following tests will be performed to determine a subject’s eligibility for this study: 
Electrocardiogram:  All subjects will be screened for signs/symptoms of coronary artery disease, 
cardiomyopathy, or any other underlying cardiovascular diseases that may increase the subject’s 
risk of performing an exercise based intervention by screening all patients with a 12 lead 
electrocardiogram (EKG).  This will be performed in the National Institutes of Health 
Electrocardiography Laboratory prior to the subject’s inclusion in the study.  Subjects will be 
required to lay supine on an examination table while 10 electrodes are placed on the subject’s chest 
and then connected to an electrocardiogram by an EKG technician.  A cardiologist will interpret 
all electrocardiograms prior to the performance of any exercise testing.
Blood Draw:  Patients will undergo a blood draw in the National Institutes of Health Phlebotomy 
Laboratory or the Department of Rehabilitation Medicine.  Two tests will be run with 
approximately 4 tablespoons of blood taken via a standard blood draw technique.  1) Nt ProBNP: 
N-terminal pro b-type natriuretic peptide assays will be performed before and after the intervention 
period to objectively monitor for potential myocardial damage.  Recent data suggests that high 
levels of NT-proBNP indicate acute heart failure.  As studies have not yet demonstrated the safety 
of exercise in patients with ILD, this assay may be informative.  This test is used as a standard of 
care in many emergency departments when patients exhibit symptoms of heart failure such as 
shortness of breath and fatigue. 2) Complete Blood Count with Differential:  Using the same 
sample of blood we will perform a test to separate the red blood cells, white blood cells and 
platelets from the plasma which will help us learn more about the oxygen carrying capacity the 
blood.   3) Glucose (diabetic subjects only):  4 mL of blood may be drawn to validate the accuracy 
of subject’s glucometer to be used before and after NIH testing and training sessions. 
Pregnancy Testing:  Female patients of childbearing potential will undergo urine dip stick 
pregnancy testing at the National Institutes of Health Phlebotomy Laboratory during baseline 
testing following blood draw.  Follow-up pregnancy tests will be performed at subsequent testing 
visits to the National Institutes of Health.  In order for a patient to be enrolled or continue with this 
study, this test must be negative.  
Echocardiogram:  Cardiac echo is required for this protocol.  Subjects must be without a pulmonary 
hypertension (PH) diagnosis and have an estimated left ventricular ejection fraction (LVEF) of 
≥50%.  To evaluate both of these measures, all subjects will be required to undergo a Doppler 
echocardiogram prior to inclusion in the study.  This may be performed at the National Institutes 
of Health Echocardiogram Laboratory.  A transducer placed on the subject’s chest will allow us to 
measure the subject’s right ventricular size/thickness and systolic pressure.  1) PH causes a 
retrograde flow of blood from the pulmonary arteries into the right ventricle which, when chronic, 
results in ventricular remodeling, increasing the size and thickness of the myocardium, thus 
increasing the chronic RV systolic pressure.  To determine the probability of pulmonary 

14.-CC-0027- Version 13
19
Leighton Chan 07.12.2021
hypertension we will use the guidelines as presented in the 2015 ESC/ERS guidelines for the 
diagnosis and treatment of pulmonary hypertension.  These guidelines suggest using tricuspid 
regurgitation velocity (TRV) at rest and the presence of additional pre-specified echocardiographic 
variables suggestive of PH.  The probability of PH may then be judged as low, intermediate, or 
high (Table A).  Echocardiographic ‘PH signs’ used in addition to criteria based on TRV provide 
an assessment of the RV size and pressure overload, the pattern of blood flow velocity out of the 
RV, the diameter of the PA and an estimate of RAP (Table B).   Based on echocardiogram 
interpretation, the patient will be admitted to the study if the probability of pulmonary hypertension 
is low or intermediate 57.
Table A
Peak tricuspid 
regurgitation velocity (m/s)
Presence of other echo ‘PH 
signs’*
Echocardiographic probability 
of pulmonary hypertension
≤2.8 or not measurable
No
Low
≤2.8 or not measurable
2.9-3.4
Yes
No
Intermediate
2.9-3.4
>3.4
Yes
Not required
High
Table B
A.  The ventricles a
B. Pulmonary artery
C:  Interior vena cava and right 
atrium
Right ventricle/left ventricle 
basal diameter ratio > 1.0
Right ventricular outflow 
Doppler acceleration time 
<105 msec and/or midsystolic 
notching
Inferior cava diameter >21 mm with 
decreased inspiratory collapse (<50% 
with a sniff or <20% with quiet 
inspiration)
Flattening of the 
interventricular septum (left 
ventricular eccentricity index 
>1.1 in systole and/or 
diastole)
Early diastolic pulmonary 
regurgitation velocity >2.2 
m/sec
Right atrial area (end-systole) >18 
cm²
PA diameter >25 mm.
a.
Echocardiographic signs from at least two different categories (A/B/C) from the list should 
be present to alter the level of echocardiographic probability of pulmonary hypertension.
 

14.-CC-0027- Version 13
20
Leighton Chan 07.12.2021
2)  LVEF will be estimated through echocardiogram volumetric measurements of the left ventricle.  
Placing the transducer over the subject’s left ventricle allows for the measurement of the chamber’s 
size in end -systolic and end-diastolic states thus giving an estimation of LVEF by comparing the 
difference in size.  Subjects in this protocol will be required to have an estimated LVEF of ≥50%, 
because a decreased LVEF will increase the risk of exercise testing/training in this study 
population.  Additional follow-up echocardiograms will be performed following completion of the 
exercise training for the AET group and following both the education phase and exercise training 
phase for the ED-only group. 
Pulmonary Function Test:  Forced Vital Capacity (FVC), Maximal Voluntary Ventilation (MVV), 
and Diffusion Capacity (DLCO) tests will be assessed for all subjects.  These tests will be 
performed at the National Institutes of Health Pulmonary Function Laboratory prior to inclusion 
in the study.  FVC is used to evaluate the degree of obstructive and restrictive lung disease.  MVV 
is used to evaluate the subject’s ventilatory limitation.  Both tests will be obtained while the subject 
is at rest.  We will determine whether subjects’ exercise capacity is limited by ventilation by 
computing the ratio between expired minute ventilation (Ve) measured at maximum exercise and 
MVV (Ve / MVV must be 0.90 or greater).  To perform the FVC and the MVV test the subject 
will be instructed to stand, plug their nose with their free hand (or wear a nose clip) and create an 
airtight seal over the mouth piece.  For the FVC, the subject will be asked to take in three regular 
breathes, followed by a deep inhalation and a quick and complete exhalation, blowing air until 
there is nothing left to expire.  This test will be performed 2-3 times.  Completion of the test will 
be when two test results are within 5% of each other.  For the MVV, the subject will be asked to 
breathe in and out normally three times followed by breathing in and out rapidly (90-100 
breaths·minˉ¹) for 12-15 seconds.  The teeth and tongue must refrain from blocking air flow.  ILD 
results in a decreased ability for the interstitial lung tissue to exchange gases across the respiratory 
membrane wall.  Therefore, a DLCO test is used to determine the lungs’ ability to exchange gases 
across this respiratory membrane wall.  Using a mouthpiece and nose clip, the subject will be 
required to inhale air containing a small amount of carbon monoxide and then exhale rapidly for 
10 seconds.  Exhaled air is then measured to determine the amount of carbon monoxide that was 
absorbed by the lung tissue and as such determine the subject’s diffusion capacity.  Additional 
follow-up pulmonary function tests will be performed following completion of the exercise 
training for the AET group and following both the education phase and exercise training phase for 
the control group.

14.-CC-0027- Version 13
21
Leighton Chan 07.12.2021
Research Tests
Once the inclusion and exclusion criteria have been satisfied, the enrolled subject will undergo 
the following tests: 
Six-minute Walk (6MWT) and Fatigability Tests:  Subjects will rest in a seated position for a 
minimum of 30 minutes during which they complete the 
study questionnaires prior to beginning the 6MWT.  Resting 
blood pressure, pulse rate, and oxygen saturation will then be 
recorded in the seated position.  The subject will then be 
asked to stand and instructed to walk as far as possible around 
a pre-measured walking course over a time period of six 
minutes. Oxygen saturation and pulse rate will be measured 
throughout the test using a portable pulse oximeter.  Oxygen 
saturation, pulse rate, rating of perceived dyspnea, rating of 
perceived exertion will be recorded upon completion of each 
lap of the walking course. Distance covered will be recorded 
at 1.5 minutes and the end of 6 minutes. The 
Fatigue/Fatigability Scale30 will be completed before the test 
begins and immediately after. Immediately upon completion 
of the six minutes the subject will be asked to stop and immediate post-exercise pulse rate and 
oxygen saturation will be recorded.  The subject will then be asked to rest in a seated position and 
pulse rate will be recorded during each minute of recovery for a total of ten minutes to evaluate 
the subject’s ability to recover from intense activity.  Supplemental oxygen will be provided for 
those patients that require supplemental oxygen while exercising and/or resting.  Those subjects 
requiring supplemental oxygen will be provided supplemental oxygen with the same delivery 
device and flow pre/post intervention to maintain consistency.  The target endpoint for this test is 
the completion of the six minutes of walking however symptomatic endpoints for stopping the 
tests will be those recommended by the American College of Sports Medicine.  Additionally 
should any subject’s oxygen saturation desaturate to ≤80% the patient will be required to stop 
walking at this point with or without the presence of symptoms of severe dyspnea. The patient will 
rest, while the timer continues to run, until oxygen saturation returns to baseline values or above 
90% at which point the patient will resume walking again.  The main outcome variable for this 
project is the change in 6MWT distance from before to after the AET+ and control regimens.  The 
performance fatigability index will be calculated as the ratio of the 1.5-minute walking speed to 
the walking speed calculated over the entire 6 minutes of the test divided by the total distance 
covered on the test. The perceived fatigability index will be calculated by having the subject rating 
their feeling of tiredness prior to the 6MWT and measuring the change in tiredness after the 
6MWT.  The change in tiredness divided by the total distance walked will be computed as the 
perceived fatigability index.30 
Blood glucose of diabetic patients will be monitored before and after testing, and as clinical 
necessary.  Testing will be performed by qualified staff using NIH glucometer or patient’s own 
glucometer.  In order to use patient’s own glucometer, it must first be validated for accuracy 
through the NIH Department of Laboratory Medicine.  

14.-CC-0027- Version 13
22
Leighton Chan 07.12.2021
Treadmill Cardiopulmonary Exercise Test (tCPET):  Subjects will complete a tCPET using the 
standard modification of the Naughton protocol for individuals with low oxidative capacity.31-33  
The 6MWT and tCPET are separated between morning and afternoon testing to allow patients 
adequate rest following the completion of the 6MWT so that fatigue will not skew the tCPET data. 
This protocol was selected because it provides two additional work stages with small increments 
in intensity at the beginning of the test to ensure an adequate number of data points can be obtained 
for interpretation of the results, while minimizing the potential for bias due to early fatigue that 
could result from large increases in work rate.  These tests will be performed on a computerized 
treadmill allowing programmed adjustment of both speed and inclination components of the work 
rate.  The treadmill was chosen as the method of testing because it is well known to evoke higher 
values of VO2 at maximal exercise, compared to other standard methods, and we are well 
experienced in treadmill testing in this patient subset.  Treadmill walking is also task specific to 
the exercise training protocol and similar to the 6MWT.  Supplemental oxygen will be provided 
through a Rudolph valve using a Douglas reservoir bag and high flow regulator for those patients 
that require supplemental oxygen while exercising and/or resting.  Those subjects requiring 
supplemental oxygen will be provided supplemental oxygen with the same delivery device and 
flow pre/post intervention to maintain consistency.  
Primary data obtained from the symptom limited treadmill exercise tests includes VO2 from 
pulmonary gas exchange analysis, heart rate (HR) from EKG, cardiac output from bioelectrical 
impedance cardiography (ZCG), and muscle oxygenation from near infrared spectroscopy (NIR). 
Additional supporting data will also be available from these devices.  Infrared pulse oximetry and 
blood pressure will also be monitored during the treadmill tests. Data from the pulmonary analysis 
system, EKG, ZCG, and NIR will be collected continuously throughout the tests.  This is a 
symptom-limited test in which the target stopping point is volitional exhaustion, defined as the 
subject’s expressed desire to stop despite strong encouragement from the testing staff.  Other 
symptomatic endpoints for stopping the tests will be those recommended by the American College 
of Sports Medicine.  Additionally should any subject’s oxygen saturation desaturate to ≤80% the 
test will be terminated at this point with or without the presence of symptoms of severe dyspnea.   
Blood glucose of diabetic patients will be monitored before and after testing, and as clinical 
necessary.  Testing will be performed by qualified staff using NIH glucometer or using patient’s 
own glucometer.  In order to use patient’s own glucometer, it must first be validated for accuracy 
through the NIH Department of Laboratory Medicine.  
Pulmonary Gas Exchange Analysis:  Pulmonary gas analyses will be performed using 
computerized system including rapid response oxygen and carbon dioxide analyzers, and a 
pneumotachometer interfaced with a microprocessor will be used for measurement of 
cardiorespiratory gas exchange. Subjects will interface the system using a mouthpiece or facemask 
that is connected to a plastic pneumotachometer.  A plastic tube connects the pnemotachometer to 
the gas analysis system. When using a mouthpiece, subjects will also wear a nose clip to prevent 
expired air from escaping through the nostrils.  Gas exchange variables measured during the tests 
will be measured continuously, on a breath-by-breath basis. Data reduction methods may utilize 
numbers bin or serial rolling averages.  The dependent variable of interest obtained from gas 
analyses is VO2. VO2 will be determined from the Haldane equation.  Volume of expired carbon 
dioxide (VCO2) will also be measured and used in the calculation RER, where RER = VCO2/VO2.  
Attainment of an RER of at least 1.10 is one of criteria indicating that oxidative metabolism is 
approaching a physiologically maximum level at volitional exhaustion34,35.

14.-CC-0027- Version 13
23
Leighton Chan 07.12.2021
Heart Rate Measurement:  Heart rate will be obtained from EKG recordings.  Electrodes will be 
placed on the subjects’ chests in the standard Mason-Likar exercise-testing configuration.  EKG 
will be monitored and recorded continuously throughout the maximum exercise test. 
Near Infrared Spectroscopy:  Muscle microcirculatory reactivity and muscle tissue oxygen 
extraction will be measured by spatially resolved near infrared spectroscopy (NIRS). Near Infrared 
(NIR) light is emitted into the muscle tissue at known distances from a sensor by a NIR emitting 
diode.  The amount of NIR light returning to a photo-sensing diode is measured and processed 
according to two wavelengths of the NIR spectrum, and the absorption and scattering coefficients 
of the medium are calculated. Oxygenated ([O2-Hb]) and de-oxygenated hemoglobin ([H-Hb]) 
concentrations are then determined as an interaction between their corresponding wavelengths and 
the amount of light that is collected by the NIR sensors.  These calculations are however influenced 
by oxygenated and deoxygenated myoglobin concentrations, which in this project may introduce 
some conservative bias.  In general, oxy and doxy hemoglobin and myoglobin dynamics tend to 
fluctuate in the same direction, often making the influence of myoglobin on the analysis 
superfluous.  Myoglobin concentration in muscle is small compared to hemoglobin and most 
accounts have indicated that the myoglobin signal accounts for less than 10% of the total NIR 
absorption, rendering its influence less confounding.  Spatially resolved measurements of total 
tissue hemoglobin, ([Tot-Hb], [O2-Hb] and [H-Hb] are absolute measures and desaturation rates 
are time constant based kinetic indices.  A single infrared transducer containing both infrared laser 
emitting diodes and frequency specific light sensors will be attached to the gastrocnemius muscle 
and worn by the subjects during the symptom limited treadmill exercise test.  The lasers are cool 
lights and will not be felt by the subjects.  Reports of burns or other tissue damage occurring with 
the use of these devices are not found. NIR measurements of muscle oxygenation will be made 
during tCPET as well as during an arterial occlusion test.  
Bioelectrical Impedance Plethysmography:  Measurements of cardiac output will be made using a 
bioelectrical impedance cardiograph (ZCG).  Silver/silver chloride electrodes are placed on the 
subjects’ chests at known distances and the electrocardiographically-gated rate of change in 
electrical conductance is measured. This produces a waveform that is the inverse of the pulse 
tracing obtained from Doppler ultrasound analyses.  The first derivative of the waveform is then 
used to estimate cardiac output.  This can occur because air in the lung provides no resistance to 
electrical current leaving impedance to vary only with changes in fluid volume.  Additional data 
accurately obtained by ZCG includes pre-ejection period, dz/dt, which is analogous to the dv/dt of 
the Doppler blood flow graph, the dz/dt second derivative, an index of cardiac inotropicity 
analogous to Doppler measured peak ascending aortic acceleration, and left ventricular ejection 
time.  Changes in total peripheral resistance can be determined when brachial artery blood pressure 
is measured (TPR= [1/3(SBP-DBP)+DBP]/cardiac output). 
Arterial Occlusion Muscle Oxygenation Capacity Test:  NIR light source and receiving sensors 
will be placed on the belly of the dominant gastrocnemius muscle to record muscle oxygen-
hemoglobin flux.  A blood pressure cuff will be placed around the distal hamstrings of the 
dominant leg. Using a Hokanson® rapid inflation vascular testing system, the cuff will be rapidly 
inflated to a pressure that totally occludes blood flow into the gastrocnemius, typically between 60 
and 80 mmHg above systolic pressure. The occlusion will be maintained for up to 10 minutes and 
tissue saturation will be measured over the time course. The tissue saturation index will be 
calculated as STI= [O2-Hb] / Tot-Hb. The rate of decline in STI will be the main muscle tissue 
saturation measure.

14.-CC-0027- Version 13
24
Leighton Chan 07.12.2021
Health Related Quality of Life:  Overall, improvement in HRQOL is one of the primary goals of 
rehabilitation and a clear understanding of the relationships amongst HRQOL, exercise, and 
psychosocial health is essential in a clinical practice.  The proposed research addresses this 
information by using a battery of quantitative, objective and subjective measures to examine 
physical activity and a range of psychosocial and behavioral patient characteristics.  Below is a list 
of the self-report tools that will be utilized in the proposed research.  Associations among these 
and the measured physiological data will also be examined to determine on the effect of aerobic 
exercise training on psychosocial and behavioral functioning and other HRQOL components. The 
tools to be used include:
St. George’s Respiratory Questionnaire – Idiopathic Pulmonary Fibrosis Specific Version 
(SGRQ-I):  The SGRQ-I is an IPF specific version of the original SGRQ designed to measure 
and quantify health-related health status for patients with chronic airflow limitations.  It has 
been shown to correlate well with established measures of disability, disease level, and 
symptom level.36
Fatigue Severity Scale (FSS): The FSS can be used to monitor change in fatigue in response 
to therapeutic interventions. The Fatigue Severity Scale is composed of nine items with a 
seven-point response format.  Clinical improvements in fatigue were associated with 
reductions in scores on the FSS.  The FSS is also a practical measure due to its brevity and 
ease of administration and scoring.37
Human Activity Profile (HAP): The HAP was designed to measure activities of patients in 
rehabilitation programs.  It is a self-report measure of energy expenditure or physical fitness.  
The Human Activity Profile appears to be a useful indicator of physical activity levels in 
people with various neurological and cardiorespiratory conditions, as well as in healthy older 
people.38
Short Form 36-Item Health Survey Version 2 (SF36v2):  The SF36v2 is widely used 
throughout the world as an instrument to measure general HRQOL. It assesses HRQOL in 
eight scales or domains.
 It is a generic measure, as opposed to one that targets a specific age, 
disease, or treatment group.39

Profile of Mood States (POMS):  The Profile of Mood States (POMS) measures present 
mood state by a list of adjectives. POMS measures six dimensions of affect or mood, 
including tension-anxiety, depression-dejection, anger-hostility, vigor-activity, fatigue-
inertia, and confusion-bewilderment. 40

King’s Brief Interstitial Lung Disease Health Status Questionnaire (K-BILD):  The K-BILD 
is designed to measure health status in patients with interstitial lung disease through three 
domains (breathlessness and activities, chest symptoms, and psychological).  The 
questionnaire has 15 items in total.41    
Randomization: Once the subjects have completed baseline testing they will be randomized to one 
of the two conditions:  AET+ or CON.  We will use block randomization to keep groups as equal 
in number as possible and to avoid early filling of one of the groups. An independent randomizer 
(Diane Brandt, P.T., Ph.D., RMD, Epidemiology and Biostatistics Section) who is not affiliated 
with this study in any other way, will perform randomization of subjects. The AET+ and CON 
procedures will occur in the Clinical Center at The National Institutes of Health. The education 
regimen will be conducted at separate times for the AET+ and CON groups to avoid cross 
contamination.

14.-CC-0027- Version 13
25
Leighton Chan 07.12.2021
Educational Sessions:  The education portion is comprised of 13 separate lectures.  Subjects in 
the AET+ arm will receive 1-2 lectures per week as needed following their exercise session to 
fulfill the education requirement within 10 weeks.  Subjects in the CON arm will receive the 13 
lectures within the 10-week education period. Many classes will take more than one class session 
to cover the material.  For example, inhaler use/lung medications will require at least 2 sessions to 
cover.  
The lectures will include the following topics: 
Lung Anatomy/Physiology/Breathing Retraining
Lung Diseases and Medications Part 1
Lung Diseases and Medications Part 2
Oxygen Therapy/Sleep Disorders
Preventing Infection/Airway Clearance
Diagnostic Testing
Advance Care Planning/Energy Conversation 
Emotional/Social Well Being
Panic Control/Relaxation
Nutrition/Fall Prevention
Benefits of Exercise/Disease Management/Community Resources
Home Recommendations (excluding exercise recommendations)
Exercise Training:  The AET+ regimen will consist of 10 weeks of supervised treadmill or track 
walking.  Exercise session duration will be 30 minutes and will progress to 45 minutes per session 
over the 10 weeks.  The sessions will be continuous unless the patient cannot tolerate the regimen, 
in which case exercise bouts will be alternated with rest intervals until the total time of the exercise 
bouts equals the 30-45 minute total exercise time target.  The intensity of the exercise will be 
between 70 and 80% of the heart rate reserve, defined as 0.70 and 0.80 (maximum heart rate – 
resting heart rate) + resting heart rate, as determined during the baseline tCPET. Should the target 
heart rate range be considered insufficient (i.e. subject stopped the CPET prematurely due to 
dyspnea and/or O2 saturation <80%, or subject achieved a higher heart rate on the 6MWT than on 
the CPET), an RPE of 4 to 6 can be used to progress exercise intensity. ECG monitoring will be 
used as appropriate to ensure proper RPE rating for the heart rate response in these subjects. The 
frequency of the sessions will be three times per week, unless make up sessions are needed in order 
to attend 80% or 24 sessions in ten weeks.  The target endpoint for each session will be the 
completion of the prescribed training time, however symptomatic endpoints for stopping the 
training session will be those recommended by the American College of Sports Medicine.  
Additionally should any subject’s oxygen saturation desaturate to ≤80% the patient will be 
required to stop walking at this point with or without the presence of symptoms of severe dyspnea.  
The patient will rest until oxygen saturation returns to baseline values or above 90% at which point 
the patient will resume walking again.  The session timer will be stopped during rest breaks and 
will only resume once the patient returns to their target heart rate zone.  Those patients requiring 
supplemental oxygen will continue to use their supplemental oxygen throughout the duration of 
exercise training.  Additionally those patients who previously did not require supplemental oxygen 
prior to exercise training but deteriorate to the point of requiring supplemental oxygen at any point 
during the training will be allowed to begin supplemental oxygen use based on their oxygen needs.  
However regardless of whether or not any changes were made to the patient’s supplemental oxygen 

14.-CC-0027- Version 13
26
Leighton Chan 07.12.2021
use or the patient began using supplemental oxygen during the exercise training, all post-training 
exercise tests will be performed with the same oxygen device/flow used in the baseline testing to 
maintain consistency between tests.
Blood glucose of diabetic patients will be monitored before and after training, or as clinically 
appropriate.  If training at NIH CC, glucose monitoring will be performed by qualified staff using 
NIH glucometer or patient’s own glucometer (if first validated for accuracy through the NIH 
Department of Laboratory Medicine).    If training at Inova Fairfax, blood glucose monitoring will 
be performed per Inova policy.
The locations for this intervention will be Inova Fairfax Hospital and the NIH CC.    At NIH, the 
intervention will take place in the Clinical Center Fitness Center located in room 7-3551 on the 7th 
floor of the Clinical Center and will be led by trained NIH AI staff.  This room has three treadmills 
that are currently used for aerobic training of CC patients.    
Participant Inclusion and Exclusion Criteria
See Appendix 2 for the Inclusion/Exclusion Checklist that will be used.
Inclusion Criteria 
ILD Groups: Subjects in this study will include individuals with ILD who are referred for 
Pulmonary Rehabilitation.  The following list provides more specific inclusion criteria:  

Between age 21-80 years.

NYHA functional class II or III, will accept NYHA functional class I and IV based on 6 
minute walk test results (≤400 meters for Class I and ≥50 meters for Class IV) 

No episodes of syncope or significant chest pain for at least one month.

No prior Pulmonary Rehabilitation received within the last 6 months and not currently in 
a maintenance program.

Physically inactive, no participation in a structured exercise program as defined as more 
than 30 minutes of exercise 3 or more days a week within the last 6 months.  

Patients may qualify if they have any one of the following conditions:
Interstitial lung disease, including idiopathic pulmonary fibrosis (IPF), non-specific 
pulmonary fibrosis (NSIP), sarcoidosis or other form of chronic lung fibrosis based on 
clinical context via clinic note from primary pulmonologist  

Low to intermediate probability of pulmonary hypertension as determined by tricuspid 
regurgitation velocity (TRV) at rest on echocardiogram and the presence of additional 
echocardiographic variables such as right ventricular size and pressure, pattern of blood 
flow velocity out of the right ventricle, the diameter of the pulmonary artery and an estimate 
of right atrial pressure. If the patient has had a recent right heart catheterization showing a 
mean PAP <25 mmHg, ruling out pulmonary hypertension..
Exclusion Criteria 
Since the goal is to examine exercise responses and adaptations as affected by ILD, patients will 
have no other medical conditions that would impair aerobic capacity or the ability to engage in 

14.-CC-0027- Version 13
27
Leighton Chan 07.12.2021
physical activity.  These conditions would include any of those affecting the cardiovascular, 
pulmonary, metabolic, neurological, or musculoskeletal systems.  Specific exclusion criteria are:

Inability to maintain a resting oxygen saturation ≥90% SpO2, measured by pulse oximetry, 
on supplemental oxygen.

Inability to complete a treadmill cardiopulmonary exercise test based on the specified 
criteria.   

Diagnosis of ischemic heart disease.

Left ventricular dysfunction with the ejection fraction <50%.

Acute cor pulmonale.

Dilated or hypertrophic cardiomyopathy.

Non-idiopathic cardiomyopathy.

Significant hepatic or renal dysfunction.

Metastatic cancer with a life expectancy of less than one year.

Disabling stroke.

Active substance abuse.

Severe psychiatric disease.

Patients on antiretroviral therapy.

Uncontrolled diabetes mellitus with a history of DKA.

Mitochondrial disease.

Pregnancy.

Ongoing tobacco use.

Acceptance onto a lung transplant waiting list. 

No participation in active ILD drug trials prior to enrolling in this study and throughout the 
duration of their participation in this study.  Patients may continue to take any currently 
prescribed medications throughout the entire protocol.  However, any changes to current 
medications or addition of other medications during the course of the study must be 
reported within one week to the PI or associate investigator.  

General medical complications that pose a risk to exercise testing or training as determined 
by the PI (for example, severe peripheral vascular disease).

Inability to read English.
Other Exclusions:  

The age range of the subjects will be limited to those between 21 and 80 years because the 
normal adaptive processes to aerobic exercise are generally less well understood in the 
childhood, adolescent, and aged subset of the population, and reference ranges for many of 
the exercise response variables are less well accepted than in the general adult subset.  The 
age range of 21 to 80 encompasses the range generally referred to in the Inova Fairfax 
pulmonary rehabilitation program, which is one of the few pulmonary rehabilitation 
programs in existence serving patients who have advanced lung disease

Subjects will not typically include individuals in Class I because patients are usually in 
Class II or III at the time of diagnosis.  

14.-CC-0027- Version 13
28
Leighton Chan 07.12.2021

Subjects in NYHA Class IV will typically be excluded as the instability of their symptoms 
is a contraindication for exercise testing or training by nearly all published guidelines. 

Subjects in Class I may be included if they walk less than 400 meters during a six-minute 
walk test.

Subjects in Class IV may be included if they are able to walk at least 50 meters during a 
six-minute walk test.  

Subjects with severe Raynaud’s phenomenon will be excluded from participation in the 
arterial occlusion muscle oxygenation capacity test.
New York Heart Association Functional Classification 
Class
Patient Symptoms
Class I (Mild)
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, or dyspnea (shortness of breath).
Class II (Mild)
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in 
fatigue, palpitation, or dyspnea.
Class III (Moderate)
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes 
fatigue, palpitation, or dyspnea.
Class IV (Severe)
Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency 
at rest. If any physical activity is undertaken, discomfort is increased.
Monitoring Subjects and Criteria for Withdrawal from the Study:  Subjects will be followed 
carefully during the study.  At the start of each study day, subjects will be asked whether they are 
experiencing any unusual symptoms, and vital signs will be measured (pulse rate, oxygen 
saturation, resting blood pressure).  All subjects will undergo EKG and echocardiography before 
and during the symptom limited exercise test.  We will monitor heart function in the rehabilitation 
medicine exercise lab during exercise, and stop the exercise if there are any signs of heart 
problems. 
Subjects enrolled who subsequently meet the exclusion criteria above at any time during the 
protocol will be excluded (off-study exclusion criteria). 
Dr. Leighton Chan, as the Principal Investigator, will make the decision to include or exclude 
potential participants based on their meeting inclusion, exclusion or off-study exclusion criteria.  
Unanticipated Problems, Adverse Events, and Protocol Deviations:
NIH IRB and CD reporting
Definitions: The PI or designee will refer to definitions of reportable events per Policy 801.

14.-CC-0027- Version 13
29
Leighton Chan 07.12.2021
Expedited reporting: Events requiring expedited reporting will be submitted to the IRB per 
Policy 801 “Reporting Research Events.
Reports to the IRB at the time of continuing review: The PI or designee will refer to HRPP 
Policy 801 “Reporting research events” to determine IRB reporting requirements. In addition, an 
independent medical monitor will monitor all adverse events.  (See section on Data and Safety 
Monitoring.)
Analysis
Our statistical model for specific Aims 1-3 will compare variables of interest between and within 
the AET+ and CON groups at baseline and post-intervention with a 2-way mixed model analysis 
of variance (2-way ANOVA). Should there be baseline differences in the specific variable of 
interest or in demographic characteristics, we will use an analysis of covariance (ANCOVA) to 
control for the group equality, but the study will be powered under the assumption that no 
informative covariates are identified and using 6MWT as the primary outcome. 
In Specific Aim 1 we will test the hypothesis that AET+ will improve scores on measures of PWC. 
The dependent variables for this Aim include total distance covered and fatigability index on the 
6MWT, and peak WR achieved on the tCPET.  6MWT distance is the primary outcome variable 
for this RCT and thus our project is powered on the sample size estimated to achieve a significant 
outcome on this variable (See Sample Size below).   
In Specific Aim 2, we will test the hypothesis that after AET+, significant increases in AT-time 
and muscle oxygenation will be observed over CON.  The main dependent variables for this aim 
are AT-time and measures of muscle oxygenation which include [Tot-Hb], [O2-Hb], [H-Hb], and 
StO2 measured during tCPET and muscle arterial occlusion cuff tests.  Additional dependent 
variables will include Qt and its components HR and SV measured during tCPETs.  
In Specific Aim 3 we will test the hypothesis that patients will report decreased fatigue severity, 
increased physical activity, and improvements in other HRQoL.  The dependent variable score for 
fatigue severity will be the Fatigue Severity Scale score.  The dependent variable score for physical 
activity will be the Human Activity Profile maximum and average scale scores, and the scores for 
HRQoL will be composite and domain scores for the SGRQ-I, SF-36v2, and K-BILD.    
In the crossover sub-study, we will determine if AET+ induces significant improvements in the 
variables of interest in the CON group.  For this analysis we will use repeated measures ANOVA’s 
to determine differences in the variables of interest among baseline, 10-week post control, and 2-
week post crossover AET data points.  Dependent variables will be those in each of the specific 
aims characterized above.
In Specific Aim 4, relationships between the post-study physiological variables and health 
outcome variables will be determined using Pearson product moment correlations and appropriate 
nonparametric procedures. 
In all of the analyses, statistical significance will be interpreted as the probability of making a 
type 1 error equal to or less than 5% (p<0.05).  

14.-CC-0027- Version 13
30
Leighton Chan 07.12.2021
Sample Size: 
The broad objective of the proposed work is based on identifying effects of exercise on, and 
relationships among, measures of physical work capacity, fatigability, oxidative metabolism, 
tissue oxygen extraction, and clinical outcomes.  The proposed study builds upon the PI’s 
preliminary study of the feasibility and safety of exercise treatment for patients with ILD in which 
the 6MWT was the primary improvement metric.  Many of the hypotheses proposed under this 
objective require measurement of variables not included in prior studies of the ILD population.  
Conversely, there are established standards for clinically relevant changes in the 6MWT and 
multiple studies of ILD patients with which to inform our sample size decisions and 6MWT is the 
primary outcome variable for the proposed study.  For these reasons we will power the study on 
6MWT. Specifically, changes in 6MWT distance between baseline and the second testing period 
are compared for ILD patients randomized to the AET+ and CON arms using a 2-way mixed model 
ANOVA.  From this, we have determined our goal is to recruit 60 patients with ILD (30 into each 
group) over the duration of this study, with details below. 
The prior information, assumptions, and calculation for the power analysis that was conducted are 
as follows.  An increase in 6MWT distance of 54 to 80 m exceeds the MCID in patients with ILD2.  
Previous studies by Holland et al.21 and Nishiyami et al.20 on exercise interventions in ILD patients 
have observed in post-hoc independent t-test an effect size between experimental and control 
groups of 0.65 and 0.86, respectively, with an increase in 6MWT distance of 31 to 42 m in the 
experimental group.  Effect sizes in this range are associated with high-moderate to large 
differences.  
In order to translate the existing literature’s results into predictions of effect size of the 2-way 
mixed model ANOVA we will use as our primary statistical test, simulations were run in STATA.  
Simulations were drawn from normal distributions for each of control and exercise groups with 
equal mean and variance chosen as the average of the mean and variance observed in the control 
and exercise groups in Holland et al.21 Specifically, both groups were assumed to have mean 
6MWT of 385 m and standard deviation 127 m at baseline in the simulation.  The control group 
was assumed in all samples to show no change between baseline and retest, while different 
simulations were run for improvement in the exercise group of 25, 30, 35, and 40 m between 
baseline and retest.  We did not simulate differences smaller than 25 m as this is below the MCID.  
At each level of improvement from treatment we simulated 3000 samples from both control and 
exercise groups at test-retest correlations of 0.25, 0.30, 0.35, and 0.40.  
It was not possible to determine from the previously published ILD literature what level of 
correlation to expect between test and retest.  The preliminary study performed by NIH observed 
a correlation of 0.840 between pre and post-treatment 6MW distances.  We expect a weaker 
correlation between patients assigned to the CON arm of the proposed study, however, due to the 
conflicting effects of education and possible decline from the progression of ILD.  Additionally, 
informal study of the plots of pre-post test change in Elia et al.55 also suggest the range of 
correlation simulated is conservative.  As we are powering on only one of the multiple study aims 
due to the limitations of prior data and the hierarchy of study goals, we feel it prudent to risk 
overpowering on this outcome by using overly conservative estimates as it may ensure proper 
power for the other study aims.
The ranges of improvement in the treatment group and test-retest correlations considered give rise 
to 16 simulated data sets of 6000 observations each. Each data set was then tested with a 2-way 
mixed model ANOVA and the effect size recorded.  Simulated effect sizes increased across the 

14.-CC-0027- Version 13
31
Leighton Chan 07.12.2021
range of correlation under consideration at each level of improvement in 6MWT distance. The 
observed effect sizes were 0.16-0.17 at 25 m, 0.18-0.20 at 30 m, 0.21-0.23 at 35 m, and 0.24-0.265 
at 40 m.  As we expect to have underestimated correlation, even at the given improvement levels 
the predicted effect sizes are highly conservative.  With either correlation modestly above 0.40 
and 30 m improvement, correlation of 0.25 and 35 m improvement, or some point in between these 
two at a sample size of n=60 the simulated effect sizes predict a power above 80% at a significance 
level of 0.05.  Modestly higher improvement, in the range of 35-38 m, and correlation of 0.38-0.45 
will result in the study having a power of approximately 95%.  This range is compatible with the 
observed effect sizes in the literature in the moderate to large range, using Cohen’s conventions 
for effect sizes where these ranges are 0.25-0.4 for ANOVA and 0.5-0.8 for t-tests.  
To support the results from simulation, we finish by observing how power is maintained at a 
slightly less conservative estimate of effect size and correlation but under the additional 
assumption of significant subject withdrawal from the study.  Assuming an effect size of 0.25 and 
test-retest correlation of 0.40 then a minimum of 33 patients in each group are necessary to achieve 
the desired power of 0.95.  Even then, if only 20 patients complete the protocol in each group post-
hoc analysis predicts a not-unacceptable power of 0.803.  
Our recruitment goal was therefore set at 60 patients, however, completion rates to date for this 
study suggest that 80 subjects may need to be consented and screened in order to achieve 60 
completed subjects. Therefore, the enrollment goal remains the same at 60 patients in total (30 in 
each group) over the course of the study as it ensures high power for comparison of 6MWT 
distance between AET+ and CON groups, with a buffer for moderate patient dropout.  However, 
recruitment will remain open until 30 subjects in each of the AET+ and CON cohorts have 
completed the entire protocol.  
Based on this recruitment goal we have agreed upon the following strategy to maintain an effective 
end power.  At which point we attain 45 completed subjects (total) an analysis of the standard 
deviations in 6MWD from pre to post will be determined in the control and intervention cohorts.  
To maintain the blinding controls of the study as much as possible, this analysis will be performed 
by our statistician only.  Based on this analysis our sample size will be adjusted thereafter to reflect 
a more accurate sample size needed to maintain an effective end power.  
Human Subject Research Protections (HSRP)
Subject Selection
Rationale:  Patients referred from the Baltimore/Washington/Northern Virginia area will be 
potential subjects for this study.  All subjects will be classified by the New York Heart Association 
Functional Classification System (NYHA) in Class II or Class III, which relates symptoms of 
cardiorespiratory dysfunction to daily activity participation.   No participants will be excluded 
based on race, gender, or ethnicity.
Recruitment:  Subjects will be primarily recruited from the pool of subjects available at Inova 
Fairfax Hospital (Associate Investigators Drs. Nathan, Ahmad, Brown, Shlobin, and NIH 
Associate Investigators). 

14.-CC-0027- Version 13
32
Leighton Chan 07.12.2021
Other recruitment efforts will be directed toward presentations to ILD support groups and an 
introductory study letter for local private pulmonary practices.  We will also utilize NIH Clinical 
Center-sponsored digital media resources such as Twitter, Facebook, CC Radio, CC TV, Photo 
Gallery; databases such as NIH Search the Studies, ClinicalTrials.gov, and Research Match; and 
local newspapers such as the Washington Post to disseminate information about the study to 
potential participants and their healthcare providers.
Pre-screening at Inova Fairfax Hospital as an Activity Preparatory to 
Research
 Inova will refer the patients to NIH after patient signs release of information authorization. The 
NIH Associate Investigator and Study Coordinator will have physical access to the medical records 
of the Inova Advanced Lung Disease (ILD) Clinic and Pulmonary Rehabilitation Department 
referral patients for purposes of pre-screening Inova patients and patient referrals for this study.  
NIH investigators represent that (1) the use or disclosure of these records is solely to review PHI 
as necessary to aid study recruitment, (2) the PHI will not be removed from the covered entity 
(Inova Fairfax Hospital) in the course of review, and (3) the PHI for which use or access is 
requested is necessary for the research.
Pre-Screening Process in the Inova Fairfax Advanced Lung Disease Clinic:
If NIH Associate Investigators are at Inova Fairfax Hospital and Dr. Steven Nathan or his 
associates at the Inova Advanced Lung Disease (ALD) Clinic feel a patient would be a 
good candidate for enrollment into this study based on inclusion/exclusion criteria, the NIH 
associate investigator will be introduced to the patient after a brief overview of the study.  
If the patient is interested, he or she will sign an Inova Authorization to Release and 
Disclose PHI form.   If the patient meets initial eligibility criteria, an appointment will be 
made for the patient to come to NIH for NIH consent and testing.
If the NIH Associate Investigator is not at the Inova Fairfax Hospital at the time of a patient 
visit and Dr. Steven Nathan or one of his associates at the Inova ALD Clinic feel a patient 
would be a good candidate for enrollment into the study based on the inclusion/exclusion 
criteria, the ALD clinic research staff will introduce the patient to the study, and the 
research team will have the patient sign an Inova Authorization to Release and Disclose 
PHI form.   Once the form has been signed the NIH Investigator may contact the patient 
directly for follow-up. 
Pre-Screening Process in the Inova Pulmonary Rehabilitation Outpatient 
Department:

14.-CC-0027- Version 13
33
Leighton Chan 07.12.2021
Patient will sign release of record authorization then the patient will be referred to NIH 
Associate Investigator and Study Coordinator in the Pulmonary Rehabilitation Outpatient 
Clinic. Then referral records of patients referred for pulmonary rehabilitation for the 
purposes of prescreening for the study may be reviewed.  When a possible patient is 
identified, the Inova Pulmonary Rehabilitation registrar will contact the patient by 
telephone to schedule pulmonary rehabilitation.   The patient will be informed about the 
study and will be given the NIH Associate Investigator’s contact information if the patient 
states they are interested.   The Inova Fairfax Pulmonary Rehabilitation registrar will state 
the following to the patient referral after beginning the process of registering the patient 
for pulmonary rehabilitation:
“You may be eligible for an NIH study examining the benefits of pulmonary rehabilitation 
for patients with interstitial lung disease.  Would you like the contact information for the 
NIH study coordinator for more information about the study?”
If the NIH Study Coordinator interviews a potential subject from any source the following 
script will be followed:
“Thank you for your interest regarding the research we are conducting to determine the benefits 
of a walking program for patients with interstitial lung disease.  We are accepting volunteers 
between the ages of 21 and 80 who have been diagnosed with interstitial lung disease and who 
have been referred by their physician for pulmonary rehabilitation.  If you are enrolled in the study 
we would ask that you come to NIH for a day of testing which would include a test to determine 
how far you can walk in 6 minutes, breathing tests and a treadmill exercise test.  During the 
treadmill test you will have 16 electrodes on your chest, we will ask that you wear a neoprene 
mask to collect data on the amount of oxygen you breathe in and out, as well an electrode on your 
calf to determine the amount of oxygen your muscle utilizes for energy.  
After testing you will be randomized into one of two groups, group 1 will receive exercise and 
education simultaneously 3 days a week for 10 weeks concluding with repeat testing at NIH.  
Group 2 is a 20 week group where you will receive education one day each week for 10 weeks, 
return to NIH for testing followed by 10 weeks of exercise 3 days a week and finally one last 
testing session at NIH.  We do not have control over which group you are assigned to.  You will 
be put into a group by a process called “randomization” where you have a 50-50 chance of landing 
in either group.  Does this sound like something that you would like to participate in?”
If they answer “yes,” we ask if they have time to answer a short questionnaire that would allow us 
to evaluate their eligibility and safety for inclusion into the study.  (Please see Appendix 2 of the 
protocol to compare the inclusion/exclusion criteria with the questions we would be asking.)
If, based on this interaction, we think the subject might meet the inclusion criteria for the study, 
we will request medical records (recent history, medication list, pulmonary function test, resting 
EKG, six minute walk and echo) to further evaluate their eligibility for the study.  Potential 
participants can either send us their medical records or they can fill out a medical release document 
and we will request this information from their physician prior to their visit to NIH.  Their medical 
records will be reviewed and, if it appears that the patient meets the inclusion criteria, we will set 

14.-CC-0027- Version 13
34
Leighton Chan 07.12.2021
up an appointment for the patient to come to the NIH Clinical Center for consent and testing.  If, 
after obtaining a patient’s medical records it is clear that the patient does not meet inclusion 
criteria, the information may be used to refine our inclusion and exclusion criteria; however, these 
medical records will not be used for any research purposes.
To prepare for the visit, we will enter their personal information into the NIH Admissions Travel 
and Vouchers system and an NIH patient number will be assigned to them.  Upon arriving at the 
NIH, the patient will proceed through admissions and then consented to the study, followed by a 
history and physical, blood draw, ECG, transthoracic echocardiogram, pulmonary function testing, 
arterial occlusion muscle oxygenation capacity test, cardiopulmonary exercise test, questionnaires, 
and six minute walk test. 
Exclusions:
Exclusion of Children:  Individuals younger than 21 years will not be included in the protocol 
because reference ranges for normative aerobic capacity and aerobic fitness have not been 
established for these age ranges.  The objectives of this project do not include establishing these 
normative reference ranges.  Moreover, far less is understood about advanced lung disease in 
children and the mechanisms by which it occurs. This lack of information could introduce critical 
levels of bias into the interpretation and cause the interpretation of our results to be misleading.  
Exercise response and adaptation in children with advanced lung disease should be studied in 
separate and specific protocols.
Exclusion of Pregnant Women: 
 Women of childbearing age will undergo urine pregnancy testing during screening and follow-up 
visits and will be excluded from the study should results be positive.   Pregnant women will 
necessarily be excluded from the study for safety reasons.  Women who do not exercise before 
pregnancy should not begin a rigorous exercise during pregnancy and would not be able to achieve 
the target heart rate required as part of the testing and training.  
Exclusion of Those Who Are Unable to Obtain Informed Consent: 
 Individuals unable to give informed consent will necessarily be excluded from the study because 
of the risk to subject safety and the need to maintain integrity of the study.  Subjects must be able 
to comprehend and follow directions, and express their own needs adequately during all testing 
and retesting procedures, and exercise and educational training sessions.  
Benefits and Risks/Discomforts: 
 A previous study found that participation in an aerobic exercise training program improved 6MW 
distance, peak VO2, and resting pulmonary artery systolic pressure.  No less is expected for 
patients completing the proposed study.  In particular, 6MWD has been used as an endpoint in 

14.-CC-0027- Version 13
35
Leighton Chan 07.12.2021
clinical trials of medications used to treat advanced lung diseases because it correlates indirectly 
with the mortality and may correlate directly with quality of life.
The risks of this study are those associated with aerobic exercise testing and training in patients 
who have circulatory disorders.  These include sudden cardiac arrest, myocardial infarction, angina 
and electrocardiographic abnormalities, shortness of breath, dizziness, early onset of fatigue and 
exhaustion, near-syncopal or syncopal episodes, and muscle or joint pain.  Many of these 
symptoms may occur during the immediate, post-exercise recovery phase, which is generally 
thought to be the first six minutes following strenuous exercise.  Risk of injury also includes those 
related to falling on a moving treadmill belt such as abrasions, contusions, cuts, sprains, fractures, 
or muscle strain.  The likelihood that any of these injuries would occur is small and preventive 
measures will be enforced to insure that the risks remain at a minimum. 
Many subjects will experience delayed onset muscle soreness after the treadmill exercise tests or 
after beginning the exercise-training phase.  This soreness will be mild to moderate in intensity 
and may be felt immediately after exercise or up to 48 hours following the exercise session.  It will 
typically subside within seven days.  Many subjects will also experience increased levels of fatigue 
that are sustained for up to 24 hours following the exercise sessions.  This fatigue will typically 
subside after one to three weeks.   
In order to minimize the possibility of an attack exacerbated by the arterial occlusion muscle 
oxygenation capacity test, subjects diagnosed with severe Raynaud’s phenomenon will be 
excluded from participation in that test.  Otherwise, the risk of exercise in this population is similar 
as for other ILD patients.  These subjects were exercised safely with no adverse events in our 
previous study examining the benefits of exercise in patients with pulmonary hypertension.  
Included in that study were patients with ILD with connective tissue disorders who had Raynaud’s 
[56]. 
Subjects with uncomplicated diabetes will be monitored before and after exercise testing and 
training for glucose levels and glycemic responses to exercise.  Physical activity generally reduces 
glycemic levels and intense activity can cause transient blood glucose elevations in individuals 
with diabetes.  Thus, the risks of hypoglycemia and hyperglycemia are associated with exercise in 
individuals with diabetes.  The acute risks of exercise for individuals with diabetes must be 
weighed against the potential long-term benefits such as a reduction in cardiovascular disease risk 
and improved hemodynamic function.  In order to reduce risks and avoid the onset of diabetic 
symptoms during participation in the study, glucose monitoring will be performed per standard of 
care. 
Exercise is a very low risk intervention in this population.  The most serious risks for those 
participating in exercise are cardiovascular abnormalities. These risks are slight even in individuals 
with known coronary atherosclerosis during maximal exercise testing.  In studies that include 
known heart disease as well as patients in whom the presence of heart disease is unknown, 
morbidity and mortality during maximal exercise testing remains low at 0.0 to 8.3 per 100,000 and 
0.0 to 1.0 per 100,000 respectively[53-62]. Morbidity and mortality remain at similar lows for 
maximal exercise testing environments that are attended by a physician and those supervised by a 
physician but operated without physician attendance [54, 57, 60, 63, 64]. Exercising at sub-
maximal intensities carries with it even lower risk of adversity.  Therefore, we would consider a 
single study related death, myocardial infarction, or stroke to be a reason to consider stopping 
the study.  Should one of these unanticipated serious adverse events occur, the PI will notify the 

14.-CC-0027- Version 13
36
Leighton Chan 07.12.2021
Clinical Director, IRB, and our independent medical monitor within the time frame and according 
to the policies specified in the currently approved NIH OHSRP SOP  Policy 801 (“Reporting 
Research Events”).  Following the completion of the SAE review and the determination of the IRB 
we will consider stopping the protocol if the IRB deems it necessary.
To minimize risk and maximize safety, exercise tests and classes will be carried out in laboratories 
that are in clinical settings with immediate response backup at the NIH Clinical Center and Inova 
Fairfax Hospital. The Principal Investigator, Dr. Leighton Chan, a physician board certified in 
Physical Medicine and Rehabilitation, will supervise the medical and safety aspects of the study 
and will be available should an emergent need arise.  If for any reason Dr. Chan is not immediately 
available should an emergency arise then the RMD medically responsible physician of the day will 
be available to assist.  In addition, all subjects will be screened by medical history and examination 
to exclude those with contraindications to exercise.  Subjects will be monitored during the exercise 
tests by an EKG. Subjects will be informed of the signs and symptoms of heart disease and 
questioned frequently during the test regarding the presence of symptoms of cardiovascular, 
neurological, or musculoskeletal conditions.  Subject’s oxygen saturation will be monitored by 
infrared pulse oximetry.  Safety procedures will be rehearsed by the laboratory personnel and 
emergency precautions will be observed continuously.  A fully equipped emergency response team 
will be readily available to respond to life threatening events.  The current response time is less 
than three minutes.  Dr. Chan will be briefed frequently and routinely regarding all testing and 
training operations. As recommended by the American Heart Association and the American 
College of Sports Medicine, exercise will be overseen by personnel appropriately trained to extend 
physician services in the form of exercise testing and training43,44,46,54 for populations included in 
this study (non-cardiac disease).  Additional clinical consults, e.g, cardiology or pulmonology, 
along with laboratory testing may be performed in order to help ensure safety for exercise.    
Health risks during exercise are very small.   In fact may decrease the risk as we are doing intensive 
peak and submaximal exercise evaluations, performed under controlled and safe clinical 
conditions as well as other medical tests and examinations related to defining the seriousness of 
the patients’ conditions.  Improvement in aerobic capacity enables individuals to accomplish a 
given amount of activity or work at a lower percentage of maximum capacity and with less fatigue. 
Moreover, improvement of exercise tolerance generally increases quality of life by permitting 
individuals to engage more easily in daily physical activities.  It is anticipated that the potential 
benefits of participating in a program of aerobic exercise conditioning outweigh the minimal risks 
associated with exercise in this group of patients who have advanced lung disease. Thus, this 
protocol involves more than minimal risk to study patients, with the prospect of direct benefit to 
individual subjects.
Participants from Inova Fairfax Hospital’s Advanced Lung Disease Clinic will be identified and 
referred to the protocol by one of the physician associate investigators.  the use and disclosure of 
patient medical records as an  “activity preparatory to research”, the NIH Associate Investigator 
and Study Coordinator may assist the Inova Principal Investigator, Dr. Steven Nathan, by 
reviewing medical records of the Inova Advanced Lung Disease (ILD) Clinic and Pulmonary 
Rehabilitation Department referral patients for purposes of pre-screening Inova patients and 
patient referrals for this study.  
Consenting:  NIH research staff will interview interested candidates.  Those deemed appropriate 
will both read and sign the NIH approved consent form.  A copy of the signed informed consent 
shall be given to the individual signing the consent and the original consent document will be 

14.-CC-0027- Version 13
37
Leighton Chan 07.12.2021
retained in the medical record.  Upon giving consent, the subject will undergo a full examination 
by a physician, and a review of available medical records will be performed to confirm their 
suitability for the trial.  After this, they will begin the baseline research tests including: treadmill 
cardiopulmonary exercise test, arterial occlusion muscle oxygenation capacity test, pulmonary gas 
exchange analysis, heart rate measurement, bioelectrical impedance plethysmography, near 
infrared spectroscopy, six-minute walk and fatigability tests, and patient self-report instruments.  
All tests will be performed again post rehabilitation for outcome comparisons.
Data and Safety Monitoring Plan: 
 As the PI, Dr. Chan will closely monitor patient safety throughout the duration of the study.  
However, this protocol has several characteristics that suggest a more extensive data monitoring 
procedure.  First, the risk of performing several exercise tests on patients with interstitial lung 
disease is unknown.  We suspect that the risk is a minor increase over minimal risk, but we are not 
sure.  Second, the protocol involves randomization and blinding.  Patients will be randomized, to 
either education or exercise + education.  In addition, while the subjects will not be blinded to their 
treatment allocation, the study personnel will be blinded to the extent that is possible with exercise 
intervention trials.  Study personnel will be blinded through initial baseline screening/testing and 
randomization, however following randomization due to the nature of exercise training and the 
time points involved in this study the blinding process will no longer be possible.  Finally, this 
study involves one extramural site:  Inova Fairfax Hospital.. 
Given these additional factors, we feel that our plan may need more than just PI monitoring, but 
fails to meet the criteria for the involvement of a full DSMB.  Therefore, we have enlisted the 
assistance of Matthew N Bartels, MD, MPH, Chairman of the Department of Physical Medicine 
and Rehabilitation at the Montefiore Medical Center/Albert Einstein College of Medicine, New 
York, as the independent medical monitor (IMM) for this study. He will be apprised of all 
significant adverse events.  In addition, this monitor will also have access to the study data.   
RMD’s Epidemiology and Biostatistics Department will examine the results on an interim basis.  
If, at any point, they feel that the study should be stopped because of concern for safety of study 
subjects, they will inform the PI, the IRB, and the clinical and scientific directors of CC and 
NHLBI.  
Conflicts of Interest:  
This study does not include any commercial interests, technology transfer, or any products made 
by a commercial interest.  No conflicts of interest have been identified for any NIH employees 
associated with this study.
 Subject compensation: 
Subjects will be compensated $300 for each completed testing session at the NIH.  For those in 
the concurrent exercise and education group of the randomized trial, this will amount to $600 
because participants will come to the NIH for initial testing and again for retesting at the end of 
the study.  For those in the education only group the amount of compensation will be $900 because 
participants will come to the NIH for initial testing, then again for a second testing after the 

14.-CC-0027- Version 13
38
Leighton Chan 07.12.2021
completion of 10 weeks of education, and again for a third time after 10 completed weeks of 
exercise.   
Data Management Plan: 
 Data will be collected using appropriately calibrated computer-assisted instrumentation, 
commercial software programs, data collection sheets and self-reported outcome questionnaires.  
Clinical Trials Survey System (CTSS) will be used to manage data collection of the following 
subject self-reported outcome questionnaires and subjects will have the choice of using an NIH 
mobile device or paper format to complete the questionnaires.    All digital CTSS forms will be 
considered source documentation.
CTSS
Source
Fatigue Severity Scale
Digital or Paper
Human Activity Profile
Digital or Paper
King’s Brief ILD Questionnaire (K-BILD)
Digital or Paper
Profile of Moods
Digital or Paper
St. George’s Respiratory Questionnaire 
Digital or Paper
SF-36
Digital or Paper
.
Clinical Trials Database (CTDB) will be used to manage data collection and tracking of the 
intervention through the use of an NIH mobile device.   Paper source may be used should capability 
of digital entry not be available.  All Digital CTDB forms will be considered source 
documentation.
Upon enrollment, subjects will be assigned a protocol number that will be used as a subject 
identifier for all subject files and data collection sheets.  All computer software with associated 
data files is kept on password-protected computers that are off-network and are stored in a locked 
laboratory with restricted access.  Paper data collection sheets will be kept in de-identified subject 
folders in locked filing cabinets in secure areas.  Patient consent forms and other relevant medical 
records with patient names and other identifiable data are kept in separate folders and locked in 
separate filing cabinets.  No information will be kept in either folder that could be used to link a 
subject’s medical record file to a subject’s study data file.  
Electronic data collected in the laboratory will be transferred to a restricted access folder on the 
Clinical Center network with appropriate firewall protection.  Only study PIs and AIs will have 
access to this folder. A password protected USB device will be used to transfer data.  Email 
communication with patient information or data will be transmitted via encrypted email as per 
NIH guidelines.  Data will be analyzed as discussed in the Data Analysis section of this document.   

14.-CC-0027- Version 13
39
Leighton Chan 07.12.2021
References
1.
Travis WD, King Jr TE, Bateman ED, et al. American thoracic society/European 
respiratory society international multidisciplinary consensus classification of the 
idiopathic interstitial pneumonias. American Journal of Respiratory and Critical Care 
Medicine. 2002;165(2):277-304.
2.
Holland AE. Review series: Aspects of interstitial lung disease: Exercise limitation in 
interstitial lung disease - mechanisms, significance and therapeutic options. Chronic 
Respiratory Disease. May 1, 2010 2010;7(2):101-111.
3.
Du Bois RM, Weycker D, Albera C, et al. Six-minute-walk test in idiopathic pulmonary 
fibrosis: Test validation and minimal clinically important difference. American Journal of 
Respiratory and Critical Care Medicine. 2011;183(9):1231-1237.
4.
Jones AM, Carter H. The effect of endurance training on parameters of aerobic fitness. 
Sports Medicine. 2000;29(6):373-386.
5.
Chan L, Chin LMK, Kennedy M, et al. Benefits of Intensive Treadmill Exercise Training 
on Cardiorespiratory Function and Quality of Life in Patients With Pulmonary 
Hypertension. CHEST 2013;143(2):333-343.
6.
Myers J, Prakash M, Froelicher V, Do D, Partington S, Edwin Atwood J. Exercise 
capacity and mortality among men referred for exercise testing. New England Journal of 
Medicine. 2002;346(11):793-801.
7.
Gulati M, Black HR, Shaw LJ, et al. The prognostic value of a nomogram for exercise 
capacity in women. New England Journal of Medicine. 2005;353(5):468-475.
8.
Thompson PD, Buchner D, Piña IL, et al. Exercise and physical activity in the prevention 
and treatment of atherosclerotic cardiovascular disease: A statement from the council on 
clinical cardiology (subcommittee on exercise, rehabilitation, and prevention) and the 
council on nutrition, physical activity, and metabolism (subcommittee on physical 
activity). Circulation. 2003;107(24):3109-3116.
9.
Kohl Iii HW. Physical activity and cardiovascular disease: Evidence for a dose response. 
Medicine and Science in Sports and Exercise. 2001;33(6 SUPPL.):S472-S483.
10.
Middleton LE, Corbett D, Brooks D, et al. Physical activity in the prevention of ischemic 
stroke and improvement of outcomes: A narrative review. Neuroscience and 
Biobehavioral Reviews. 2013;37(2):133-137.
11.
Leeper NJ, Myers J, Zhou M, et al. Exercise capacity is the strongest predictor of 
mortality in patients with peripheral arterial disease. Journal of Vascular Surgery. 
2013;57(3):728-733.
12.
Martinez FJ, Foster G, Curtis JL, et al. Predictors of mortality in patients with 
emphysema and severe airflow obstruction. American Journal of Respiratory and 
Critical Care Medicine. 2006;173(12):1326-1334.
13.
Nylen ES, Kokkinos P, Myers J, Faselis C. Prognostic effect of exercise capacity on 
mortality in older adults with diabetes mellitus. Journal of the American Geriatrics 
Society. 2010;58(10):1850-1854.
14.
Rosas SE, Reese PP, Huan Y, Doria C, Cochetti PT, Doyle A. Pretransplant physical 
activity predicts all-cause mortality in kidney transplant recipients. American Journal of 
Nephrology. 2012;35(1):17-23.
15.
Barnes JN, Tanaka H. Cardiovascular benefits of habitual exercise in systemic lupus 
erythematosus: A review. Physician and Sportsmedicine. 2012;40(3).

14.-CC-0027- Version 13
40
Leighton Chan 07.12.2021
16.
Iversen MD, Brawerman M, Iversen CN. Recommendations and the state of the evidence 
for physical activity interventions for adults with rheumatoid arthritis: 2007 to present. 
International Journal of Clinical Rheumatology. 2012;7(5):489-503.
17.
Pinto ALS, Oliveira NC, Gualano B, et al. Efficacy and safety of concurrent training in 
systemic sclerosis. Journal of Strength and Conditioning Research. 2011;25(5):1423-
1428.
18.
Foster S, Thomas Iii HM. Pulmonary rehabilitation in lung disease other than chronic 
obstructive pulmonary disease. American Review of Respiratory Disease. 1990;141(3 
I):601-604.
19.
Ferreira G, Feuerman M, Spiegler P. Results of an 8-week, outpatient pulmonary 
rehabilitation program on patients with and without chronic obstructive pulmonary 
disease. Journal of Cardiopulmonary Rehabilitation. 2006;26(1):54-60.
20.
Nishiyama O, Kondoh Y, Kimura T, et al. Effects of pulmonary rehabilitation in patients 
with idiopathic pulmonary fibrosis. Respirology. 2008;13(3):394-399.
21.
Holland AE, Hill CJ, Conron M, Munro P, McDonald CF. Short term improvement in 
exercise capacity and symptoms following exercise training in interstitial lung disease. 
Thorax. 2008;63(6):549-554.
22.
Ferreira A, Garvey C, Connors GL, et al. Pulmonary Rehabilitation in Interstitial Lung 
DiseaseBenefits and Predictors of Response. CHEST Journal. 2009;135(2):442-447.
23.
Naji NA, Connor MC, Donnelly SC, McDonnell TJ. Effectiveness of Pulmonary 
Rehabilitation in Restrictive Lung Disease. Journal of Cardiopulmonary Rehabilitation 
and Prevention. 2006;26(4):237-243.
24.
Jastrzȩbski D, Gumola A, Gawlik R, Kozielski J. Dyspnea and quality of life in patients 
with pulmonary fibrosis after six weeks of respiratory rehabilitation. Journal of 
Physiology and Pharmacology. 2006;57(SUPPL. 4):139-148.
25.
Huppmann P, Sczepanski B, Boensch M, et al. Effects of in-patient pulmonary 
rehabilitation in patients with interstitial lung disease. European Respiratory Journal. 
October 25, 2012 2012.
26.
Jastrzebski D, Ochman M, Ziora D, et al. Pulmonary rehabilitation in patients referred for 
lung transplantation. Vol 7552013:19-25.
27.
Crapo RO, Casaburi R, Coates AL, et al. ATS statement: Guidelines for the six-minute 
walk test. American Journal of Respiratory and Critical Care Medicine. 
2002;166(1):111-117.
28.
Karvonen MJ KE, Mustala O. The effects of training on heart rate; a longitudinal study. 
Ann Med Exp Biol Fenn. 1957;35(3):307-315.
29.
Wenger HA, Bell GJ. The interactions of intensity, frequency and duration of exercise 
training in altering cardiorespiratory fitness. Sports Medicine. 1986;3(5):346-356.
30.
Schnelle JF, Buchowski MS, Ikizler TA, Durkin DW, Beuscher L, Simmons SF. 
Evaluation of two fatigability severity measures in elderly adults. Journal of the 
American Geriatrics Society. 2012;60(8):1527-1533.
31.
Handler CE, Sowton E. A comparison of the Naughton and modified Bruce treadmill 
exercise protocols in their ability to detect ischaemic abnormalities six weeks after 
myocardial infarction. European heart journal. Sep 1984;5(9):752-755.
32.
LeJemtel TH, Liang CS, Stewart DK, et al. Reduced peak aerobic capacity in 
asymptomatic left ventricular systolic dysfunction. A substudy of the studies of left 
ventricular dysfunction (SOLVD). SOLVD Investigator. Studies of Left Ventricular 
Dysfunction. Circulation. Dec 1994;90(6):2757-2760.

14.-CC-0027- Version 13
41
Leighton Chan 07.12.2021
33.
Page E, Cohen-Solal A, Jondeau G, et al. Comparison of treadmill and bicycle exercise in 
patients with chronic heart failure. Chest. Oct 1994;106(4):1002-1006.
34.
McLaughlin VV, Presberg KW, Doyle RL, et al. Prognosis of pulmonary arterial 
hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(1 
SUPPL.):78S-92S.
35.
Cade WT, Fantry LE, Nabar SR, Shaw DK, Keyser RE. Impaired oxygen on-kinetics in 
persons with human immunodeficiency virus are not due to highly active antiretroviral 
therapy. Archives of physical medicine and rehabilitation. Dec 2003;84(12):1831-1838.
36.
Yorke J, Jones PW, Swigris JJ. Development and validity testing of an ipf-specific 
version of the St George's respiratory questionnaire. Thorax. 2010;65(10):921-926.
37.
Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. 
Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch 
Neurol. Oct 1989;46(10):1121-1123.
38.
Tran PV, Schwarz J, Gorman M, Helme RD. Validation of an automated up-timer for 
measurement of mobility in older adults. The Medical journal of Australia. Oct 20 
1997;167(8):434-436.
39.
Hawthorne G, Osborne RH, Taylor A, Sansoni J. The SF36 Version 2: critical analyses of 
population weights, scoring algorithms and population norms. Qual Life Res. May 
2007;16(4):661-673.
40.
Bulpitt CJ, Fletcher AE, Dossegger L, Neiss A, Nielsen T, Viergutz S. Quality of life in 
chronic heart failure: cilazapril and captopril versus placebo. Cilazapril-Captopril 
Multicentre Group. Heart. Jun 1998;79(6):593-598.
41.
Patel AS, Siegert RJ, Brignall K, et al. The development and validation of the King's 
Brief Interstitial Lung Disease (K-BILD) health status questionnaire. Thorax. 
2012;67(9):804-810.
42.
Atterhog JH, Jonsson B, Samuelsson R. Exercise testing: a prospective study of 
complication rates. Am Heart J. Nov 1979;98(5):572-579.
43.
Franklin B, Hellerstein H, Gordon S, Timmis G. Exercise Testing: Basic Principles. New 
York: Churchill Livingstone; 1992.
44.
Gibbons L, Blair SN, Kohl HW, Cooper K. The safety of maximal exercise testing. 
Circulation. 1989;80(4):846-852.
45.
Gibbons LW, Mitchell TL, Gonzalez V. The safety of exercise testing. Prim Care. Sep 
1994;21(3):611-629.
46.
Hamm LF, Crow RS, Stull GA, Hannan P. Safety and characteristics of exercise testing 
early after acute myocardial infarction. The American journal of cardiology. May 15 
1989;63(17):1193-1197.
47.
Modesto KM, Moller JE, Freeman WK, Shub C, Bailey KR, Pellikka PA. Safety of 
exercise stress testing in patients with abnormal concentrations of serum potassium. The 
American journal of cardiology. Apr 15 2006;97(8):1247-1249.
48.
Squires RW, Allison TG, Johnson BD, Gau GT. Non-physician supervision of 
cardiopulmonary exercise testing in chronic heart failure: safety and results of a 
preliminary investigation. J Cardiopulm Rehabil. Jul-Aug 1999;19(4):249-253.
49.
Stuart RJ, Jr., Ellestad MH. National survey of exercise stress testing facilities. Chest. Jan 
1980;77(1):94-97.
50.
Vacanti LJ, Sespedes LB, Sarpi Mde O. Exercise stress testing is useful, safe, and 
efficient even in patients aged 75 years or older. Arquivos brasileiros de cardiologia. Feb 
2004;82(2):151-154, 147-150.

14.-CC-0027- Version 13
42
Leighton Chan 07.12.2021
51.
Young DZ, Lampert S, Graboys TB, Lown B. Safety of maximal exercise testing in 
patients at high risk for ventricular arrhythmia. Circulation. Aug 1984;70(2):184-191.
52.
Irwin S, Blessy R. Patient Evaluation. In: Irwin S, Tecklin J, eds. Cardiopulmonary 
Physical Therapy Second ed. St. Louis: C.V. Mosby; 1990:139-140.
53.
Rochmis P, Blackburn H. Exercise tests. A survey of procedures, safety, and litigation 
experience in approximately 170,000 tests. Jama. Aug 23 1971;217(8):1061-1066.
54.
Gibbons LW, Mitchell TL, Gonzalez V. The safety of exercise testing. Primary Care - 
Clinics in Office Practice. 1994;21(3):611-629.
55.       Elia D, Kelly JL, Martolini D, Renzoni, EA, Boutou AK, Chetta A, Polkey MI, 
Hopkinson NS. Respiratory muscle fatigue following exercise in patients with interstitial 
lung disease. Respiration 2013;85(3):220-227.
56.       Keyser, R.E., Woolstenhulme, J., Chin, LMK, Nathan, S.B., Weir, N.A., Connors, G., 
Drinkard, B., Lamberti, J., and Chan, L.E.  Cardiorespiratory function before and after 
aerobic exercise training in patients with interstitial lung disease.  Journal of 
Cardiopulmonary Rehabilitation and Prevention 2015 January/February 35(1):47-55. 
57.       Galie, N, Humbert, M, Vachiery, J, Gibbs, S, Lang, I, Torbicki, A, Simonneau, G, 
Peacock, A, Noordegraaf, A, Beghetti, M, Ghofrani, A, Gomez Sanchez, M, Hansmann, 
G, Klepetko, W, Lancellotti, P, Matucci, M, McDonagh, T, Pierard, L, Trindade, P, 
Zompatori, M, Hoeper, M.  2015 ESC/ERS Guidelines for the diagnosis and treatment of 
pulmonary hypertension.  European Heart Journal  Jan 2016, 37 (1) 67-119.   
List of Abbreviations
6MWD
Six Minute Walk Distance
6MWT 
Six Minute Walk Test
A-VO2
Arteriovenous Oxygen Difference
AET
Aerobic Exercise Training
AET+
Aerobic Exercise Training Group
AI
Associate Investigator
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
AT-Time
Anaerobic Threshold
ΔVO2
Amplitude of Change in Oxygen Consumption from Baseline
CON
Control Group (Education Only)
COPD
Chronic Obstructive Pulmonary Disease
CP
Conditional Power
DBP
Diastolic Blood Pressure
DKA
Diabetic Ketoacidosis
DLCO
Diffusion Capacity
EKG
Electrocardiogram

14.-CC-0027- Version 13
43
Leighton Chan 07.12.2021
FIO2
Fraction of Inspired Oxygen
FSS
Fatigue Severity Scale
FVC
Forced Vital Capacity
GET
Gas Exchange Threshold
HAP
Human Activity Profile
HRQOL
Health Related Quality of Life
HRR 
Heart Rate Reserve
ILD
Interstitial Lung Disease
IMM
Independent Medical Monitor
IPF
Idiopathic Pulmonary Fibrosis 
K-BILD
King’s Brief Interstitial Lung Disease Health Status Questionnaire
LVEF
Left Ventricular Ejection Fraction
MCID 
Minimal Clinical Important Difference
MRT
Mean Response Time
MVV
Maximal Voluntary Ventilation 
NIRS 
Near Infrared Spectrometry
NYHA
New York Heart Association
ORI
Oxidative Response Index
PA
Pulmonary Artery
PAH
Pulmonary Arterial Hypertension
PETCO2
Partial Pressure of End-Tidal Carbon Dioxide
PETO2
Partial Pressure of End-Tidal Oxygen 
PH
Pulmonary Hypertension
PI           
Principal Investigator
POMS 
Profile of Mood States
PPH 
Primary Pulmonary Hypertension
PWC
Peak Work Capacity
QOD
Quantifiable Oxygen Deficit
QOL
Quality of Life
Qt
Cardiac Output
r
Correlation Coefficient
r2
Coefficient of Determination
RAP
Right Atrial Pressure
RCT 
Randomized Control Trial
RER
Respiratory Exchange Ratio
RHC
Right Heart Catheterization 
RMD 
Rehabilitation Medicine Department
RV
Right Ventricle
RVSP
Right Ventricular Systolic Pressure 
SGRQ-I
St. George’s Respiratory Questionnaire-IPF Specific Version
SBP
Systolic Blood Pressure
SF36v2
Short Form 36 Health Survey Version 2
SpO2
Saturation of Peripheral Oxygen
SSQ
Social Support Questionnaire
tCPET
Treadmill Cardiopulmonary Exercise Test
TPR 
Total Peripheral Resistance
TRV
Tricuspid Regurgitation Velocity

14.-CC-0027- Version 13
44
Leighton Chan 07.12.2021
VCO2
Volume of Expired Carbon Dioxide
Ve
Expired Minute Ventilation
VO2 
Oxygen Consumption (Volume of Oxygen Consumed per Minute)
Vs (or SV)
Stroke Volume
Vt
Tidal Volume
WHO
World Health Organization
WR
Work Rate
ZCG
Impedance Cardiogram