Inspiratory Muscle Rehabilitation in Children With Obesity to Promote Physical Activity
Phase: NA
Conditions: Pediatric Obesity
Sponsor: Duke University

 
 
Inspiratory Muscle Rehabilitation in Children With Obesity 
(BREATHE Fit) 
 
Funding Sponsor: 
Derfner Foundation 
 
Protocol Date: 
02-26-2022 
Protocol Version: 
0.1 
 
 
NCT number: 
NCT05412134 
Principal Investigator: 
Jason E. Lang, MD, MPH 
Associate Professor of Pediatrics-
Pulmonary and Sleep Medicine 
Duke University Medical Center 
Duke Clinical Research Institute 
Durham, NC 27710 
Phone: 919-684-9590 
Fax: 919-668-3750 
Email: Jason.Lang@duke.edu 
 

 
STATEMENT OF COMPLIANCE 
This trial will be conducted in compliance with the protocol, International Council for Harmonisation 
(ICH) E6(R2) guideline for Good Clinical Practice (GCP), and the applicable regulatory 
requirements from the United States Code of Federal Regulations (CFR), including 45 CFR 46 
(Human Subjects Protection); 21 CFR 50 (Informed Consent), and 21 CFR 56 (Institutional Review 
Board [IRB]). 
All individuals who are responsible for the conduct, management, or oversight of this study have 
completed Human Subjects Protection and ICH GCP Training. 
 
 
 
 
 
 
 
Site Principal Investigator Name (Print) 
 
 
 
 
 
 
Site Principal Investigator Signature 
 
Date 
 
 

 
STUDY PRINCIPAL INVESTIGATOR/IND SPONSOR SIGNATURE 
The signature below documents the review and approval of this protocol and the attachments (e.g., 
MOP, package inserts), and provides the necessary assurances that this clinical study will be 
conducted according to all stipulations of the protocol, including all statements regarding 
confidentiality and according to local legal and regulatory requirements and to the principles 
outlined in applicable U.S. and international regulations and ICH guidelines. 
 
Jason E. Lang, MD, MPH 
 
 
Study Principal Investigator Name 
 
 
 
 
 
 
Study Principal Investigator Signature 
 
Date 
 
 
 
 

 
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE 
ii 
STUDY PRINCIPAL INVESTIGATOR/IND SPONSOR SIGNATURE 
iii 
TABLE OF CONTENTS 
iv 
LIST OF TABLES 
ix 
LIST OF FIGURES 
x 
LIST OF ABBREVIATIONS 
xi 
PROTOCOL HISTORY OF CHANGES 
xiii 
PROTOCOL SYNOPSIS 
xiv 
SCHEMATIC/DESCRIPTION OF STUDY DESIGN 
xvi 
1. 
KEY ROLES 
1 
2. 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
3 
2.1  
Background Information 
3 
2.2  
Potential Benefits 
4 
2.3  
Compensation 
5 
2.4 
Potential Study Risks 
5 
2.4.1 
Risks of Inspiratory muscle training 
5 
2.4.2 
Risks of Maximal inspiratory pressure measurement 
5 
2.4.3 
Risks of Stair-step challenge 
5 
2.4.4 
Potential Risk of Loss of Confidentiality 
6 
2.4.5 
Unforeseen Risks 
6 

 
3. 
OBJECTIVES AND OUTCOME MEASURES 
7 
4. 
STUDY DESIGN 
9 
4.1 
Randomization 
9 
4.2 
Blinding/Masking 
9 
4.3 
Study Interventions 
9 
4.4 
Duration of Participation for Participant 
10 
4.5 
Biological Specimen Testing 
10 
4.6 
Safety 
10 
4.7 
Events of Special Interest 
10 
4.8 
Rationale for Dose Selection 
10 
4.9 
Study Definition of Enrollment 
12 
4.10 
Study Definition of Completion 
12 
5. 
STUDY POPULATION 
13 
 
Selection of the Study Population 
13 
 
Inclusion/Exclusion Criteria 
13 
 
Screen Failures 
13 
5.4. 
Treatment Assignment Procedures 
13 
5.4.1 
Randomization Procedures 
13 
5.5. 
Participant Discontinuation/Withdrawal 
14 
5.5.1 
Participant Decides to Withdraw Consent 
14 
5.5.2 
Participant Decides to Withdraw from Study Intervention/Product 
14 
5.5.3 
Study Investigator/Sponsor Decides to Withdraw Participant 
14 
5.5.4 
Individual Stopping of Dosing Criteria: 
14 

 
5.5.5 
Handling of Withdrawals 
14 
5.5.6 
Replacements 
15 
6. 
STUDY PROCEDURES 
16 
6.1 
Screening 
16 
6.2 
Summary of Procedures 
17 
6.2.1  
Visit 1 (goal timing: day -10 to -14) 
17 
6.2.2  
Visit 2 (day 0) 
17 
6.2.3  
Visit 3 (Day 42) 
18 
6.3 
Early Study Termination Visit 
19 
6.4 
Continuation Visit 
Error! Bookmark not defined. 
6.5 
Phone check-ins (days 7, 14, 21, 28, and 35) 
Error! Bookmark not defined. 
6.6 
Actigraphy/physical activity assessment 
19 
6.7 
Spirometry 
19 
6.8 
Maximal Inspiratory Pressure measurement 
Error! Bookmark not defined. 
6.9 
Questionnaires 
20 
6.9.1  
Baseline medical history questionnaire. 
20 
6.9.2  
Questionnaires during Exercise: Modified Borg dyspnea scale. 
20 
6.9.3  
Questionnaires during Exercise: Dalhousie Rating with exercise 
20 
 
6.9.4  
Retrospective Questionnaire assessing Dyspnea during daily activity: Baseline 
Dyspnea Index (BDI). 
22 
6.9.5    Retrospective Questionnaire assessing Dyspnea during daily activity: MRC      
Breathlessness scale. 
 
24 
6.10 
Stair-step Challenge 
Error! Bookmark not defined. 
6.10.1 
Preparation for administration of Step Test 
24 

 
6.10.2 
Administering the Step Test 
24 
6.10.3 
Recording HR and pulse oximetry 
25 
6.11 
Specimen Preparation, Handling, Storage and Shipping 
25 
7. 
STUDY PRODUCT DESCRIPTION 
26 
7.1 Dosage and Study Intervention Information 
26 
7.1.1 
Dose of Inspiratory muscle training 
26 
7.1.2 
Formulation, Packaging, and Labeling 
26 
7.1.3 
Product use and directions 
26 
7.2 Accountability Procedures for the Study Product(s) 
26 
8. 
ASSESSMENT OF SAFETY 
27 
 
Adverse Event 
27 
 
Guidelines for Assessing Association of an Adverse Event 
27 
 
Guidelines for Assessing Intensity of an Adverse Event 
27 
 
Guidelines for Assessing Causality 
27 
 
Collection Period and Reporting Procedures 
28 
 
Event of Special Interest 
28 
 
Pregnancy 
Error! Bookmark not defined. 
 
Safety Interim Analysis 
29 
9. STUDY HALTING/TERMINATION 
30 
9.1 
Study or Site Halting/Termination Criteria 
30 
9.2 
Halting Rules 
30 
10. 
STATISTICAL CONSIDERATIONS 
31 
10.1 
Study Hypotheses 
31 

 
10.2 
Objectives and Endpoints 
31 
10.3 
Analysis Populations 
32 
10.3.1 Exposure-Response Population 
Error! Bookmark not defined. 
10.3.2 Safety Population 
Error! Bookmark not defined. 
10.4 
General Analysis Plan 
32 
10.4.1  Statistical design and power. 
Error! Bookmark not defined. 
10.4.2 Demographics and Baseline Characteristics 
Error! Bookmark not defined. 
10.5  
Sample Size Considerations 
33 
11. ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
34 
11.1  
Informed Consent Process 
34 
11.2  
Permission from Participants 
34 
11.3  
Documentation of Consent 
34 
11.4  
Confidentiality and Privacy 
35 
12. DATA HANDLING AND RECORD KEEPING 
37 
12.1  
Data Handling 
37 
12.2  
Data Management Responsibilities 
37 
12.3  
Data Capture Methods 
37 
12.4  
Types of Data 
37 
12.5  
Timing/Reports 
37 
12.6  
Study Records Retention 
37 
12.7  
Protocol Deviations 
38 
13. 
PUBLICATION POLICY 
Error! Bookmark not defined. 
14. 
REFERENCES 
40 

 
LIST OF TABLES  
 
Table 1 Objectives an Outcomes Measures ......................................................................... 7 
Table 2 Prior Duke IMR Projects ........................................................................................ 10 
Table 3 Effects of Daily IMR treatment over 6 weeks on Respiratory Outcomes – 
Preliminary data ........................................................................................................... 11 
Table 4 Study Procedures .................................................................................................. 16 
Table 5 Statistical power based on effect size .................................................................... 33 
 
 
 

 
LIST OF FIGURES 
 
Figure 1 Study schematic.  Mechanisms of action of (A) obesity leading to dyspnea and 
activity avoidance, and (B) IMR facilitating greater activity. ......................................... xvi 
Figure 2 Mechanisms of action of (A) obesity leading to dyspnea and activity avoidance, 
and (B) ........................................................................................................................... 3 
Figure 3 Change in validated asthma symptom scores with IMR. ACT – asthma control test, 
ACQ6 – asthma control questionnaire 6 item ............................................................... 11 
Figure 4 Dalhousie Questionnaire ...................................................................................... 21 
 
 
 
 

 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATS 
American Thoracic Society 
BPM 
Beats Per Minute 
BMI 
Body Mass Index 
BPCA 
Best Pharmaceutical for Children Act 
CI 
Confidence Interval 
CmH2O 
Centimeter of Water 
CoC 
Certificate of Confidentiality 
COVID-19 
Coronavirus Disease 2019 
CVF 
Cardiovascular Fitness 
DCC 
Data Coordinating Center 
DHBS 
Duke Healthy Breathing Study 
DUHS 
Duke University Health System 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FEF25-75 
Forced Expiratory Flow at 25% to 75% 
FEV1 
Forced Expiratory Volume in 1 second 
FVC 
Forced Vital Capacity 
GPS 
Global Positioning System 
HIPAA 
Health Insurance Portability and Accountability Act 
HL 
Healthy Lifestyles 
ICF 
International Council for Harmonisation 
ICS 
Inhaled corticosteroids 
IEC 
Institutional Ethics Committee 
IMR 
Inspiratory Muscle Rehabilitation 
IRB 
Institutional Review Board 
ITT 
Intention to treat 
LAMA 
Long-acting muscarinic antagonist 
LTRA 
Leukotriene Receptor Antagonist 
m 
Meter 
Max 
Maximum 
MIP 
Maximum Inspiratory Pressure 
mm 
Millimeter 
MVPA 
Moderate-Vigorous Physical Activity 
BDI 
Baseline Dyspnea Index 
FWA 
Federal-wide Assurance 
DMC 
Data Monitoring Committee 
ACQ 
Asthma Control Questionnaire 
MOP 
Manual of Procedures 
NC 
North Carolina 

 
 
 
 
 
NIH 
National Institute of Health 
O2 
Oxygen 
PI 
Principal Investigator 
REB 
Research Ethics Board 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SD 
Standard Deviation 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 

 
 
PROTOCOL HISTORY OF CHANGES 
Version 
Date 
Summary of Changes 
1.0 
DD-MMM-
2021 
N/A Original protocol 
 
 
 

 
PROTOCOL SYNOPSIS 
Protocol Title: 
 
BREATHE Fit: Inspiratory Muscle Rehabilitation in Children with 
Obesity to Promote Physical Activity 
 
Phase: 
 
Pilot 
 
Product: 
 
PrO2 IMR ™ trainer  
 
Objectives: 
 
Primary: Demonstrate inspiratory muscle rehabilitation (IMR) as an 
acceptable add-on intervention in children with obesity. 
 
Secondary: 
1. Demonstrate changes in inspiratory muscle functioning and dyspnea reporting 
following IMR. 
2. Demonstrate changes in daily physical activity following IMR. 
 
Exploratory: Demonstrate changes in exercise capacity following IMR. 
 
Study Design: 
 
Single-center, randomized, SHAM-controlled, parallel assignment, double 
masked, interventional study. 
 
Study 
Population: 
 
Inclusion Criteria 
1. Documented informed consent from legal guardian and assent from 
participant as appropriate. 
2. Children 8 to 17 years of age with obesity (BMI ≥ 95th percentile for age and 
sex) being seen at Duke Healthy Lifestyles clinic. 
3. Participants (or parent/guardian) must have access to the internet and an 
approved smart device/computer. 
4. Child must have a designated caregiver who expresses a commitment to 
encourage the participant to complete the study procedures. 
5. Participant and legal guardian must speak and read English or Spanish. 
 
Exclusion Criteria 
6. Prior enrollment in an IMR program. 
7. Contraindications for IMR including a history of recent lung surgery, recent 
pulmonary embolism, or history of recurrent spontaneous pneumothorax 
8. Progressive neurological or neuromuscular disorders or need for 
chronic O2 therapy. 

 
9. Inability to complete baseline measurements in a satisfactory manner 
according to the judgment of the research coordinator or PI. 
10. Current self-reported pregnancy or planning to become pregnant. 
11. Body weight greater than 300 pounds. 
12. Any condition in the opinion of the PI that would not allow safe conduct of 
study procedures (including IMR, MIP testing or step-test), such as a 
physical disability, recent musculoskeletal injury or illness, current and 
ongoing evaluation for undiagnosed cardiopulmonary or neurologic 
symptoms, undiagnosed chest pain, pneumothorax in the past 12 months, 
inner ear surgery in the past 12 months, or undiagnosed syncopal episodes. 
 
Number of 
Participants: 
 
Up to 30 
 
Number of 
Sites: 
 
1 site 
 
Duration of 
Participation: 
 
Planned participation will be approximately 56 days. Total participation may 
be up to 77 days.  
 
Intervention: 
 
Intervention: Inspiratory Muscle Trainer at 75% of the participant’s maximal 
inspiratory pressure (MIP). Target dose: 3 sets of 50 inspiratory breaths 3 
times per week.  
 
Sham comparator: Inspiratory Muscle Trainer at 15% MIP. Target dose: 3 
sets of 50 inspiratory breaths 3 times per week. 
 
Estimated 
start:  
 
Q1 2022 
 
 
Estimated 
time to 
complete 
enrollment 
 
 
Q3-4 2022 

 
SCHEMATIC/DESCRIPTION OF STUDY DESIGN 
 
 
 
 
Figure 1 Study schematic.  Mechanisms of action of (A) obesity leading to dyspnea and 
activity avoidance, and (B) IMR facilitating greater activity. 

 
1. KEY ROLES 
Study Principal Investigator: 
Jason E. Lang, MD, MPH 
Associate Professor of Pediatrics-Pulmonary and Sleep Medicine 
Duke University Medical Center 
Duke Clinical Research Institute 
Durham, NC 27710 
Phone:  919-684-9590 
Fax:  919-668-7063 
Email:  Jason.Lang@duke.edu 
 
Co-Investigator:  
Zeni Scott, MD 
Pediatric Pulmonology Fellow 
Duke University Medical Center 
Durham, NC 27705 
Email: zeni.scott@duke.edu 
 
Co-Investigator:  
Sarah Armstrong, MD, FAAP 
Professor of Pediatrics and Department of Family Medicine and Community Health 
Duke University Medical Center 
Duke Clinical Research Institute 
Durham, NC 27710 
Phone: 919-620-5374 
Email: sarah.c.armstrong@duke.edu 
 
Co-Investigator:  
Cindy Green, PhD 
Associate Professor of Biostatistics & Bioinformatics 
Duke University Medical Center 
Duke Clinical Research Institute 
Durham, NC 27710 
Phone: 919-308-5887 
Email: cindy.green@duke.edu 
 
Co-Investigator:  
Verónica M. Palacios 
Clinical Research Coordinator  
Duke Office of Clinical Research (DOCR) 
Duke University School of Medicine  
veronica.palacios@duke.edu  
 
Co-Investigator:  
Janna B. Howard, MPH 

 
 
 
Research Program Leader 
Duke Center for Childhood Obesity Research 
Department of Pediatrics, Duke University Medical Center 
Phone: 919-620-4793 
Email: janna.howard@duke.edu 
 
Co-Investigator:  
Nicholas Fitzpatrick, MD 
Pediatric Pulmonology Fellow 
Duke University Medical Center 
Durham, NC 27705 
Email: nicholas.fitzpatrick@duke.edu 
 
 
 
 

 
 
2. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1  Background Information 
Improved management of obesity is an urgent public health need. Nearly 40% 
of US children and adolescents have a body mass index that markedly increases 
their risk for serious metabolic and cardiopulmonary sequelae. Current childhood 
obesity rates, for the first time in US history, predict a decline in life US expectancy. 
Importantly, childhood obesity is a key driver of health disparities in the US, with 
obesity disproportionately affecting African-American, Hispanic-Latino and Native 
American children. A key contributor to the sequelae of obesity is sedentariness. 
Thus, best practice in obesity management includes both reducing sedentariness 
and establishing durable increases in daily physical activity1,2, however, attrition from 
planned exercise programs remains high. 3 A key challenge to initiating and 
sustaining physical activity in children with obesity is the extreme dyspnea 
(breathlessness) they experience. This is due to the altered thoracic mechanics of 
obesity which lead to enhanced inspiratory muscle fatigue and dyspnea, with even 
modest physical activity (Figure 2A). Our group has confirmed that among 
adolescents, higher body mass index (BMI) associates with lower inspiratory muscle 
endurance (r= -0.680, p=0.049, n=14), and that this lower endurance correlates with 
more frequent dyspnea (r= - 0.672, p=0.023, n=12). Treating obesity-related 
inspiratory muscle impairment and dyspnea is a promising approach to support 
physical activity in children with obesity, but is yet unproven. 
 
Inspiratory muscle rehabilitation (IMR) is a promising approach to reduce 
obesity-related dyspnea and 
boost physical activity. 
Pulmonary rehabilitation (in its 
various forms, including IMR) is 
a treatment cornerstone in 
adult medicine but is 
underutilized in pediatrics.4 In 
adults, IMR has been studied 
in healthy athletes5,6, and 
numerous lung 7-10 and neuromuscular 11-13 diseases. In adults, IMR consistently 
improves inspiratory muscle function, reduces dyspnea and improves exercise 
tolerance.14-19  Adding IMR to an exercise training regimen in healthy young adults 
who were obese led to significant improvements in subjective ratings of dyspnea and 
objectively measured exercise capacity.20 IMR has not been sufficiently studied in 
children with obesity. However, recently in our pilot work at Duke, children with 
obesity (and asthma) underwent the ‘DHBS’ pilot IMR trial (NCT03911206). Children 
(n=11) were randomized to IMR (3 sets of 50 reps, three times/week), exercise or 
usual care for 6 weeks. Ten of 11 completed all visits, and 11 reported wanting to 
continue IMR after the study. IMR improved mean maximum inspiratory pressures 
(MIP) (+34 cm H2O, p=0.014) and improved exercise capacity measured by 6-
minute walk distance (+115 meters) (p=0.136) compared to IMR. Based on these 
 
 Figure 2 Mechanisms of action of (A) obesity 
leading to dyspnea and activity avoidance, and (B) 

 
 
data, we are highly encouraged that IMR will help children with obesity increase their 
physical activity (Figure 2B). 
 
 
Duke Pediatrics is expertly equipped to advance IMR in Children with Obesity. 
Duke Pediatrics’ Healthy Lifestyles (HL) clinic, led by Co-I Dr. Sarah Armstrong, 
treats >7000 children ages 8-17 with obesity each year (>35% Black, >20% 
Hispanic).21 Treatment includes intensive lifestyle counseling, community-based 
physical activity, pharmacotherapy, or weight-reduction surgery.22 As part of routine 
clinical monitoring, patients in HL complete measures of exercise capacity to assess 
physical activity gains, and have (as part of consented research) provided wearable 
accelerometers to track total daily activity (i.e. steps) and time achieving moderate to 
vigorous physical activity (MVPA).23,24 Dr. Armstrong has led or facilitated multiple 
research studies within the obesity clinic, with established protocols and regulatory 
processes for recruitment, consent, and follow up study visits.21,25-27 This 
collaboration between the Pediatric Pulmonary and Healthy Lifestyles clinical 
research teams focuses on a completely new area of research for the investigators 
(IMR) and provides a superior environment for studying impactful innovations in 
pediatric obesity.  
Together, we propose BREATHE Fit, a randomized SHAM-controlled 6-week trial of 
inspiratory muscle rehabilitation in children aged 8-17 years with obesity enrolled in 
the Duke HL.  Primary research question: Is IMR an acceptable add-on 
intervention that promotes greater activity in children with obesity?  The BREATHE 
Fit trial will address the following aims: 
Aim 1. Demonstrate the acceptability of IMR in children with obesity. 
Hypothesis 1a (H1a). More than 80% of participants will be satisfied with active IMR 
at study completion. H1b. Total IMR adherence will be >80% of planned active IMR 
repetitions. H1c. Active IMR will not be associated with any serious adverse 
reactions.  
Aim 2. Demonstrate changes in inspiratory muscle functioning and dyspnea 
reporting following IMR. H2a. IMR will significantly increase inspiratory strength 
(measured by mean change in MIP). H2b. IMR will reduce patient-reported 
retrospective dyspnea scores during activities of daily living.   
Aim 3. Demonstrate changes in daily physical activity following IMR. 
H3a. IMR will lead to reduced sedentary time, increased moderate-strenuous time 
and increased total daily activity measured by a wrist-worn continuous activity 
tracking monitor. 
 
2.2  Potential Benefits 
IMR is very likely to improve inspiratory muscle strength. These benefits in 
inspiratory muscle strength may reduce dyspnea (breathlessness) with daily activity 
and with exercise. In addition, IMR may improve exercise capacity and exercise 
tolerance. Although improvements in these outcomes are not guaranteed, 
improvements in general health, daily activity and weight loss are a possibility. 

 
 
Conclusions drawn from this study may benefit children with obesity by adding to the 
understanding of how IMR affects breathing. All participants will have baseline lung 
function testing and will have their daily physical activity monitored.  
 
2.3  Compensation 
Participants will be fairly compensated for their time and effort. Successful 
completion of the study (visit 3) will result in a $75 monetary payment (gift cards). In 
addition, participants will be gifted the Garmin Vivosmart 4 study activity tracker 
(retail value $100) on visit 1. If participants do not complete the study, they will be 
asked to return the activity tracker and inspiratory muscle trainer. Participants will 
receive a $25 gift card with the successful completion of visit 2, and $50 gift card 
with the successful completion of visit 3.  
 
VISIT # 
COMPENSATION 
 
V1 
Garmin Vivosmart 4 
study activity tracker 
(retail value $100) 
 
V2 
 
$25 Nike gift card 
 
V3 
 
$50 Nike gift card 
 
 
2.4 Potential Study Risks 
2.4.1   Risks of inspiratory muscle training 
The risk of inspiratory muscle training is minimum. Inspiratory muscle training 
is deep breathing exercises against a resistance. Risks are thought to be 
generally minimal and similar to daily living or routine exercise. No known 
systematic reports are known describing risks from IMR. However, patients 
will be advised that they may experience mild, self-limited dizziness, 
headache, or dyspnea. 
2.4.2  Risks of maximal inspiratory pressure measurement 
Inspiratory muscle strength testing is a routine clinical test performed in the 
outpatient setting. The side-effect profile is expected to be similar to that of 
inspiratory muscle training. 
2.4.3  Risks of stair-step challenge 
The stair-step challenge is a generally safe exercise procedure conducted in 
the outpatient setting. There is a small chance of tripping or falling during the 
procedure and possible resulting injury. Close supervision and spotting of the 
participant will take place to reduce the chance of injury. 

 
 
2.4.4  Potential risk of loss of confidentiality 
There is a potential risk of loss of confidentiality. Every effort will be made to 
protect the participant’s confidential medical information, but this cannot be 
guaranteed. 
2.4.5  Unforeseen risks 
There may be other risks to the participant from this research that are not 
known or foreseeable at this time. 

 
 
3. OBJECTIVES AND OUTCOME MEASURES 
 
Table 1 Objectives an Outcomes Measures 
Primary Objectives 
Outcome 
Measures 
Endpoints 
Analysis 
Demonstrate IMR as 
an acceptable add-on 
intervention in children 
with obesity. 
1. completion of 
study Visit 3 (V3) 
2. adherence to 
active IMR 
3. participant 
satisfaction among 
active IMR 
participants 
1. prevalence of 
completer status 
2. prevalence of IMR 
completion (actual / 
planned reps over 
intervention period) in 
active IMR group 
3. prevalence of agree 
or strongly agree to 
question of satisfaction 
with active IMR 
Simple 
descriptive 
statistics: 
calculation of 
prevalence 
 
Secondary 
Objectives 
Outcome 
Measures 
Endpoints 
Analysis 
Demonstrate changes 
in inspiratory muscle 
functioning and 
dyspnea reporting 
following IMR 
1. Maximum 
inspiratory 
pressure (MIP) 
2. Baseline Dyspnea 
Index score 
3. MRC 
breathlessness 
scale 
1. change in MIP over 
intervention period 
2. change in dyspnea 
scores over intervention 
period 
Analysis of 
covariance 
(ANCOVA) 
Demonstrate changes in 
daily physical activity 
following IMR 
1. moderate-
vigorous physical 
activity (MVPA) 
time 
2. sedentary 
physical activity 
(SPA) time 
3.   total steps 
1. change in average daily 
MVPA time  
2. change in average daily 
SPA time 
3. change in average daily 
step count 
Analysis of 
covariance 
(ANCOVA) 
Exploratory Objectives 
Outcome 
Measures 
Endpoints 
Analysis 
Demonstrate changes in 
exercise capacity 
following IMR 
1. heart rate during 3 
minute step test 
1. heart rate change during 
3-minute step test 
Analysis of 
covariance 
(ANCOVA) 
 
 
 
 
 

 
 
 
 
 

 
 
4. STUDY DESIGN 
Overall Design 
Single-center, randomized, SHAM-controlled, parallel assignment, double masked, 
interventional study. 
4.1 Randomization 
Participants (n=30) will be randomized to one of two treatment arms. 
• 
Arm A (n=15): IMR 
• 
Arm B (n=15): Sham 
4.2 Blinding/Masking 
Treatment assignment will be obtained through the Duke REDCap randomization 
system. All participant-facing study staff and participants will be blinded to the 
treatment assignment. Participants may come to feel that they can surmise whether 
their device is set to the active resistance. Although complete masking may not be 
possible in all participants, participants will only be informed that they are receiving 
one of two resistances (low or active). However, all study staff that assess outcomes 
(and the lead statistician) will remain blinded. Participants will be instructed to not 
discuss their presumed IMR assignment with study staff. 
4.3 
Study Interventions 
Active IMR or SHAM using the PrO2™ device. Each participant will be provided a 
PrO2™ device and trained on its use as well as its accompanying PrO2 Fit™ app. 
The PrO2™ is a flow-resistive device that provides inspiratory resistance via a fixed 
2mm orifice and has Bluetooth connectivity to most IOS/Android devices or 
Mac/Windows computers. The PrO2™ device and app allows for both 100% 
adherence monitoring and immediate user biofeedback.  
Participants will be instructed at Visit 1 and Visit 2 to inspire forcefully through 
PrO2™ until the device signals that the user has achieved the target resistance (via 
audible alarm and visible light signal). The research team will implement 
biofeedback signals at a specific inspiratory resistance to provide precise and 
individualized training target. Successful IMR repetitions will require that subjects 
achieve a pressure target that is 75% of their MIP.   
SHAM intervention. Participants in the control intervention will also use the same 
PrO2™ device but at a reduced peak resistance of 15% MIP. The research team will 
implement biofeedback signals at a specific inspiratory resistance to provide precise 
and individualized training target. Successful IMR repetitions will require that 
subjects achieve a pressure target that is 15% of their MIP. 
Adherence monitoring. All device repetitions are automatically captured and 
documented via the Bluetooth connection with the PrO2™ app and end-to-end 
encrypted and transferred to a HIPAA-compliant cloud server (Amazon Web 
Services). Study staff will review each participant’s adherence each week and will 
provide encouragement as needed.  

 
 
4.4 
Duration of Participation for Participant 
The approximate duration of participation is 56 days. The maximum duration of 
participation will be 77 days.  
4.5 Biological Specimen Testing 
No biologic specimens will be taken. 
4.6 
Safety 
See Section 8. 
4.7 
Events of Special Interest 
Not applicable. 
4.8 
Rationale for Dose (inspiratory load) Selection 
We used published IMR regimens to select an initial resistive load (intensity), 
number of repetitions/sets per day, and weekly session number for our pilot work 
(Table 2). We first completed an IRB-approved pilot study called the Duke Healthy 
Breathing Study 1(DHBS1) of directly supervised IMR in 10-17 year-olds with 
asthma. Using a commercially available IMR respiratory training device, participants 
with asthma completed and tolerated 4 sets of 60 reps of IMR at 60-75% MIP. We 
solicited feedback from both adolescents and parents regarding tolerability, 
acceptability, and future interest in IMR as a potential chronic breathing intervention. 
Nearly 95% of participants were able to complete all repetitions at 60-75% of MIP. 
This one-time session was well-tolerated in all participants without any significant 
adverse events. Thirteen of 14 (93%) participants wanted to continue daily IMR after 
study completion. Based on DHBS1, we initiated the DHBS2 study, an IRB-
approved (NCT03911206) randomized, ‘usual care’-controlled, parallel-group, 6-
Table 2 Prior Duke IMR Projects 
Investigator 
(year) 
Population 
IMR characteristics 
Results 
Lang/Jones (2017) 
DHBS1 (Duke 
funded) 
14 children and 
adolescents (10-
17 years of age) 
with persistent 
asthma 
Repetitions: 4 sets of 50 inspirations 
No significant AEs 
100% acceptability 
13 of 14 were interested in 
a home intervention 
Intensity: 60-75% MIP 
Duration: 1 session 
Lang/Jones (2018-
2020) DHBS2 (Duke 
funded) 
Participants 10-
17 years of age 
with persistent 
asthma and 
obesity or 
sedentariness 
Dose: 1 session twice daily, 3 
days/wk. 
Week 1: session= 1 set of 60 reps 
Week 2: session= 2 sets of 60 reps 
Week 3-6: session= 3 sets of 60 reps 
(with automated IMR monitoring) 
11 subjects have completed 
6-week intervention:  
10/11 (91%) completed all 
visits 
11 (100%) reported desire 
to continue IMR 
IMR treated participants 
showed non-significant 
improvements in inspiratory 
muscle strength/ 
endurance, asthma control 
and exercise tolerance 
Intensity: 75% MIP 
Duration: 6 weeks 
MIP – maximal inspiratory pressure, IMR – inspiratory muscle rehabilitation, AE – adverse event 

 
 
week intervention trial in which we tested the IMR regimen (75% MIP) in 10-17 year-
olds with obesity and asthma. 
 
Participants randomized to the IMR treatment completed 3 sets of 60 repetitions at 
75% MIP three days per week. Preliminary IMR findings from 11 participants 
involving changes in respiratory muscle strength and endurance, 6-minute walk 
distance and asthma symptom scores are encouraging and support the aims of this 
proposal (See Figure 3 and Table 3). Adherence of IMR (n=6) was 79.2% of 
prescribed repetitions over 6 weeks, which is superior to published adherence rates 
(47-57%) for daily asthma controller drugs. 
Table 3 Effects of Daily IMR treatment over 6 weeks on Respiratory Outcomes – 
Preliminary data 
Outcome type 
Intervention 
 
 
 
IMR 
(n=6) 
No IMR 
(n=5) 
p-value Summary 
Asthma Symptoms: change in ACT, 
mean (SD) (for ACT, higher score 
means better asthma) 
+1.0 (0) 
-3.0 (2) 
p=0.075 
IMR-treated participants showed a 
near significant improvement in 
ACT compared to controls (Figure 
3) 
Asthma Symptoms: change in 
ACQ-6, 
Mean (SD) (for ACQ-6, lower score 
means better asthma) 
-0.10 (0.56) 
 
0.90 (0.90) 
p=0.094 
IMR-treated participants showed a 
near significant improvement in 
ACQ-6 compared to control (Figure 
3) 
Inspiratory muscle strength: change 
in baseline MIP (cm H20), mean 
(SD)** 
+37.0 (24.1)1 
 
+12.5 (16.4)1 
 
p=0.128 
 
IMR-treated participants showed 
near significant greater MIP 
improvement compared to controls  
Inspiratory muscle strength: change 
in post-exercise MIP (cm H20), 
mean (SD)** 
+14.6 (10.5)2 
-19.0 (19.9)2 
p=0.014 
IMR-treated participants showed a 
significantly greater post-exercise 
MIP improvement compared to 
controls 
Exercise tolerance: improvement in 
six-minute walk distance (meters), 
mean (SD) 
119.1 (93.3) 
 
4.0 (112.7) 
p=0.136 
IMR-treated participants showed 
non-significant improvement in 
 
Figure 3 Change in validated asthma symptom scores with IMR. ACT – asthma 
control test, ACQ6 – asthma control questionnaire 6 item 

 
 
 
4.9 
Study Definition of Enrollment 
 A participant will be considered enrolled in the active study once eligibility criteria are 
satisfied, informed consent is signed, and the participant receives at least one dose 
of a study intervention (i.e. one training session).  
 
4.10 Study Definition of Completion 
Participant study completion will be defined as a participant who has been enrolled 
and completes Visit 3.  
 
 
 
 
 
 
 
 
 
 
 
 
6MW distance compared to 
controls 
**two MIP measures were analyzed at each visit because of acute strengthening. 1 – MIP1 start of visit (before exercise), 2 – MIP2 end 
of visit (after exercise).  ACQ-6 – score ranges from 0 to 6 with lower score meaning better asthma. Minimal important difference =0.4-
0.5. ACT – score ranges from 6 to 30 with higher score meaning better asthma. Minimal important difference = 3 

 
 
5. STUDY POPULATION 
 Selection of the Study Population 
Children 8 to 17 years of age with obesity (BMI ≥ 95th percentile for age and sex) being seen 
for a visit at the Duke HL clinic, and meeting study inclusion and exclusion criteria will be 
enrolled. Both males and females are eligible, as are participants of any race or ethnicity. 
Participants (or parent/guardian) must have access to the internet and an approved 
device/computer (see below). 
 Inclusion/Exclusion Criteria 
Inclusion 
Criteria 
 
1. Documented informed consent from legal guardian and assent from 
participant as appropriate. 
2. Children 8 to 17 years of age with obesity (BMI ≥ 95th percentile for age 
and sex) being seen at Duke Healthy Lifestyles clinic. 
3. Participants (or parent/guardian) must have access to the internet and an 
approved smart device/computer. 
4. Child must have a designated caregiver who expresses a commitment to 
encourage the participant to complete the study procedures. 
5. Participant and legal guardian must speak and read English or Spanish. 
Exclusion 
Criteria 
 
1. Prior enrollment in an IMR program. 
2. Contraindications for IMR including a history of recent lung surgery, recent 
pulmonary embolism, or history of recurrent spontaneous pneumothorax 
3. Progressive neurological or neuromuscular disorders or need for 
chronic O2 therapy. 
4. Inability to complete baseline measurements in a satisfactory manner 
according to the judgment of the research coordinator or PI. 
5. Body weight greater than 300 pounds. 
6. Any condition in the opinion of the PI that would not allow safe conduct of 
study procedures (including IMR, MIP testing or step-test), such as a 
physical disability, recent musculoskeletal injury or illness, current and 
ongoing evaluation for undiagnosed cardiopulmonary or neurologic 
symptoms, undiagnosed chest pain, pneumothorax in the past 12 months, 
inner ear surgery in the past 12 months, or undiagnosed syncopal 
episodes. 
 Screen Failures 
Participants who sign informed consent but are not enrolled in the active study are 
considered screen failures and will be recorded in the Screen Failures area of the electronic 
data capture (EDC). Participants who do not initially satisfy eligibility requirements may be 
rescreened up to 2 additional times. Re-consent is not required for rescreened participants 
unless a revised version of the consent that requires re-consent is made available.  
5.4. Treatment Assignment Procedures 
5.4.1 Randomization procedures 
Treatment assignment will be 1:1 (IMR or sham intervention), and will be obtained 
through the Duke REDCap randomization system using the randomization schedule as 

 
 
designed by the unblinded statistician. All study staff and participants will be blinded to 
the treatment assignment with the exception of one un-blinded clinical research 
coordinator. Participants may be able to tell whether their device is set to the active 
resistance. Although complete masking may not be possible in all participants, 
participants will only be informed that they are receiving one of two resistances (low or 
active). However, all study staff that assess outcomes (and the lead statistician) will 
remain blinded. Participants will be instructed to not discuss their presumed IMR 
assignment with study staff. 
5.5. Participant Discontinuation/Withdrawal 
5.5.1 Participant decides to withdraw consent 
A participant may voluntarily withdraw consent to participate in the study at any 
time. Participants are not obligated to state the reason for withdrawal. Participant 
withdrawal should not affect the participant’s medical care outside of this study. 
The reasons for withdrawal, or failure to provide a reason, must be documented 
by the investigator. No additional study procedures or data should be collected 
after consent has been withdrawn. 
5.5.2 Participant decides to withdraw from study intervention/product 
Participants may also withdraw from receiving the study intervention/product for 
any reason but continue to be followed for safety. Participants are not obligated to 
state the reason for withdrawal. 
5.5.3 Study investigator/sponsor decides to withdraw participant 
The study investigators or sponsor may decide to take the participant out of this 
study at any time without consent if: 
• 
Participant’s condition changes and the study is no longer in his/her best interest; 
• 
Participant non-compliance with the study protocol; 
• 
The entire study is stopped by the sponsor. 
5.5.4 Individual stopping of dosing criteria:  
The study investigators will stop treatment of study intervention and the participant 
will not receive additional doses of study intervention if:  
• 
Participant has a clinically significant severe AE or SAE related to the study 
intervention;  
• 
Participant becomes pregnant;  
• 
Participant newly meets criteria for study exclusion; 
• 
In the opinion of the investigator, the participant is at significant risk.  
 
If the intervention is discontinued for safety concerns, participants must be followed for 
safety until 7 days after the last study training session. Participants who are discontinued 
from study intervention due to an AE, whether serious or non-serious, must be followed 
by the investigator until the AE is resolved or considered stable.  
If any of the above occurs, the participant will be informed, and the investigator 
will discuss other options. 
 
5.5.5 Handling of withdrawals 
The reasons for withdrawal, or failure to provide a reason, must be documented 
by the investigator. Reasons for withdrawal may include: 

 
 
a. Participant withdraws consent and requests no further follow-up; 
b. Participant does not withdraw consent but withdraws from study intervention;  
c. Study PI/Sponsor decision. 
Unless there is complete withdrawal of consent from the participant, every effort 
will be made to continue follow-up visits. 
 
5.5.6 Replacements 
Females who become pregnant during the study will not receive further study 
intervention. In cases of early withdrawal, an additional participant may be 
enrolled.  
 

 
 
6. STUDY PROCEDURES 
Procedures will occur as in 
Table 4. 
6.1 Screening 
The investigator will 
screen participants in 
accordance with the 
eligibility criteria 
detailed previously. 
Research staff will 
document applicable 
informed consent for 
all participants who 
satisfy eligibility 
criteria, and will follow 
all site policies, 
procedures and 
criteria for control of 
COVID-19. 
Participants must 
satisfy all 
Inclusion/Exclusion 
criteria to be enrolled 
in the active study. 
Information will be 
recorded from the 
clinical medical record 
or from interview of 
the participant. The 
investigator will not 
exercise selectivity so that bias is prevented. 
 
Informed consent and collection of demographic information will be performed at 
screening. The following screening assessments must be done to confirm study 
eligibility: medical history (past medical/surgical history, medications, and 
smoking/drug history), review of concomitant medications, height/weight/physical 
exam, and confirm satisfaction of all eligibility criteria (inclusion and exclusion) for 
the study. Assessments not recorded per standard of care, must be conducted as a 
study specific procedure. 
 
 
 
Table 4 Study Procedures 
 
Screen 
visit 
Randomization 
visit 
Completion 
visit 
Visit number 
V1 
V2 
V3 
Timeline in days (target) 
-10-14a 
0 
42 
(40-56) 
Consent/assent 
x 
 
 
Height/Weight/BMI# 
x 
 
x 
Eligibility assessment 
x 
x5 
 
Study instructions 
x 
x 
 
Actigraphy training1 
x 
x 
 
PrO2 device/app training 
 
x 
 
Retrospective Dyspnea scoring## 
 
x 
x 
Dyspnea scoring with exercise2 
 
x 
x 
Randomization 
 
x 
 
Maximal inspiratory pressure (MIP)### 
 
x 
x 
Stair Step Test 
 
x 
x 
Adverse event monitoring 
 
x 
x 
Follow-up actigraphy3 
 
 
x 
Patient satisfaction questionnaire 
 
 
x 
phone check-ins4 
will occur on day (+/- 2) 7, 14, 21, 28, and 35 
to assess any problems, encourage adherence 
and give appreciation for efforts 
1 – worn at least 7 full days (max of 14) prior to randomization 
2 – Modified Borg Dyspnea scale and Dalhousie Dyspnea 
3 – worn at least 7 full days (max of 14) during week prior to V3; the follow-up actigraphy should 
occur during the last 14 days. 
4 – communication will be made by (IRB approved) mode of participant’s choosing including 
voice call or direct messaging.  
5 – assess for eligibility for randomization (tracker adherence, no new exclusions prior to 
randomization) 
a – a date range of 10-14 days prior to randomization is preferred but can be extended up to -28 
days. A randomization visit can be scheduled beyond 28 days only at the discretion of the PI.  
# - should be taken from clinic visit data; may be performed as a research procedure only if needed 
## - Baseline Dyspnea index (BDI) and MRC Breathlessness Scale 
### - MIP will be collected before and after the Stair step test 

 
 
6.2 Summary of Procedures 
6.2.1  Visit 1 (goal timing: day -10 to -14 prior to randomization) 
General Visit Description: Eligibility criteria will be confirmed at Visit 1 or via 
phone call before their visit to the Healthy lifestyle’s clinic, if the researcher 
believes the participant meets eligibility criteria. Research staff will document 
informed consent from the parent/ guardian in eligible participants. 
Participants above the age of 12 years will also provide assent. Eligible 
participants will receive a Breathe Fit study packet with study handouts and 
study materials. 
 
Equipment/Supplies needed: Body weight scale, stadiometer, eligibility 
checklist (printed or electronic), participant informational handouts (for activity 
tracker accompanying smart device(s) to link with activity tracker). 
 
Anticipated duration: Goal is 30-45 minutes. 
 
Visit 1 Procedures: 
1. Confirm eligibility (eligibility checklist). 
2. Obtain consent and assent (if child is <12 years old). The consenting process will 
include instruction about general study details (visits, durations, compensation) 
and participants will be given a study packet of instructions. 
3. Obtain participant demographics, including height, weight, and BMI data (these 
data should be taken from the electronic health record if already collected). If not 
obtained during routine care, these data will be collected by research staff. 
4. Questionnaires (printed or electronic). 
5. Actigraphy training (participants will be given a Vivosmart 4 activity tracker in the 
correct size and taught on its proper fit and use). 
6. Following consent, if all V1 procedures are not able to be completed (due to 
participant time constraints or family preference), an optional V1a (continuation 
visit) may be scheduled by phone or in-person home or by follow-up clinic visit. 
7. Plan day -7 phone check-in (see phone check-in section below). 
 
6.2.2  Visit 2 (Day 0) 
General Visit Description: Visit 2 will be Day 0, will re-confirm eligibility prior to 
randomization, will include randomization if eligible and will start the intervention and 
observation period. Participants must not newly meet any exclusion criteria and must 
continue to meet all inclusion criteria. Inclusion criteria for randomization will include 
collection of at least 7 days of valid actigraphy data (confirmed at Visit 2).  
 
Equipment/Supplies needed: Activity tracker (from participant), accompanying 
smart device(s), printed questionnaires, participant informational handouts, PrO2 
trainer, Stair Step Test equipment. 
 
Anticipated duration: 60 minutes. 
 
 
Visit 2 Procedures:  
1. Assessment of baseline actigraphy (participants must have worn the Vivosmart 4 
activity tracker for at least 7 full days (max of 14) prior to randomization. If not, 

 
 
the date of Visit 2 may be extended for an additional 4-14 days for a continuation 
Visit 2). 
2. Questionnaires and eligibility assessment (eligibility checklist, questionnaires can 
be printed or electronic) (see questionnaires section). 
3. Interval history and event monitoring. 
4. Measure Maximal inspiratory pressure (MIP) before and after step test (see MIP 
section). 
5. Stair Step Test (see stair step section). 
6. Retrospective dyspnea scoring that assesses dyspnea from daily activities 
(Baseline Dyspnea Index (BDI), the MRC Breathlessness scale), and during the 
step-test (Modified Borg Dyspnea scale and Dalhousie Dyspnea/Perceived 
Exertion Scale). 
7. Randomization (see the randomization procedure section). 
8. Study instruction refresher and questions/answers. 
9. PrO2 Fit app and device IMR training. 
10. Refresher Training (question and answers) on the use of Vivosmart 4 activity 
tracker. 
11. Discuss plan for phone call visits and future study visit. Plan next phone call 
check-in visit (Day 7). 
 
6.2.3 Continuation visit 
In the event that during the initiation of Visit 1, 2, or 3, the participant is not able to complete 
the visit (but remains eligible for study participation), a continuation visit (e.g. 1b, 2b) can be 
scheduled to finish protocol-defined procedures.  The continuation visit will be scheduled at 
the earliest possible date but no later than 14 days from the previous visit. The continuation 
visits beyond 14 days out of this window must be approved by the study PI.   
 
6.2.4 Home visit 
Conducting all or part of a planned visit is allowed but will only be conducted as a last 
option, is requested by the participant and legal guardian, and meets all home visit 
requirements. The home visit must be approved in advance by the PI and deemed to be an 
appropriate setting (adequate space available, approved by participant’s legal guardian, 
safe environment). Home visits will occur only when two or more IRB-approved study staff 
members are present and occurring during normal business hours. 
6.2.5 Phone check-ins (days -7, 7, 14, 21, 28, and 35)  
During phone check-ins, communication will be made by a (IRB approved) mode of 
participant’s choosing including voice-only or zoom call. Research staff will ask if there are 
any problems, concerns or questions about the study or intervention.  Study staff will 
encourage adherence, and give appreciation for the participant’s efforts.  
 
 
6.2.3  Visit 3 (Day 42) Final In-person visit 
General Visit Description: Visit 3 will be on approximately day 42, final assessment 
of the study. This visit is preferred as an in-person study visit, but may be conducted 
as an in-home visit if needed (as with Visit 2). Day 42 (+/- 5 days) will be the goal 
day for study Visit 3. With PI approval, Visit 3 may be conducted up to 14 days away 
from Day 42, if necessary.  
 

 
 
Equipment/Supplies needed: Scale, stadiometer, activity tracker (from participant), 
accompanying smart device(s), printed questionnaires (or tablet-based REDCap 
questionnaires), PrO2 trainer (from participant), Stair Step Test equipment, 
assignment and thank you letter. 
 
Anticipated duration: 60 minutes. 
 
 
Visit 3 Procedures:  
1. Reassessment of participant height, weight, and BMI. 
2. Dyspnea scoring assessing daily activities [Baseline Dyspnea Index (BDI), the 
MRC Breathlessness scale]. 
3. Dyspnea scoring during the step-test (Modified Borg Dyspnea scale and 
Dalhousie Dyspnea and Perceived Exertion Scale). 
4. Adverse effect monitoring. 
5. Measure Maximal inspiratory pressure (MIP) before and after step test. 
6. Stair Step Test. 
7. Follow up actigraphy (participants must have worn the Vivosmart 4 activity 
tracker for at least 7 full days (max of 10) during week prior to Visit 3).  
8. Patient satisfaction questionnaire. 
9. Close out procedures:  
i. Assignment envelope; 
ii. Close out letter (i.e. thank you letter). 
 
6.3 Early Study Termination Visit 
No clinic visit will be planned following termination (withdrawal of consent or PI termination). 
Participants who stop the study intervention early due to a safety concern will still be 
followed according to the protocol.   
 
 
 
6.4 Actigraphy/Physical Activity Assessment 
Actigraphy is non-invasive method used to assess cycles of activity and rest over several 
days to weeks. Actigraphy will be measured using Vivosmart 4 activity tracker, a wrist-band 
based device that tracks and displays participant fitness activity progress, including steps, 
floors climbed, calories burned, intensity minutes, oxygen saturation, and heart rate.  
 
Participants will be asked to wear the tracker with the proper fitting (as directed in Visit 1) for 
at least 7 full days (7 full 24 hour blocks) (max of 14) prior to Visit 2 and at least 7 full days 
(max of 14) during the week prior to Visit 3. 
 
Participants will be given the safety and product information handout and user’s manual 
from the company that comes with the device. This will include information on battery life 
and handling, and device precautions.  
 
https://www.garmin.com/en-US/p/605739/pn/010-01995-13#specs 
 
6.5 Maximal Inspiratory Pressure (MIP) Measurement  
Each participant will be asked to perform five MIP maneuvers, with a goal of matching the 
highest two within 10 cmH2O. MIP will be recorded using the PrO2 Fit device. The patient 

 
 
will be seated for the test. The study staff member will first demonstrate the correct 
maneuver. The participant will be instructed to exhale slowly and completely, seal lips firmly 
around the MIP mouthpiece, and then “breathe in as hard as you can, like you are trying to 
suck up a thick milkshake.” The study staff member will note the largest negative pressure 
sustained on the pressure reading. The participant will be allowed to rest for about 30-45 
seconds and then repeat the maneuver 5 times.  This procedure will be completed before 
and again after the 3-minute step test. The change in best MIP value (post minus pre) will 
be computed. 
 
6.6 Questionnaires/Data Forms 
6.6.1  Baseline medical history form  
The baseline medical history form will ascertain general demographics, 
medical evaluation (for eligibility), degree of dyspnea at rest and related to 
daily activity, and other general respiratory symptoms. This will be completed 
by the research staff using a combination of adjudicating the electronic health 
record and direct enquiry from the participant or guardian. 
 
6.6.2  Questionnaire during exercise: Modified Borg dyspnea scale  
 Ten-unit scale used to denote degree of dyspnea with exercise28,29 will be  assessed 
at the 1-, 2- and 3-minute marks during the 3-minute step test, and again at post-1, 
post-2 and post-3.  
 
 Patient Instructions for Borg Dyspnea Scale 
“This is a scale that asks you to rate the difficulty of your breathing. It starts at 
number 0 where your breathing is causing you no difficulty at all and progresses 
through to number 10 where your breathing difficulty is maximal. How much difficulty 
is your breathing causing you right now?” 
 
 
 
 
 
6.6.3 
 Questionnaire during Exercise: Dalhousie rating with exercise  
This will be assessed at the 1-, 2- and 3-minute marks during the 3-minute 
step test. 
The purpose of this test is to assess breathing and leg and body fatigue 
during exercise. Participants will be told that there is no right or wrong 
answer. The pictures in the Dalhousie questionnaire30 will be shown to the 
0 
Nothing at all 
0.5 
Very, very slight (just noticeable) 
1 
Very Slight 
2 
Slight 
3 
Moderate 
4 
Somewhat severe 
5 
Severe 
6 
 
7 
Very Severe 
8 
 
9 
Very, very severe (almost maximal) 
10 
Maximal 

 
 
participant and asked to rate their experience from no difficulty at all, to the 
most difficulty you can imagine. (Figure 4) 
 
Research staff will say, “You might feel this difficulty breathing in your chest 
or in your throat. Another scale simply asks you to tell us how hard it is to 
breathe—from nothing at all, to the hardest breathing imaginable. With the 
final set of pictures, tell us how your legs feel—from nothing at all, to the 
hardest imaginable.”  
 
 
 

 
 
 
6.6.4  Retrospective questionnaire assessing dyspnea during daily activity: Baseline 
Dyspnea Index (BDI).  
The BDI 31 is a retrospective questionnaire assessing perceived dyspnea during 
activities of daily living ‘on a typical day’ over the past two weeks and will be 
assessed at Visits 2 and 3.  
   
   
Baseline Dyspnea Index Questionnaire 
I. Functional impairment 
_____ Grade 4 
No impairment 
Able to carry out usual activities and occupation without 
shortness of breath. 
_____ Grade 3 
Slight Impairment 
Distinct impairment in at least one activity but no activities 
completely abandoned.  
Reduction, in activity at work or in usual activities, that seems 
slight or not clearly caused by shortness of breath. 
_____ Grade 2 
Moderate Impairment 
Patient has changed jobs and/or has abandoned at least one 
usual activity due to shortness of breath. 
_____ Grade 1 
Severe Impairment. 
Patient unable to work or has given up most or all usual 
activities due to shortness of breath. 
_____ Grade 0 
Very Severe Impairment. 
Unable to work and has given up most or all usual activities 
due to shortness of breath. 
_____ W 
Amount Uncertain 
Patient is impaired due to shortness of breath, but amount 
cannot be specified. Details are not sufficient to allow 
impairment to be categorized.  
_____ X 
Unknown 
Information unavailable regarding impairment. 
_____ Y 
Impaired for Reasons Other than 
Shortness of Breath.  
For example, musculoskeletal problem or chest pain. Usual 
activities refer to requirements of daily living, maintenance or 
upkeep of residence, yard work, gardening, shopping, etc. 
 
II. Magnitude of Task  
_____ Grade 4 
Extraordinary 
Becomes short of breath only with extraordinary activity such 
as carrying very heavy loads on the level, lighter loads uphill, 
or running. No shortness of breath with ordinary tasks. 
_____ Grade 3 
Major 
Becomes short of breath only with such major activities as 
walking up a steep hill, climbing more than three flights of 
stairs, or carrying a moderate load on the level.  
_____ Grade 2 
Moderate 
Becomes short of breath with moderate or average tasks such 
as walking up a gradual hill, climbing fewer than three flights of 
stairs, or carrying a light load on the level.  
_____ Grade 1 
Light 
Becomes short of breath with light activities such as walking 
on the level, washing, or standing.  
_____ Grade 0 
No Task 
Becomes short of breath at rest, while sitting, or lying down.  
_____ W 
Amount Uncertain 
Patient’s ability to perform tasks is impaired due to shortness 
of breath, but amount cannot be specified. Details are not 
sufficient to allow impairment to be categorized.  
_____ X 
Unknown 
Information unavailable regarding imitation of magnitude of 
task.  
_____ Y 
Impaired for Reasons Other than 
Shortness of Breath.  
For example, musculoskeletal problem or chest pain.  
 
 
 
 
 
 
 
 
 
 
 
III. Magnitude of Effort  

 
 
_____ Grade 4 
Extraordinary 
Becomes short of breath only with the greatest imaginable 
effort. No shortness of breath with ordinary effort.  
_____ Grade 3 
Major 
Becomes short of breath with effort distinctly submaximal, but 
of major proportion. Tasks performed without pause unless the 
task requires extraordinary effort that may be performed with 
pauses.  
_____ Grade 2 
Moderate 
Becomes short of breath with moderate effort. tasks performed 
with occasional pauses and requiring longer to complete than 
the average person  
_____ Grade 1 
Light 
Becomes short of breath with little effort tasks performed with 
little effort or more difficult tasks performed with frequent 
pauses and requiring 50-100% longer to complete than the 
average person might require.  
_____ Grade 0 
No effort 
Becomes short of breath at rest, while sitting, or lying down.  
_____ W 
Amount Uncertain 
Patient’s exertional ability is impaired due to shortness of 
breath, but amount cannot be specified. Details are not 
sufficient to allow impairment to be categorized.  
_____ X 
Unknown 
Information unavailable regarding limitation of effort. 
_____ Y 
Impaired for Reasons Other than 
Shortness of Breath.  
For example, musculoskeletal problems or chest pain.  
 
 
 

 
 
6.6.5    Retrospective questionnaire assessing dyspnea during daily activity: MRC  
 
Breathlessness scale. 
The MRC breathlessness questionnaire is a retrospective questionnaire assessing 
perceived dyspnea during activities of daily living ‘on a typical day’ over the past two 
weeks and will be assessed at Visits 2 and 3. The score ranges from 0 to 5 with 
higher score representing worse dyspnea.31,32  
 
 
6.7 Stair-step Challenge.  
The Stair-step Test is a recognized clinical procedure used to measure cardiovascular fitness in 
adults aged 18 and up. The Bench Stepping Test has been adapted for children aged 5-18 for 
the purposes of this study. It has been validated in other clinical studies designed to measure 
the effectiveness of exercise and/or dietary interventions to improve cardiovascular fitness and 
other clinical measures related to obesity.33,34 
6.7.1 Preparation for administration of Stair-step Test 
1. Ensure that all of the necessary materials are present. Study materials include a 
stable step, 8 risers, metronome, timer, pulse oximeter, and chair. 
2. Step Setup 
a. For ages 8-9: Have child set one foot on the floor and one foot on the step and 
measure with protractor. Protractor should read between 20 and 30 degrees. 
Add/remove risers as necessary. 
b. For ages 10-17: Set step on two risers (8 inches). 
c. If patient is ≥ 6’0”, have them place one foot on the floor and one on the riser and 
measure with protractor. Add/remove a riser until protractor reads between 20 
and 30 degrees.  
d. Patients over 300 lbs. do not complete the step test 
3. Set metronome to beat at 96 beats per minute. 
4. Set timer for 3 minutes. 
5. Train the subject to complete the Step Test. 
a. In time with the metronome, the subject will step one foot onto the step (1st 
beat), step the second foot up (2nd step), step down with one food (3rd beat), 
and step down with other food (4th beat). 
b. Allow a short rest before beginning test. 
6.7.2 Administering the Step Test 
• 
Measure baseline (at time 0) heart rate with pulse-oximetry before child begins 
 step test. 
• 
Have child step up and down step at 96 bpm for 3 minutes. 
• 
Assess dyspnea scores at minutes 1, 2 and 3, and post-1, post-2 and post-3. 
The MRC Breathlessness scale 
Grade Degree of breathlessness related to activities 
0 
No breathlessness even with strenuous exercise 
1 
Not troubled by breathlessness except on strenuous exercise 
2 
Short of breath when hurrying on the level or walking up a slight hill  
3 
Walks slower than most people on the level, stops after a mile or so, or stops after 15 
minutes walking at own pace 
4 
Stops for breath after walking about 100 yards or after a few minutes on level ground 
5 
Too breathless to leave the house, or breathless when undressing 

 
 
• 
After 3 minutes, end the stepping and check child’s heart rate on pulse-oximetry 
(post-1). 
• 
Direct child to sit in chair for one minute, then check heart rate again (post-2). 
• 
Direct child to remain in chair for another minute, then check heart rate (post-3). 
6.7.3 Recording heart rate and pulse oximetry 
a. Heart rate at baseline, post-1, post-2 and post-3. 
b. Pulse oximetry at baseline, post-1, post-2 and post-3. 
 
6.11 Specimen Preparation, Handling, Storage and Shipping 
No biological specimens will be collected. 
 
 
 
 
 
 
 
 

 
 
7. STUDY PRODUCT DESCRIPTION 
7.1 Dosage and Study Intervention Information 
7.1.1 Dose of inspiratory muscle training 
Arm A: The intervention group will be required to achieve a pressure target that is 75% 
of their MIP for each repetition. Participants will perform 3 sets of 50 inspiratory breaths 
3 times per week. 
Arm B: The sham group will be required to achieve a pressure target that is 15% of 
their MIP for each repetition. Participants will perform 3 sets of 50 inspiratory breaths 3 
times per week. 
7.1.2 Formulation, packaging, and labeling 
The PrO2™ is a flow-resistive device that provides inspiratory resistance via a fixed 
2mm orifice and has Bluetooth connectivity to most IOS/Android devices or 
Mac/Windows computers. The PrO2™ device and app allows for both 100% adherence 
monitoring and immediate user biofeedback. 
7.1.3 Product use and directions  
Participants will be instructed to inspire forcefully through PrO2™ until the device signals 
that the user has achieved the target resistance (via audible alarm and visible light 
signal). The research team can implement biofeedback signals at a specific inspiratory 
resistance, which allows for a precise and individualized training target. 
At Visit 1: Participants will download the PrO2™ Fit App from the Apple App Store or 
Google Play. They will be shown how to set up their own PrO2 Fit account and how to 
connect with their PrO2™ trainer. Research staff will review the planned dosing to start 
after visit 2. They will be instructed to try to avoid inferring what treatment assignment 
they have been given, and to not share any impressions they have developed on 
treatment assignment. The proper use of the trainer will be taught, including safe 
storage, cleaning and maintenance. Participants will be taught to create an air-tight seal 
over the mouthpiece after maximal exhalation. The participant will be instructed to 
breathe in forcefully until the device alarms then continue to maximal inspiration. At Visit 
1, participants will be taught on the device while the alarm is set for 15% of their MIP. 
They will complete a set of 50 repetitions supervised so their technique is assessed and 
re-direction can occur if needed. 
At Visit 2: participants will have refresher training on the use of the PrO2™ Fit app and 
will repeat their supervised single set of 50 repetitions while supervised to ensure they 
have the proper technique and the device is working properly.  
Research staff will encourage participant and guardian to discuss a plan to optimize 
adherence to the IMR intervention. This may include picking particular days of the week 
(e.g. MWF, TuThS) and particular activities to link with IMR (e.g. in mornings before 
school, evenings before homework, etc.). Guardians will be asked to commit to helping 
the participant remember their intervention days. 
7.2 Accountability Procedures for the Study Product(s) 
The PrO2™ devices will be purchased and provided by PrO2 Health Inc.  

 
 
8. ASSESSMENT OF SAFETY 
 Adverse Event 
All adverse events during the study period will be collected.  
An adverse event (AE) is any untoward medical occurrence in humans, whether or not 
considered study drug-related, which occurs during the conduct of a clinical trial. Any change in 
clinical status, ECGs, routine labs, x-rays, physical examinations, etc., that is considered 
clinically significant by the study investigator is considered an AE.  
An unexpected Adverse Event is defined as any adverse event, the nature, specificity, or 
severity of which is not consistent with the applicable product information (e.g., package 
insert/approved label) or investigational plan. 
A suspected adverse reaction (SAR) is any adverse event for which there is a reasonable 
possibility that the study intervention caused the adverse event. A reasonable possibility implies 
that there is evidence that the study intervention caused the event. An adverse reaction is any 
AE caused by the study intervention. 
 Guidelines for Assessing Association of an Adverse Event 
A serious adverse event (SAE) or serious suspected adverse reaction or serious 
adverse reaction as determined by the investigator or the sponsor is an adverse event 
or suspected adverse reaction that results in any of the following outcomes: 
• 
Death  
• 
Life-threatening AE (“life-threatening” means that the study participant was, in the 
opinion of the investigator or sponsor, at immediate risk of death from the reaction as it 
occurred and required immediate intervention)  
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
• 
Inpatient hospitalization or prolongation of existing hospitalization  
• 
Congenital abnormality or birth defect  
• 
Important medical event that may not result in one of the above outcomes, but may 
jeopardize the health of the study participant or require medical or surgical intervention 
to prevent one of the outcomes listed in the above definition of serious event 
 Guidelines for Assessing Intensity of an Adverse Event  
The investigator/delegate (defined as a clinician licensed to make a diagnosis) should 
use the following definitions when assessing intensity of an adverse event: 
• 
Mild - Participant is aware of symptoms or has minor findings but tolerates them well, 
and no or minimal intervention required.  
• 
Moderate - Participant experiences enough symptoms or findings to require 
intervention.  
• 
Severe - Participant experiences symptoms or findings that require significant 
intervention.  
 
 Guidelines for Assessing Causality 
The investigator/delegate (defined as a clinician licensed to make a diagnosis) will use 
the following question when assessing causality of an AE to study intervention: Is there 
a reasonable possibility that the intervention caused the event? “Reasonable possibility” 
means that there is evidence to suggest a causal relationship between the study 

 
 
intervention and the AE. An affirmative answer designates the event as a suspected 
adverse reaction. The investigator/delegate (defined as a clinician licensed to make a 
diagnosis) must document their assessment of severity and causality in the participant 
records in a timely manner and submit safety reports as required by their IRB/REB/IEC.  
 
 Collection Period and Reporting Procedures 
Adverse event information will be gained from direct monitoring of the study 
participants as well as from clinician observation and self-reporting by the study 
participants. The investigator/delegate (defined as a clinician licensed to make a 
diagnosis) must document their assessment of intensity and causality in the 
participant records in a timely manner and submit safety reports as required by their 
IRB. 
 
8.5.1 Adverse Events and Serious Adverse Events 
Adverse events (AEs) and SAEs will be reported from the time of consent 
through the end of study participation. 
Participants who have study intervention stopped due to a safety concern will be 
followed for an additional 7 days from the time the intervention was stopped. 
Adverse events (AEs) will be followed until resolution, even if this extends 
beyond the study-reporting period. Resolution of an AE is defined as the return 
to pretreatment status or stabilization of the condition with the expectation that it 
will remain chronic. 
Adverse events (AEs) will be entered in the data system within 7 days of 
identification. Serious adverse events (SAEs) will be entered in the data system 
within 24 hours of identification. 
Any SAE entered in the EDC system will generate an automatic email 
notification to the DCC, BPCA medical monitor, and the sponsor. The BPCA 
medical monitor will review all SAEs at the time they are reported. The 
investigator/delegate (defined as a clinician licensed to make a diagnosis) must 
document their assessment of severity and causality in the participant records in 
a timely manner and submit safety reports as required by their Institutional 
Review Board (IRB)/ Research Ethics Board (REB)/ Institutional Ethics 
Committee (IEC). 
8.5.2 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Serious, unexpected, suspected adverse reactions related to terbutaline sulfate 
will be reported from the time of first study procedure through the end of study 
participation. SUSARs can be elicited at any time during the defined study 
period. SUSARs will be entered in the data system within 24 hours of site 
awareness.  
 Event of Special Interest 
Not applicable. 

 
 
 
 Safety Interim Analysis 
No interim analysis is planned. 

 
 
9. STUDY HALTING/TERMINATION 
9.1 Study or Site Halting/Termination Criteria 
This study may be terminated at any time by the study PI or sponsor. Reasons for 
termination include but are not limited to, if in their judgment, there are no further 
benefits to be achieved from the study, or, if the treatment presents an unreasonable 
and significant risk to participants. If the study is terminated, notifications will be made to 
the regulatory authorities, investigators, or study participants, as appropriate, in 
accordance with all applicable regulations governing the study and site/investigator. 
9.2 Halting Rules 
No halting rules are planned. 
Individual participant stopping criteria are outlined in the section above titled Study 
Investigator/Sponsor Decides to Withdraw Participant 
 
 

 
 
10. STATISTICAL CONSIDERATIONS 
10.1 Study Hypotheses 
Primary Specific Aims: Compare measures of satisfaction, adherence and safety between 
patients randomized to IMR as compared to sham to demonstrate IMR as an acceptable 
add-on intervention that promotes greater activity in children with obesity with no safety 
concerns.  More satisfaction and adherence are expected in the IMR group compared to 
sham. 
• 
Hypothesis 1: More than 80% of participants will be satisfied with active IMR at study 
completion.  
• 
Hypothesis 2: Total active IMR adherence will be >80% of planned IMR repetitions.  
• 
Hypothesis 3: Active IMR will not be associated with any serious adverse reactions. 
Secondary Aim:  Compare inspiratory strength (measured by mean change in MIP) in IMR 
versus sham participants to demonstrate changes in inspiratory muscle functioning and 
dyspnea following IMR. Also, to demonstrate changes in daily physical activity following IMR 
versus sham participants. 
• 
Hypothesis 1: IMR will significantly increase inspiratory strength (measured by mean 
change in MIP) with more improvements in IMR compared to participants receiving 
sham.  
• 
Hypothesis 2: IMR will reduce patient-reported dyspnea scores from activities of daily 
living and during the step test.  
• 
Hypothesis 3: IMR will lead to reduced sedentary time, increased moderate-
strenuous time and increased total daily activity measured by a wrist-worn 
continuous activity tracking monitor. 
Exploratory Aim: Demonstrate changes in exercise capacity following IMR versus sham 
participants. 
• 
Hypothesis 1: IMR will reduce the peak heart rate increase induced by the step test 
in IMR compared to sham participants. 
10.2 Objectives and Endpoints 
Aim 1: 
• 
Satisfaction with active IMR (yes/no) as an intervention rated at study completion 
measured as a percentage of study completers.  
• 
Active IMR adherence measured as a percentage of planned IMR repetitions 
(completer status).  
• 
Serious adverse events (yes/no) measured as a percentage of participants receiving 
at least one active IMR intervention. 
Aim 2: 
• 
Change in maximum inspiratory pressure as measured by maximal inspiration in 
centimeters of water.  
• 
Change in dyspnea as measured retrospectively of activities of daily living. 
• 
Change in sedentary time measured by mean daily sedentary time assessed by the 
Vivosmart 4 activity tracker. 

 
 
• 
Change in moderate-strenuous physical activity time measured by the mean daily 
MVPA time assessed by the Vivosmart 4 activity tracker. 
• 
Change in total daily activity measured by mean daily step count and mean daily 
calorie expenditure.  
Aim 3: 
• 
Change in heart rate during step test. 
 
10.3 Analysis Population 
All participants who are randomized and receive at least one IMR intervention will be included 
in the modified intention-to-treat (MITT) population.  
 
10.4 Timing of Analyses 
 The final analysis will be performed when the last recruited patient has completed Visit 3 and 
after the finalization and approval of the statistical analysis plan document. The final analysis 
will be performed on blinded data transferred to the lead statistician following data cleaning 
conducted by a study research coordinator. Data cleaning will include checking for missing 
data/extreme values and outliers. 
 
 
10.5 Missing Data 
 Missing at random will be judged based on tabulating missing Visit 3 primary outcome values 
by intervention group and demographic characteristics. If there is a substantial amount of 
missing data and missingness is considered to be not random, sensitivity analyses utilizing 
worst-case/baseline scenarios or imputation will be used for descriptive and inferential 
assessments to address attrition bias. 
 
10.6 Multiple Testing 
 Adjustment for multiple testing will not be performed given the exploratory nature of 
this study.   
 
10.7 General Summary of Study Data 
 
Statistical analyses will be overseen by Dr. Cindy Green, a faculty member within the 
Department of Biostatistics & Bioinformatics at Duke. She will serve as the unblinded 
statistician and oversee the lead statistician.  
Patient disposition, demographics, baseline measurements, outcomes and adverse events will 
be summarized overall and by intervention group.  We will use standard summary statistics to 
describe the distribution of outcome measures outlined in each aim by intervention group 
including mean, standard deviation (SD), median, 25th and 75th percentiles (Q1-Q3) and range 
for continuous variables and frequency counts with percentages for non-missing data. We will 
assess distribution and normality assumptions, identify outliers, evaluate missing data and 
check for unusual patterns. We will use SAS version 9.4 or higher (SAS Institute, Inc., Cary 
NC) for all analyses, and a two-sided p-value <0.05 will be considered statistically significant. 
Data derivations, calculations and analysis programs will be archived to allow future 
replication of our results. 

 
 
 
10.8 Subject Disposition 
 
Some withdrawal from the study is expected for various reasons. A CONSORT diagram will 
be used to describe the number of patients that reached the various stages of the trial and the 
number of participants that dropped out and for what reasons. 
 
10.9 Protocol Deviations 
 
Protocol deviations are expected to be minimal and will be summarized in tables by 
randomized intervention group.  
 
10.10 Efficacy Analyses 
 
Aim 1:  We will use exact 95% confidence intervals and Fisher’s exact test to report and 
compare the expected satisfaction, adherence and SAE percentages within the IMR 
compared to the sham group.   
Aim 2:  We will use analysis of covariance (ANCOVA) to estimate and test the difference in 
mean 6-week change between treatment groups (IMR versus Sham) for each outcome 
adjusting for the baseline value of the outcome variable.  Given the small sample size, sex 
(male/female), age, and BMI will each be evaluated in separate ANCOVA models. We will 
report adjusted (least squares) means with 95% confidence intervals (CI) for each group, as 
well as the estimated between-group difference in means with 95% CI and p-value for testing 
the null hypothesis of no difference between group means. The model assumptions will be 
verified for each outcome, and model fit will be assessed using residual plots.  
 
  
10.11  Sample Size Considerations 
For pilot studies, determining the sample size based on power calculations is problematic and 
often not recommended35,36 due to problems of type II error and the inability for a small study 
to reject the null hypothesis.  Pilot sample sizes between 10-16 per intervention arm37-39 are 
justified.  Our plan of 15 participants in each IMR arm is feasible given past HL recruitment 
success and will result in reasonably good power estimates as shown in (Table 5). 
 
Table 5 Statistical power based on effect size 
 
Attrition 
 
0% 
6.7% 
13.3% 
20% 
Effect size 
N=30 
N=28 
N=26 
N=24 
Cohen’s d=0.75 
0.509 
0.480 
0.451 
0.420 
Cohen’s d=0.85 
0.613 
0.581 
0.548 
0.512 
Cohen’s d=0.95 
0.709 
0.677 
0.642 
0.604 
Cohen’s d=1.05 
0.793 
0.762 
0.729 
0.691 
Cohen’s d=1.15 
0.860 
0.834 
0.803 
0.768 
Cohen’s d=1.25 
0.910 
0.889 
0.864 
0.833 

 
 
11. ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
11.1  Informed Consent Process 
Informed consent is a process that is initiated prior to the participant agreeing to 
participate in the study and continuing throughout the individual’s study participation. 
11.2  Permission from Participants 
Consent forms describing in detail the study intervention, study procedures, and risks 
are given to the participant and written documentation of informed consent is required 
prior to starting study specific procedures or intervention. 
Extensive discussion of risks and possible benefits of participation in this study will be 
provided to the participant. Consent forms will be IRB-approved, and the participant 
will be asked to read and review the document. Upon reviewing the document, the 
investigator will explain the research study to the participant and answer any 
questions that may arise. The participant will provide consent prior to being enrolled in 
the study. The participant may withdraw consent at any time throughout the course of 
the study. A copy of the executed informed consent document will be given to the 
participants for his/her records. The rights and welfare of the participants will be 
protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. 
The IND sponsor, or designee will provide the investigator, in writing, any new 
information that bears significantly on the participant’s risk to participating in the study. 
This new information will be communicated by the investigator to participants who 
consent to participate in the trial in accordance with IRB requirements. The informed 
consent document will be updated, and participants will be re-consented, if necessary. 
Site staff may employ IRB-approved recruitment efforts prior to the participant 
consenting; however, before any protocol-specific procedures are performed to 
determine protocol eligibility, an informed consent form must be executed. By 
providing informed consent, the participant agrees to complete all evaluations required 
by the trial, unless the participant withdraws voluntarily or is involuntarily withdrawn 
from the trial for any reason. Participants may be asked to authorize exchange of 
information between the study staff and their primary care provider and/or other 
significant medical providers. 
11.3  Documentation of Consent 
Consent must be documented using forms and processes determined by the Duke 
University Health System (DUHS) IRB.  
Prior to enrollment of participants into this trial, the protocol, the applicable informed consent 
template, and any materials or advertisements presented to participants will be reviewed and 
approved by the DUHS IRB. The consent templates approved by DUHS IRB will then be 
provided to sites and revised as necessary to comply with local regulations and institutional 
requirements. Sites are required to submit all changes to the templates to the BPCA DCC, 
which ensures compliance with US and international regulations and sponsor (NIH) policies, 
prior to submission and approval to the IRB/REB/IEC of record for each site. Notification of the 
IRB/REB/IEC 's approval, its composition, and the institution’s federal-wide assurance number 
(FWA) will be provided to the BPCA DCC. 

 
 
Should amendments to the protocol and consent documents be required, the 
amendments will be written by the sponsor, approved by the DUHS IRB, and provided 
to the site investigator for submission to the site’s IRB/REB/IEC of record. 
Participants may be compensated for their participation in this study. Compensation 
will be in accordance with the local IRB/REB/IEC’s policies and procedures and 
requires IRB/REB/IEC approval, and must be documented in the consent forms.  
For non-English speakers, a fully translated consent or an oral presentation 
accompanied by a short form may be used to obtain informed consent. The fully 
translated consent and the short form must be approved by the site’s IRB of record 
and executed according to local requirements. 
Participants must be informed that participation is voluntary and that they may 
withdraw from the study at any time, without prejudice. A copy of the executed 
informed consent document will be given to the participant for their records. 
Site staff may employ IRB/REB/IEC-approved recruitment efforts prior to the 
participant consenting; however, before any protocol-specific procedures are 
performed to determine protocol eligibility, informed consent or waiver of informed 
consent must be obtained. The informed consent process will be conducted and the 
form fully executed e.g., signed and dated, before the participant undergoes any 
study-specific procedures. The rights and welfare of the participants will be protected 
by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
The IND sponsor, or designee will provide the investigator, in writing, with any new 
information that bears significantly on the participants' risk to receive the 
investigational product. This new information will be communicated by the site 
investigator to participants who consent to participate in the trial in accordance with 
IRB/REB/IEC requirements. The informed consent document will be updated, and 
participants will be re-consented, if necessary. 
 
11.4  Confidentiality and Privacy 
All research activities will be conducted in as private a setting as possible. 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their agents. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data 
will be released to any unauthorized third party without prior written approval of the sponsor.  
The PI will ensure that the use and disclosure of protected health information obtained during 
a research study complies with the HIPAA Privacy Rule. The rule provides U.S. federal 
protection for the privacy of PHI by implementing standards to protect and guard against the 
misuse of individually identifiable health information of participants participating in clinical 
trials. Authorization is required from each research participant (i.e., specific permission 
granted by an individual to a covered entity for the use or disclosure of an individual’s 
protected health information. A valid authorization must meet the implementation 
specifications under the HIPAA Privacy Rule. Authorization may be combined in the informed 
consent document (if approved by the IRB). 

 
 
The study monitor, other authorized representatives of the sponsor, representatives of the 
IRB/REB/IEC, and regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will 
permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB/REB/IEC, Institutional 
policies, or sponsor requirements. Both the site PI and the Institution at which the study is 
contracted to be conducted, will hold responsibility to maintain custody of all study records 
until the sponsor permits their destruction. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the BPCA-DCC. Individual participants and their 
research data will be identified by a unique study identification number. The study data entry 
and study management systems used by clinical sites and by the BPCA-DCC research staff 
will be secured and password protected.  
To further protect the privacy of study participants, this study is covered by a Certificate of 
Confidentiality (CoC) from the NIH. The CoC limits the ability of courts and other agencies 
from forcing the study team to share participant information or body fluids during a legal or 
legislative action without the participant’s permission.  

 
 
12. DATA HANDLING AND RECORD KEEPING 
The investigator is obligated to conduct this study in accordance with U.S. Federal Regulation 21 
CFR 312.60-69 as specified on the signed form FDA 1572, applicable state and federal laws, and 
the International Council for Harmonisation: Good Clinical Practice: Consolidation Guideline. The 
investigator is responsible for informing the IRB/REB/IEC of any safety issues related to the study 
and the study intervention, including reports of serious adverse events, and all IND safety reports, 
as required by their IRB/REB/IEC. 
12.1  Data Handling 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. Data collection forms will be derived from the eCRFs to record 
and maintain data for each participant enrolled in the study. All source documents should be 
completed in a neat, legible manner to ensure accurate interpretation of data. Permanent ink 
is required to ensure clarity of reproduced copies. When making a change or correction, the 
original entry should be crossed out with a single line, and the change should be initialed and 
dated. Do not erase, overwrite, or use correction fluid or tape on the original.  
Data reported in the eCRF should be consistent with the data collection form/source 
documents, or the discrepancies should be documented. The sponsor and/or its designee will 
provide guidance to investigators on making corrections to the data collection forms and 
eCRFs. 
12.2  Data Management Responsibilities 
All data collection forms and laboratory reports must be reviewed by the clinical team and 
data entry staff, who will ensure that they are accurate and complete. Adverse events must 
be graded, assessed for severity and causality by a licensed clinician, and reviewed by the 
site principal investigator or designee. Data collection, management and quality review is the 
responsibility of the clinical trial staff at the site under the supervision of the principal 
investigator. During the study, the investigator must maintain complete, current and accurate 
documentation for the study. 
The unblinded and lead statistician will be responsible for the statistical analyses, and 
reporting of the final study results. 
12.3  Data Capture Methods 
Clinical data (including AEs) will be entered into a 21 CFR Part 11-compliant web-based data 
capture system (REDCap). The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the data collection 
forms/source documents. 
12.4  Types of Data 
Data for this study will include safety, efficacy, and outcome measures. 
12.5  Timing/Reports 
No interim analysis is planned, so the final report will serve as a summary of the study. 
12.6  Study Records Retention 
Study records and source documents will be kept until the child is 21 years of age. The 
research data collected in this study will be kept indefinitely.  
The disposition date related to FDA application will be posted on the PTN website for the 
Investigator’s reference.  

 
 
 
12.7  Protocol Deviations 
A protocol deviation is any noncompliance/unplanned excursion from approved 
investigational plan (e.g., protocol, MOP), or ICH GCP guidelines. The noncompliance may 
be on the part of the participant, investigator, or site staff. As a result of deviations, 
corrective actions are to be developed by the site and implemented promptly. For this study, 
certain procedures obtained out of window will not be considered protocol deviations in 
order to facilitate retention of participants for later study assessments but will be tracked and 
reported to the sponsor.  
Each investigator must adhere to the investigational plan as detailed in the study protocol 
and/or associated study materials (e.g. MOPs, Forms Instructions, User Guides etc.). Each 
investigator will be responsible for the training of delegated staff and enrolling only those 
participants who have satisfied all protocol eligibility criteria. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation or within 5 working days of 
the scheduled protocol-required activity. All deviations must be promptly reported to the 
sponsor, via the BPCA DCC’s Electronic Data Capture (EDC) system. 
All deviations from the protocol must be reported in the study records/data system. Protocol 
deviations must be submitted to the local IRB/REB/IEC per their guidelines. The site 
investigator and study staff are responsible for knowing and adhering to their IRB/REB/IEC 
requirements. 
 

 
 
 
 
 
 
 

 
 
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