A Mobile Health Intervention in Pulmonary Arterial Hypertension
Phase: NA
Conditions: Pulmonary Arterial Hypertension, Idiopathic Pulmonary Arterial Hypertension, Heritable Pulmonary Arterial Hypertension, Associated Pulmonary Arterial Hypertension
Sponsor: Vanderbilt University Medical Center

 
 
 
 
 
A Mobile Health Intervention in Pulmonary Arterial 
Hypertension Protocol 
 
 
 
 
Date: 
6 August 2019  
 
 
Version: 
4.3 
Principal Investigator: 
Evan L. Brittain, MD, MSc 
Cardiovascular Medicine 
2525 West End Avenue, Suite 300A 
Nashville, TN 37203 
Phone: +1 615-322-4382 
Fax: 
+1 615-936-2029 
 
Confidential Information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Summary 
OBJECTIVES: 
The primary objective of this study is to test the 
feasibility of a mobile health (mHealth) intervention to 
increase mean daily step counts in patients with 
pulmonary arterial hypertension (PAH) after 12 
weeks.  
Secondary objectives include: 
• Change from baseline of six minute walk test 
distance (meters) at week 12. 
• Change from baseline of RV free wall longitudinal 
strain at week 12 (RV Strain). 
• Assess the frequency that the daily step target 
was achieved over 12 weeks (Daily goal 
attainment).  
• Change in minutes of activity per day between 
week 12 and baseline (Daily aerobic time). 
• Change in survey score between week 12 and 
baseline (emPHasis-10 Quality of Life survey) 
• Change in survey score between week 12 and 
baseline (SF-36 Quality of Life Mental 
Component Score). 
• Change in Borg Dyspnea Score between week 12 
and Baseline. 
• Change in heart rate between week 12 and 
Baseline (Resting heart rate).  
• Change from baseline insulin resistance at week 
12 (HOMA-IR). 
• Change from baseline B-type natiurectic peptide 
level at week 12 (BNP).  
• Change in SF-36 score between week 12 and 
Baseline (SF-36 Physical Component Score).  
• Change in minutes between week 12 and 
baseline in minutes of moderate-vigorous activity. 
• Change in fat volume between week 12 and 
baseline (visceral fat  volume).  
STUDY DESIGN: 
 
Randomized, single-blinded, parallel group, Phase II 
study of 50 subjects with PAH. Eligible subjects will 
be randomly assigned to receive the mHealth 
intervention or not for twelve weeks. 

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STUDY POPULATION:      
 
 
Inclusion criteria: 
• Adults aged 18 or older. 
• Diagnosed with idiopathic, heritable, or 
associated (connective tissue disease, drugs, or 
toxins) pulmonary arterial hypertension (PAH) 
according to World Health Organization 
consensus recommendations.  
• Stable PAH-specific medication regimen for three 
months prior to enrollment. Subjects with only a 
single diuretic adjustment in the prior three 
months will be included. 
• Subjects must own a Bluetooth capable modern 
smartphone capable of receiving and sending text 
messages.  
• Forced vital capacity >65% predicted with no or 
minimal interstitial lung disease based on reviews 
of imaging studies by PI and medical monitor.   
 
 
Exclusion criteria: 
• 
Prohibited from normal activity due to wheelchair 
bound status, bed bound status, reliance on a 
cane/walker, activity-limiting angina, activity-
limiting osteoarthritis, or other condition that limits 
activity. 
• Pregnancy 
• Diagnosis of PAH etiology other than idiopathic, 
heritable, or associated 
• Functional class IV heart failure 
• Requirement of > 1 diuretic adjustment in the 
prior three months 
• Preferred form of activity is not measured by an 
activity tracker (swimming, yoga, ice skating, stair 
master, or activities on wheels such as bicycling 
or rollerblading)                                                  
PRIMARY ENDPOINT: 
 
• Change from baseline mean daily step count at 
week 12.  

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SECONDARY ENDPOINTS: 
 
• Change from baseline of six minute walk test 
distance (meters) at week 12. 
• Change from baseline of RV free wall longitudinal 
strain at week 12 (RV Strain). 
• Assess the frequency that the daily step target 
was achieved over 12 weeks (Daily goal 
attainment).  
• Change in minutes of activity per day between 
week 12 and baseline (Daily aerobic time). 
• Change in survey score between week 12 and 
baseline (emPHasis-10 Quality of Life survey) 
• Change in survey score between week 12 and 
baseline (SF-36 Quality of Life Mental 
Component Score). 
• Change in Borg Dyspnea Score between week 12 
and Baseline. 
• Change in heart rate between week 12 and 
Baseline (Resting heart rate).  
• Change from baseline insulin resistance at week 
12 (HOMA-IR). 
• Change from baseline B-type natriuretic peptide 
level at week 12 (BNP).  
• Change in SF-36 score between week 12 and 
Baseline (SF-36 Physical Component Score).  
• Change in minutes between week 12 and 
baseline in minutes of moderate-vigorous activity. 
• Change in fat volume between week 12 and 
baseline (visceral fat volume).  
 
• OBSERVATIONS: 
 
 
• Subjects will be evaluated in person at screening, 
baseline, 12 weeks.  
• Subjects will have telephone follow-ups at 2, 4, 6, 
8, and 10 weeks.  
• BNP levels, other biomarkers will be assessed at 
baseline and 12 weeks.  
• Subjects will have six minute walk testing at 
baseline and 12 weeks. 
• Subjects will have a transthoracic 
echocardiogram at baseline and 12 weeks. 

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• Subjects will have a Dual-Energy X-ray 
Absorptiometry (DEXA) at baseline and 12 
weeks. 
• Subjects will answer quality of life questionnaires 
at baseline and 12 weeks.  
SAMPLE SIZE AND POWER: 
 
A total of 50 subjects will be enrolled with 1:1 
randomization to either mHealth intervention or no 
intervention. For the primary study endpoint of daily 
step count, we will have 85% power to detect a 25% 
difference at week 12 between the mHealth 
intervention and no intervention groups (α = 0.05). 
DATA ANALYSIS: 
The primary study endpoint will be evaluated using a 
general linear model, adjusting for age, sex, and 
baseline 6MWD. Secondary endpoints will be 
evaluated in a similar manner. All univariate analyses 
will be evaluated using t-tests or rank-sum tests and 
χ2 and Fisher’s exact tests as appropriate. 
 
 
 
 
 
 
 
 
 
 
 
 
Brief Table of Contents 
Protocol Summary .............................................................................................................. 1 
ABSTRACT ......................................................................................................................... 9 

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Background & Significance .................................................................................... 10 
 
Objectives and Specific Aims ................................................................................. 12 
 
Screening, Subject Selection, and Randomization ............................................... 13 
 
Study Designs ........................................................................................................ 14 
 
Data Collection ....................................................................................................... 16 
 
Assessments of Efficacy and Outcome Measures ................................................ 20 
 
Statistical Considerations ..................................................................................... 24 
 
Study Risks and Discomforts ................................................................................. 26 
 
Quality Control ........................................................................................................ 27 
 
Data and Safety Monitoring and Reporting ........................................................ 28 
 
Confidentiality of Study Data .............................................................................. 35 
REFERENCES ................................................................................................................. 36 

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Contents 
ABSTRACT ......................................................................................................................... 9 
 
Background & Significance .................................................................................... 10 
1.1 
Morbidity, mortality, and limitations of medical therapy in pulmonary arterial 
hypertension.................................................................................................................. 10 
1.2 
Functional impairment and efficacy of exercise. ................................................ 10 
1.3 
Mechanisms of the beneficial effects of physical activity in PAH. ................ 11 
1.4 
Mobile health tools to promote behavioral change. ....................................... 11 
 
Objectives and Specific Aims ................................................................................. 12 
2.1 
Objectives ............................................................................................................ 12 
2.2 
Specific Aims ....................................................................................................... 12 
Primary Aim: ........................................................................................................................................ 12 
Secondary Aims: .................................................................................................................................. 12 
 
Screening, Subject Selection, and Randomization ............................................... 13 
3.1 
Recruitment of Study Sample ............................................................................. 13 
3.2 
Inclusion/Exclusion Criteria................................................................................. 13 
3.3 
Study Arm Assignment, Randomization, and Subject Retention ...................... 13 
 
Study Designs ........................................................................................................ 14 
4.1 
Overview ............................................................................................................. 14 
4.2 
Monitoring Device .............................................................................................. 14 
4.3 
Fitbit Application and Data Management ........................................................... 14 
4.4 
mHealth Intervention ......................................................................................... 15 
4.5 
Run-in Period and Step Count Targets ........................................................... 15 
4.6 
Remuneration ...................................................................................................... 16 
 
Data Collection ....................................................................................................... 16 
5.1 
Consent ............................................................................................................... 16 
5.2 
Study Visits and Contacts ................................................................................... 17 
 
Screening Visit...................................................................................................................... 17 
 
Study Day – Visit 1 (Baseline) .............................................................................................. 17 
 
Phone Calls ( Week -1, 2, 4, 6, 8, 10) ................................................................................... 18 
 
Study Day – Visit 2 (Week 12) .............................................................................................. 18 
5.3 
Study Schedule of Endpoints and Procedures .................................................. 19 
 
Assessments of Efficacy and Outcome Measures ................................................ 20 
6.1 
Assessments of Efficacy ..................................................................................... 20 

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Step Counts and Physical Activity ........................................................................................ 21 
6.2 
Secondary Outcome Measures .......................................................................... 21 
 
Six Minute Walk Distance .................................................................................................... 21 
 
Transthoracic Echocardiographic Measures........................................................................ 22 
 
Fidelity of Data Collection and Text Transmission .............................................................. 22 
 
The Borg Dyspnea Score ...................................................................................................... 22 
 
Resting Heart Rate ............................................................................................................... 22 
 
Quality of Life Questionnaires (SF36 & emPHasis–10).................................................... 22 
 
Dual Energy X-ray Absorptiometry (DEXA)....................................................................... 23 
 
Blood Biomarkers ............................................................................................................... 23 
 
WHO Functional Class ........................................................................................................ 23 
 
Other Feasibility Endpoints ............................................................................................... 23 
 
Medication Regimen Escalation/Reduction ..................................................................... 24 
 
Hospitalization for PAH progression or right-sided heart failure ........................................ 24 
 
Death.................................................................................................................................... 24 
 
Statistical Considerations ..................................................................................... 24 
7.1 
Study design ....................................................................................................... 24 
7.2 
Statistical Analysis .............................................................................................. 25 
7.3 
Missing Data and Dropouts .............................................................................. 25 
7.4 
Statistical Power ................................................................................................ 25 
7.5 
Interim Monitoring Guidelines ............................................................................. 26 
7.6 
Protocol Violations .............................................................................................. 26 
 
Study Risks and Discomforts ................................................................................. 26 
8.1 
Activity Tracking .................................................................................................. 26 
8.2 
Echocardiography ............................................................................................... 26 
8.3 
Venipuncture ....................................................................................................... 26 
8.4 
Privacy ................................................................................................................. 26 
8.5 
Financial Risk ...................................................................................................... 27 
 
Quality Control ........................................................................................................ 27 
9.1 
Personnel Training .............................................................................................. 27 
9.2 
Data Quality......................................................................................................... 27 
 
Data and Safety Monitoring and Reporting ........................................................ 28 
10.1 
Consent ............................................................................................................ 28 
10.2 
Designated Medical Director ........................................................................... 28 

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10.3 
Monitoring ........................................................................................................ 28 
10.4 
Data Safety Monitor Board (DSMB) ................................................................ 28 
10.5 
Safety and Adverse Events ............................................................................. 29 
 
Definitions ............................................................................................................................ 29 
 
Classifying AEs ...................................................................................................................... 30 
 
Interpretation of Definitions................................................................................................ 31 
 
Expedited Reporting Procedures ......................................................................................... 33 
 
Subject Withdrawal ............................................................................................................. 34 
 
Unblinding of Intervention Assignment .............................................................................. 35 
 
Confidentiality of Study Data .............................................................................. 35 
11.1 
Privacy/Confidentiality Issues ......................................................................... 36 
11.2 
Follow-up and Record Retention..................................................................... 36 
REFERENCES ................................................................................................................. 36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ABSTRACT 
 
Patients with pulmonary arterial hypertension (PAH) have impaired exercise 
capacity and reduced quality of life. Current therapies only modestly improve exercise 
capacity and are often prohibitively expensive, highlighting the need for additional, cost-
effective interventions. Multiple studies have demonstrated that increasing physical 
activity is highly efficacious in PAH, resulting in six-minute walk distance (6MWD) 
improvement that exceeds the effect of medications. However, previously tested 
protocols have required inpatient rehabilitation, making them impractical and poorly 
scalable to the general PAH population. Moreover, cardiopulmonary rehabilitation is not 
reimbursed by insurance companies or Medicare in the United States underscoring the 
need for alternatives to promote physical activity.  
We have shown that daily step counts are markedly reduced in PAH and 
associated with increased adverse events. We have also developed a fully-automated 
mobile health (mHealth) intervention that increased step counts in an ambulatory 
cardiology population in a randomized trial. The key feature of the intervention was the 
addition of a “smart text” component delivered to the subject’s smartphone, which 
generated personalized, encouraging content based in behavioral change theory (e.g. 
feedback loops and habit formation). This aspect of the mHealth intervention alone 
increased step counts over 300% compared with blinded step count tracking. The 
proposed study will be the first to test the feasibility of a mHealth intervention in the PAH 
population.  
We propose a randomized trial of step tracking with smart texts versus tracking 
without smart texts for 12 weeks to increase step counts in 50 men and women with 
PAH.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 Background & Significance  
1.1 Morbidity, mortality, and limitations of medical therapy in pulmonary arterial 
hypertension. 
PAH is a highly morbid disease1. Despite great progress in understanding disease 
mechanisms and nine FDA-approved drugs for PAH, contemporary data show that 
patients live on average 7 years after diagnosis1,2. The six minute walk test (6MWT) 
distance has been used as a surrogate marker of drug efficacy in PAH, with a 
minimally important distance of about 33m3. Most drug therapy for PAH improves 
6MWT distance approximately 30-40m4-8, indicating that current PAH therapies only 
modestly improve exercise capacity. Importantly, distance walked correlates directly 
with quality of life and mortality9-12. These data highlight the need for additional 
interventions to improve clinical outcomes in PAH.  
1.2 Functional impairment and efficacy of exercise. 
Patients with PAH have severely reduced exercise capacity when measured by 6MWT 
distance or cardiopulmonary exercise testing9-15. At diagnosis, most PAH patients are 
NYHA functional class III with symptoms of fatigue and shortness of breath with less 
than ordinary activity16. Although once thought to be potentially dangerous17, recent 
studies show exercise to be safe and effective at improving functional capacity. It is 
important to consider that in the context of PAH, “exercise” is equivalent to a mild or 
moderate increase in physical activity, such as sustained walking. Thus, the two terms 
can be used interchangeably in reference to this population. In a landmark study, 
Mereles et al. tested an intensive physical activity program in patients with severe PAH 
on stable therapy18. The intervention arm underwent three weeks of inpatient 
rehabilitation involving several hours per day of supervised walking, bicycle ergometer 
training, and dumbbell training followed by a 12 week home program. In the control 
group, the three inpatient weeks involved counseling, relaxation therapy, and activities 
of daily living. 6MWT distance in the intervention arm increased by 96±61 meters versus 
a decrease of -15±54 meters in the control group (p<0.0001). Importantly, the effect of 
exercise on functional capacity and quality of life is additive to standard medical 
therapy. Since this trial, others have validated the efficacy of inpatient exercise 
programs in PAH19-22. All of these studies have been performed in Europe where 
inpatient (and outpatient) rehabilitation is covered by insurance or national health 
services. In the United States, major insurers and Medicare do not currently reimburse 
cardiopulmonary rehabilitation for pulmonary hypertension. Therefore, an inpatient 
physical activity program is infeasible in the United States23. Moreover, the intensity of 
these interventions and requirement for travel make them impractical for many patients 
and poorly scalable to the general PAH population. These studies provide important 
evidence for the efficacy of increasing physical activity, but the methods present 
significant obstacles to widespread adoption, underscoring the need for more pragmatic 
interventions. 
 
 
 
 

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1.3 Mechanisms of the beneficial effects of physical activity in PAH. 
The mechanisms by which physical activity improves 6MWT distance and quality of 
life in PAH are unknown. In the Mereles trial and subsequent studies, an increase in 
exercise capacity was associated with a very modest reduction in estimated 
pulmonary arterial pressure (3-5mmHg), suggesting that physical activity does not 
ameliorate pulmonary vascular disease18. Potential alternative mechanisms include 
improvement in RV function, systemic metabolism, and/or skeletal muscle function. 
Although increased pulmonary blood flow has been observed after training 
programs in PAH patients24, the effects on RV function were not described. Thus, it 
is unknown if improved pulmonary flow is due to enhanced RV function. Insulin 
resistance is common in PAH (even in lean patients) and linked to pulmonary 
vascular disease and RV dysfunction1,25-28. Increased physical activity may improve 
insulin resistance, thereby potentially improving pulmonary vascular and/or RV 
function. Finally, skeletal muscle metabolism is abnormal in PAH patients, exhibited 
by lipid deposition and impaired mitochondrial function2,29-32. Skeletal muscle 
dysfunction contributes to reduced functional capacity in PAH22,32. Physical activity 
improves skeletal muscle function in PAH22,33,34, but has not been tested in the 
context of an unsupervised, pragmatic randomized trial. This study will be the first to 
probe several potential mechanisms of improved exercise capacity in the context of 
a randomized physical activity intervention in the PAH population. 
1.4 Mobile health tools to promote behavioral change. 
Mobile health (mHealth) technology has been used to promote behavioral change in 
a wide range of chronic conditions. Physical inactivity is a known modifiable 
cardiovascular risk factor35, yet less than half of the US adult population meets the 
goal of at least 150 minutes per week of moderate activity36. A 2012 Cochrane 
review confirmed the efficacy of telephone and web-based interventions to increase 
physical activity37. Recent advances in mHealth technology – particularly the 
widespread use of Bluetooth compatible accelerometers – now allow remote 
monitoring of physical activity and real time data tracking. Wearable accelerometers 
provide accurate measurements of steps and activity in three dimensions. These 
devices are popular with consumers and often recommended by physicians, but 
there are very limited data on their effectiveness at increasing activity38-40. The 
Tobacco, Exercise and Diet Management (TEXT ME) trial demonstrated that a 
personalized, text-based intervention in subjects with coronary heart disease 
resulted significant reductions in LDL, blood pressure, and smoking and an increase 
in physical activity41. Also recently, our Co-investigators demonstrated in the 
mActive trial that combining behavioral change based text messages with activity 
tracking led to a marked increase in step counts and aerobic activity42. A key 
innovation of the mActive trial was the addition of “smart” texting that adapted to 
real time activity data. Behavioral change elements such as coaching texts appear 
to be a necessary addition to simple activity tracking40. A mHealth activity 
intervention is an attractive approach in PAH for several reasons: 1) PAH is 
associated with baseline functional impairment and proven efficacy of physical 
activity; 2) no requirement for proximity to a major hospital or rehabilitation facility; 
3) cost-effective intervention compared with standard therapy; and 4) highly 

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amenable to a multi-site trial, which is critical for Phase III studies in a rare disease. 
Given the success of similar interventions in other populations, testing of a mHealth 
intervention in PAH seems warranted. 
 Objectives and Specific Aims 
2.1 Objectives 
This is a Phase II, single center, randomized, parallel group trial to demonstrate the 
efficacy of a mHealth intervention in PAH 
2.2 Specific Aims 
Primary Aim:  
1. To determine whether a mHealth intervention affects mean daily step counts at 
week 12 in patients with PAH.  
Secondary Aims:  
• Change from baseline of six minute walk test 
distance (meters) at week 12. 
• Change from baseline of RV free wall longitudinal 
strain at week 12 (RV Strain). 
• Assess the frequency that the daily step target 
was achieved over 12 weeks (Daily goal 
attainment).  
• Change in minutes of activity per day between 
week 12 and baseline (Daily aerobic time). 
• Change in survey score between week 12 and 
baseline (emPHasis-10 Quality of Life survey) 
• Change in survey score between week 12 and 
baseline (SF-36 Quality of Life Mental 
Component Score). 
• Change in Borg Dyspnea Score between week 12 
and Baseline. 
• Change in heart rate between week 12 and 
Baseline (Resting heart rate).  
• Change from baseline insulin resistance at week 
12 (HOMA-IR). 
• Change from baseline B-type natiurectic peptide 
level at week 12 (BNP).  
• Change in SF-36 score between week 12 and 
Baseline (SF-36 Physical Component Score).  
• Change in minutes between week 12 and 
baseline in minutes of moderate-vigorous activity. 
• Change in fat volume between week 12 and 
baseline (visceral fat volume).  

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The primary endpoint mainly focuses on testing the feasibility of a mHealth intervention 
to increase step counts in patients with PAH. Secondary endpoints mainly focus on 
examine the effect of a mHealth intervention on exercise capacity, quality of life, and 
mechanisms of improved exercise capacity.  
 Screening, Subject Selection, and Randomization 
3.1 Recruitment of Study Sample 
Patients will be recruited from the Center for Pulmonary Vascular Disease (CPVD) at 
Vanderbilt University Medical Center. Potentially eligible subjects will be pre-screened 
and informed about that study to determine if they have an interest in enrolling. After the 
initial pre-screening, the subject will provide informed consent before any study 
procedures are performed. 
3.2 Inclusion/Exclusion Criteria  
Inclusion criteria: 
1) Adults (aged 18 or older) 
2) Diagnosed with idiopathic, heritable, or associated (connective tissue 
disease, drugs, or toxins) pulmonary arterial hypertension (PAH) 
according to World Health Organization consensus recommendations  
3) Stable PAH-specific medication regimen for three months prior to 
enrollment. Subjects with only a single diuretic adjustment in the prior 
three months will be included 
4) Subjects must have a Bluetooth capable modern smartphone capable of 
receiving and sending text messages and an active data plan. Study staff 
will provide a temporary smartphone with data plan in the event that a 
participant is otherwise qualified but does not own a smartphone 
5) Forced vital capacity >65% predicted with no or minimal interstitial lung 
disease based on reviews of imaging studies by PI and medical monitor.   
 
 
 
Exclusion criteria: 
1) Prohibited from normal activity due to wheelchair bound status, bed bound 
status, reliance on a cane/walker, activity-limiting angina, activity-limiting 
osteoarthritis, or other condition 
2) Pregnancy 
3) Diagnosis of PAH etiology other than idiopathic, heritable, or associated 
4) Functional class IV heart failure 
5) Requirement of > 1 diuretic adjustment in the prior three months 
6) Preferred form of activity is not measured by an activity tracker 
(swimming, yoga, ice skating, stair master, or activities on wheels such as 
bicycling or rollerblading) 
3.3 Study Arm Assignment, Randomization, and Subject Retention 

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Participants will be assigned to either the intervention or no intervention arms after 
the run-in period in a random manner until 25 participants are enrolled into each 
arm. Permuted block randomization stratified by functional class (I/II vs. III) will be 
used to ensure approximate balance of treatment groups within each stratum over 
time.  Based on our previous studies in PAH subjects in our catchment area, African 
Americans will represent approximately 16% of the study population. 
Randomization will be performed in small blocks, which vary in size. Investigators 
will be unaware of the size or order of the blocks. Projected dropout during the 12 
week study has been incorporated into the power calculations. The Data Safety 
Monitor Board may be unblinded at any time to investigate possible adverse events. 
Procedures for reporting adverse events are outlined in section 7.0. 
The group randomization code will be maintained by the research coordinator. The code 
is to be broken only if knowledge of group assignment for that subject is required to 
initiate appropriate therapy of an adverse event (AE) or if the safety of the subject is at 
serious risk without knowledge of the group assignment. The decision to unmask will be 
made by the PI and the Medical Monitor. The Data Safety Monitoring Board will be 
notified as soon as possible. 
 Study Designs 
4.1 Overview 
We propose a randomized trial to examine the feasibility of a mHealth intervention to 
improve step counts in patients with PAH. Subjects will be randomized to step tracking 
plus smart texts versus tracking with usual activity for 12 weeks.  
4.2 Monitoring Device 
The Fitbit Charge HR tri-axial accelerometer will be used to continuously gather data on 
physical activity, heart rate, and sleep. This device provides feedback in units of activity 
(steps, stairs climbed, activity time, and exercise time) and heart rate (per second when 
active, per 5 seconds when inactive). It has been validated against research devices in 
free-living conditions and is relatively inexpensive. 
4.3 Fitbit Application and Data Management 
During enrollment, study personnel will install the Fitbit on the subject's smartphone, 
paired via Bluetooth 4.0 to the Fitbit Charge HR. The Fitabase subscription service 
(https://www.fitabase.com/) will be used to create a study dashboard, enabling real-time 
monitoring of battery charge, device syncing, and physical activity variables allowing 
real-time monitoring of participant compliance with the study protocol. Fitabase is a 
HIPPA compliant platform that can link and aggregate the Application Programming 
Interfaces of the Fitbit Charge HR. Real time activity data will be transmitted from the 
subject’s smartphone to our mHealth platform via cellular network. The Charge HR has 
a battery life of 5 days and recharges in 1-2 hours. Subjects will be instructed to leave 
the app running and Bluetooth enabled for the duration of the trial. If the participant 
owns a smart phone but does not currently have a data plan, the study may offer to 
purchase a temporary data plan for the participant. The study may offer a temporary 

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smartphone and data plan for the duration of the study in the event that a participant is 
otherwise qualified but does not own a smartphone. 
4.4 mHealth Intervention 
Our HIPPA compliant texting platform is linked to the Fitbit Application Program 
Interface. Real time activity data will be transmitted from the subject’s smartphone 
to our mHealth platform via cellular network. Subjects assigned to the texting arm 
will receive 3 texts/day in sync with their preferred morning, lunch, and evening 
leisure schedule, which is defined at enrollment. These texts will use personal, 
disease-specific, and provider information (Table 1) to deliver 2 types of messages 
customized to the current step count and sent in equal proportion. Messages are 
designed to facilitate self-awareness, reinforce step targets, and link physical 
activity with a reward or memorable cue.
Booster: 
“Megan, you were pretty active 
yesterday! You got 8994 steps, which 
is close to your goal of 10,000. There 
are immediate benefits to exercise: you 
will feel better and have more energy!” 
Positive reinforcement: 
“Jon, you are on track to have a VERY 
ACTIVE day! Already halfway to your 
target of 10,000 steps – Outstanding
Subjects in both study arms may receive additional texts during the day for 
reminders about charging, syncing, and the Fitbit Charge HR. Subjects will receive 
weekly email reminders about the importance of wearing their device from a secure 
email address created for this study. Subjects can email this account with study 
questions. If there is loss of data transmission for a full day, subjects will be emailed 
with a reminder to wear their device and/or reestablish a connection with their 
phone. After 3 days of absent data, another email reminder will be sent and the 
study coordinator will call the subject to determine the cause. If subjects have 
regularly scheduled clinic visits with their treating physician, they will be counseled 
not to reveal their group assignment. 
4.5 Run-in Period and Step Count Targets 
We will use a two-week run-in 
period, which will improve our ability 
to identify a true baseline step count 
and reduce dropout after 
randomization. Participants will wear 
the Fitbit Charge 3 HR device 24 
hours a day for seven days a week 
(with the option to remove device 
during showering or bathing) to 
determine their baseline daily step 
count. We will assume a Hawthorne 
or observer effect during the first 
week of the run-in period and 
discard this data. The baseline daily 
 
Table 1. Factors in Personalization of Text 
Messages 
Preferred name 
Occupation 
Age 
Name of spouse/partner 
Sex 
Name of children 
Physician name 
Name of dog 
Preferred activity 
Local park 
Favorite athlete 
Gym 
Body mass index 
Work schedule 
Other co-morbidities 
Television watching habits 
PAH-specific medications 
 

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step count will be calculated as total steps during run-in Week 2 divided by 7 days. 
Randomization will occur after the run-in phase to account for potential dropout 
during this period. Participants displaying noncompliance during the run-in period will 
not be randomized. Noncompliance will be defined as having more than one bad data or 
no data day per week. However, depending on the reason for noncompliance, this 
requirement may be waived at the discretion of the PI and study team. 
The initial daily step target Weeks 1-4 for the intervention group will be 20% higher 
than the run-in baseline value. For example, if the run-in daily step count is 2,000 
steps/day, the daily step target for Weeks 1-4 will be 2,400 steps/day. An increment 
of 20% was selected because it reflects the average increase in treadmill workload 
achieved over 4 weeks in chronic obstructive lung disease patients with PH who 
attend pulmonary rehabilitation at our facility. Average daily step counts during 
Week 4 will be calculated and used to define the target (20% above the Week 4 
average) for Weeks 5-8. The daily target for Weeks 9-12 will be calculated in the 
same manner. New targets will be communicated with patients via text message. If 
outliers are observed, we reserve the right to adjust the increase in the daily step 
target. Outliers will be identified based on preset qualifications for days providing 
good data.   
4.6 Remuneration 
Subjects will have an option to receive $200 for completing the study or be paid $100 
and keep the Fitbit Charge HR device after completing all study procedures. 
 Data Collection 
5.1 Consent 
Written consent will be obtained for enrollment from participants. For each consent 
process, study personnel will discuss over the phone or in person the details of the 
study, the risks and benefits, and the subject’s rights and responsibilities if they choose 
to participate in the trial and their right to refuse to participate.  It will be made clear that 
their clinical care will not be affected by their decision.   
The subject consent process will be conducted either by phone, in person at the 
Vanderbilt Pulmonary Clinic or at the Vanderbilt Center for Translational and Clinical 
Research, or by using a REDCap-based electronic consent form.  The eConsent form 
has been developed in REDCap, a secure, web-based, HIPAA-compliant, data 
collection platform with a user management system allowing project owners to grant 
and control varying levels of access to data collection instruments and data (e.g. read 
only, de-identified-only data views) for other users. If the subject chooses to complete 
the electronic consent through REDCap, then a link will be emailed to the subject. 
Subject self-initiated accessing of the REDCap consent form may occur via 
smartphone, computer, or other electronic device. If the subject does not have access 
to a computer, then a phone consent will be offered. If the subject prefers to have a 
hard copy of the consent to review instead of an emailed PDF, it will be mailed to the 
subject. 
 

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Contact information will be provided (email and phone) for subject to contact a member 
of the key study personnel with questions, prior to consent. Subject signatures will be 
obtained using written signature via stylus/cursor. Upon completion of the consent, 
subject will be provided with a copy of their version of the consent document by 
providing home address for mailing of a hard copy of the consent. Should the subject 
choose to receive a link to the consent document in lieu of a hard copy (or if they sign 
electronically from a remote location), they will receive a link to a ROCKET site 
containing the consent form appropriate to the version date that they signed.  Signed 
consent documents will NOT be housed electronically on ROCKET.   
5.2 Study Visits and Contacts 
This study will consist of two visits, baseline and week 12. The baseline and week 12 
visits will take approximately 4 hours.  The subject will be offered the option of eConsent 
through a web link to REDCap, or the option of verbal phone consent. Subjects will 
have the option to be consented in the Pulmonary Vascular Disease Clinic, the Clinical 
Research Center, or the Vanderbilt Translational and Clinical Cardiovascular Research 
Center by the PI or a clinical research coordinator if they do not wish to do a eConsent 
or phone consent. There will be no changes to a subject’s medication regimen. 
 Screening 
At time of initial phone or in-person screening, all subject questions are adequately 
answered. After consenting, subjects will be mailed or given the Fitbit device and the 
application will be uploaded to their smartphone. The subject will be asked to continue 
wearing the device for 14 days and the application password will be concealed during 
the screening period. The following will be reviewed at time of screening: 
• Informed consent  
• Review inclusion/exclusion criteria  
• Review of medical history 
• Demographic data 
• Review of current medications 
• WHO functional class 
• Education on FitBit device 
 Study Day – Visit 1 (Baseline) 
Baseline testing will take place over 1 day at the Clinical Research Center. The visit will 
last approximately 4 hours. Baseline information will be used to characterize the 
participants and to compare the experimental groups with regards to demographics and 
other variables. Eligibility criteria will be confirmed prior to randomization to treatment 
group. The following procedures will be performed:  
• Transthoracic Echocardiography 
• Six Minute Walk Test 
• Dual Energy X-ray Absorptiometry (DEXA) 
• Blood collection 
• Quality of Life Questionnaires (SF-36 and emPHasis-10) 
• Vital signs 

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• Physical exam 
• Interim medical history 
• Review current medications 
 
After fasting research labs have been drawn, the subject will have the opportunity to eat 
a snack. The subject will complete the SF36 and emPHasis-10.  The investigator or 
research nurse will take a history/interim history and perform a physical examination 
including checking vital signs, and review current medications. The subject will perform 
the six minute walk test. Echocardiography and DXA bone density scan will be 
performed.  
All inclusion/exclusion criteria will be confirmed by an investigator before the subject can 
be formally randomized. The subject will be randomized to a treatment group using a 
web-based database. 
 Phone Calls ( Week -1, 2, 4, 6, 8, 10) 
The research coordinator will call the subject. Symptoms and potential side effects will 
be assessed and changes in medications will be reviewed and recorded. Study 
compliance will be assessed and reinforced. 
 Study Day – Visit 2 (Week 12) 
All tests done at baseline will be repeated at the Week 12 Visit. The following 
procedures will be performed:  
• Transthoracic Echocardiography 
• Six Minute Walk Test 
• Dual Energy X-ray Absorptiometry (DEXA) 
• Blood collection 
• Quality of Life Questionnaires (SF-36 and emPHasis-10) 
• Vital signs 
• Physical exam 
• Review current medications 
 
After fasting research labs have been drawn, the subject will have the opportunity to eat 
a snack. The subject will complete the SF36 and emPHasis-10.  The investigator or 
research nurse will take a history/interim history and perform a physical examination 
including checking vital signs, and review current medications. The subject will perform 
the six minute walk test. Echocardiography and DXA bone density scan will be 
performed. Subjects will be asked to continue wearing the activity monitor for another 
21 days. Subjects who have preferred to receive a money payment as compensation for 
their participation will be given a prepaid envelope to return the activity monitor 21 days.  
 
 
 
 
 
 

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5.3 Study Schedule of Endpoints and Procedures 
The table below summarizes the study endpoint assessments and procedures.  
 
Table 2. Study Procedures 
 
Screening 
Run-In 
Treatment Period 
Wash 
Out 
Week -2 to -4 Week 
-2 
Week 
-1 
Week 
1 
Week
2 
Week
4 
Week
6 
Week
8 
Week
10 
Week 
12 
Week 
15 
Week 
17 
Visit # 
 
 
 
1 
 
 
 
 
 
2 
 
 
Telephone Call # 
 
 
1 
 
2 
3 
4 
5 
6 
 
7 
8 
Day# 
(-14 to -30 
days to Study 
Hour 0) 
-14 to 
-30 
-7 to  
-23 
0 
14  3 28  3 42  3 56  3 70   
3 
84  3 105  
3 
119  
3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 Run-In  
 
X 
X 
 
 
 
 
 
 
 
 
 
 Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
 Wash-Out  
 
 
 
 
 
 
 
 
 
 
X 
 
 Follow-Up 
 
 
 
 
 
 
 
 
 
 
 
X 
 History And Physical Exam
 
 
 
X 
 
 
 
 
 
X 
 
 
    Medical History 
X 
 
 
X 
 
 
 
 
 
X 
 
 
    Symptom Assessment 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
    Medications 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
    Vital Signs 
 
 
 
X 
 
 
 
 
 
X 
 
 
    Physical Exam 
 
 
 
X 
 
 
 
 
 
X 
 
 
    WHO Functional Class 
X 
 
 
X 
 
 
 
 
 
X 
 
 
Testing 
 
 
 
 
 
 
 
 
 
 
 
 
    Phlebotomy 
 
 
 
X 
 
 
 
 
 
X 
 
 

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      Glucose & Insulin 
 
 
 
X 
 
 
 
 
 
X 
 
 
      Fatty Acid &  
      Acylcarnitine Profiles 
 
 
 
X 
 
 
 
 
 
X 
 
 
    NT-proBNP 
 
 
 
X 
 
 
 
 
 
X 
 
 
    DXA 
 
 
 
X 
 
 
 
 
 
X 
 
 
    Six Minute Walk Test 
 
 
 
X 
 
 
 
 
 
X 
 
 
    SF-36, emPHasis-10 
 
 
 
X 
 
 
 
 
 
X 
 
 
    Echocardiogram 
 
 
 
X 
 
 
 
 
 
X 
 
 
    Urine Pregnancy Test  
    (women only) 
X 
 
 
 
 
 
 
 
 
 
 
 
Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
    Adverse Events 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
    Compliance 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 Assessments of Efficacy and Outcome Measures 
6.1 Assessments of Efficacy  
Primary Outcome Measure(s): Daily Step Count (Time Frame: 12 weeks)  
 
Secondary Outcome Measure(s):  
There are several secondary objectives of this study. They include: 
• To assess the effect of a mHealth intervention on frequency of daily goal 
attainment at week 12. 
• To assess the effect of a mHealth intervention vs. no intervention on daily aerobic 
time at week 12. 
• To assess the effect of a mHealth intervention vs. no intervention on total daily 
activity at week 12. 
• To assess the effect of a mHealth intervention vs. no intervention on 6MWD at 
week 12.  
• To assess the effect of a mHealth intervention vs. no intervention on Borg Dyspnea 
Score at week 12.  
• To assess the effect of a mHealth intervention vs. no intervention on resting heart 
rate at week 12.  
• To assess the effect of a mHealth intervention vs. no intervention on the SF36 and 
emPHasis-10 at week 12.  
• To assess the effect of a mHealth intervention vs. no intervention on RV free wall 
longitudinal strain at week 12.  
• To assess the effect of a mHealth intervention vs. no intervention on tricuspid 
annular plane systolic excursion (TAPSE) at week 12.  
• To assess the effect of a mHealth intervention vs. no intervention on tricuspid 
annular velocity (S’) at week 12.  
• To assess the effect of a mHealth intervention vs. no intervention on HOMA-IR at 
week 12.  
• To assess the effect of a mHealth intervention vs. no intervention on BNP at week 
12.  

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• To assess the effect of a mHealth intervention vs. no intervention on skeletal 
muscle and fat mass at week 12.  
• To assess the effect of a mHealth intervention vs. no intervention on WHO 
functional classification for PAH at week 12.  
• To assess the fidelity of data collection and text transmission of a mHealth 
intervention over 12 weeks.  
• To assess the effect of a mHealth intervention vs. no intervention on patient 
satisfaction at week 12 
• To assess the effect of a mHealth intervention vs. no intervention on dropout rates 
over 12 weeks. 
• To assess the effect of a mHealth intervention vs. no intervention on PAH-related 
hospitalizations over 12 weeks. 
• To assess the effect of a mHealth intervention vs. no intervention on medication 
regimen escalation/reduction over 12 weeks. 
• To assess the effect of a mHealth intervention vs. no intervention on incidence of 
death over 12 weeks. 
 Step Counts and Physical Activity  
Wearable accelerometers can provide accurate measurements of steps and activity in 
three dimensions. 
Accelerometery is a direct measure of physical activity in patients’ day-to-day lives.  
Step counts and physical activity will be measured using the Fitbit Charge HR monitor, 
a lightweight device that has a three-axis acceleration sensor, altimeter, vibration motor, 
and optical heart rate monitor. This device provides feedback in units of activity (steps, 
stairs climbed, activity time, and exercise time) and heart rate (per second when active, 
per 5 seconds when inactive). Initialization and data download will be performed using 
the Fitbit Application Program Interface. Step counts will be (1) tracked by the Fitbit 
Charge HR device, (2) transmitted to the participant’s smartphone via Bluetooth, and (3) 
finally transmitted from the subject’s smartphone to our mHealth platform via cellular 
network. 
Subjects will begin wearing the Fitbit on the day of their screening visit and will wear it 
for the next 17 weeks. Participants will wear the Fitbit Charge HR device 24 hours a day 
for seven days a week (excluding only bathing/showering and charging), starting on the 
day after the screening visit and for the next 17 weeks. In addition to absolute step 
counts, we will assess frequency of goal attainment, daily aerobic time (total time spent 
walking continuously for > 10 minutes without breaking for > 1 minute), and total daily 
activity (time spent above 3 metabolic equivalents) 
6.2 Secondary Outcome Measures  
 Six Minute Walk Distance 
Walking is the most basic form of exercise and is integral to daily activities. The 6MWT 
is a standardized, timed submaximal test of unencouraged, self-determined distance 

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walked which is reliable and valid45. Standardized test methods and scripted and timed 
statements have been established in prior studies of PAH and will be used3,9-15.The 
6MWT will be performed at baseline and 12 weeks. The subject will be instructed to 
wear comfortable clothing and shoes. The test will be performed at approximately the 
same time of day at each visit. In addition, Borg dyspnea Score, oxygen saturation, and 
heart rate will be recorded at the beginning and conclusion of each test. 
 Transthoracic Echocardiographic Measures 
We will assess RV free wall longitudinal strain and other parameters as secondary 
endpoints via transthoracic echocardiography. The ultimate determinant of outcome in 
subjects with PAH is right ventricular function, so we have focused on metrics, which 
are predictors of survival in PAH, including RV strain and qualitative RV function.  
 Fidelity of Data Collection and Text Transmission 
In order to analyze the fidelity of the intervention, we will assess data collection and text 
transmission. Endpoints evaluating fidelity of data collection will be percent days with 
incomplete activity data and percent weeks with at least 6 days of activity data. The 
endpoint evaluating text transmission will be defined as percent total texts successfully 
delivered. Data for these endpoints will be gathered by the Fitbit Charge HR, 
transmitted to the subject’s smartphone via Bluetooth, and then sent out to our mHealth 
platform via cellular network. 
 The Borg Dyspnea Score 
In order to assess exercise capacity, the Borg score for dyspnea and overall fatigue will 
be recorded before and after subjects complete the six-minute walk, performed at 
baseline and week 12. This score is a measure of the physical activity intensity level 
based on the subject's perceived exertion. Subjects will rate at resting and peak 
exercise. 
  Resting Heart Rate 
Resting heart rate will be monitored regularly using the activity tracking device (per 
second when active, per 5 seconds when inactive). In addition, subject's heart rate will 
be measured will be recorded before and after subjects complete the six-minute walk 
test. This will provide resting and peak exercise heart rate at baseline and week 12.  
 Quality of Life Questionnaires (SF36 & emPHasis–10) 
The SF36 is one of the most widely used generic measures of subjective health 
status. The SF36 includes one multi-item scale that assesses eight health concepts: 
1) limitations in physical activities because of health problems; 2) limitations in 
social activities because of physical and emotional problems; 3) limitations in usual 
role activities because of physical health problems; 4) bodily pain; 5) general mental 
health (psychological distress and well-being); 6) limitations in usual role activities 
because of emotional problems; 7) vitality (energy and fatigue); and 8) general 
health perceptions. Subjects will complete the SF36 at baseline and each 
subsequent clinic visit during the therapy phase of the study.  

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The emPHasis-10 is a pulmonary hypertension-specific questionnaire to assess 
health related quality of life. It covers breathlessness, fatigue and lack of energy, 
social restrictions, and concerns regarding effects on patient’s significant others, 
such as family and friends50. Each item is scored on a semantic differential six-point 
scale (0-5), with contrasting adjectives at each end. A total emPHasis-10 score is 
derived using simple aggregation of the 10 items. emPHasis-10 scores range from 
0 to 50, higher scores indicate worse quality of life50. 
 Dual Energy X-ray Absorptiometry (DEXA) 
DXA is the technique most commonly used to assess bone density in adults. The 
lumbar spine and proximal femur are recommended sites. The technique uses very 
low-dose x-ray exposures (<4µSv per scan) and measurements are rapid. Body 
composition will be assessed at baseline and 12 weeks for changes in relative lean 
muscle and body fat mass.   
 Blood Biomarkers 
a. Plasma NT-proBNP 
Plasma NT-proBNP reflects right ventricular function in PAH and is a strong 
predictor of outcome in PAH. BNP will be assessed at baseline and 12 weeks.  
b. HOMA-IR 
Insulin resistance will be quantified using the homeostasic model assessment of 
insulin resistance (HOMA-IR), which estimates insulin resistance through fasting 
plasma insulin and glucose ratios, at baseline and 12 weeks.  
c. Fatty Acid Metabolism  
To evaluate the effect of this intervention on fatty acid metabolism, we will measure 
fasting long-chain fatty acid and acylcarnitine profiles using mass spectrometry at 
baseline and 12 weeks.  
 WHO Functional Class 
The WHO functional classification for PAH has been modified from the well-known 
New York Heart Association functional classification. This functional classification is 
based on symptoms, with Class I being defined by no symptoms, Class II as having 
mild limitation in physical activity, Class III as having markedly limited physical 
activity and Class IV as being unable to perform any physical activity. The WHO 
functional class will be assessed at every visit. 
 Other Feasibility Endpoints  
a. Drop Out Rates 
b. Patient Satisfaction: Patient satisfaction will be assessed using a 
customized survey developed for the mActive trial and adapted for the PAH 
population.  

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 Medication Regimen Escalation/Reduction 
The addition of new therapy for PAH indicates disease worsening (or subsequent) right 
heart failure. New PAH-specific medications added to the subjects’ medical regimen 
and the dates when added will be recorded during the study. Often, specific PAH 
medications which are administered at a stable dose have increased dosing with clinical 
worsening (specifically, prostacyclin analog therapy). All dose changes will therefore be 
recorded. 
 Hospitalization for PAH progression or right-sided heart failure 
A hospital admission due to PAH progression and/or right-sided heart failure will be 
defined as a hospitalization because of lower extremity edema or dyspnea and/or PAH 
symptoms (e.g., syncope) refractory to outpatient increases in dose or frequency of 
diuretics or specific PAH medications. 
We will record all hospitalizations during the time of the study. Records from each 
hospitalization will be obtained by the local study coordinator. These records will be 
reviewed by an independent panel of three physicians who are unrelated to the study. 
 
 
 Death 
Cardiovascular Death: We define as cardiovascular death as:  
1) sudden death 
or 
2) death preceded by: 
a) cardiogenic shock (hypotension resulting in a failure to maintain normal 
renal or cerebral function for >15 minutes prior to death) 
     or 
3) heart failure symptoms or signs requiring: 
i) intravenous therapy or oxygen in the hospital  
or 
 
 
ii) confinement to bed 
in the absence of secondary causes (such as systemic infection or dysfunction of 
intravenous or subcutaneous medication delivery devices) or alternative causes 
of death.  
Non-Cardiovascular Death: A death which does not meet the criteria above will 
be considered a non-cardiovascular death. 
 Statistical Considerations 
7.1 Study design 
The proposed research project involves primary and several secondary objectives. To 
address these aims, we will conduct a single-blinded, randomized, parallel group trial. 
Step counts, activity, 6MWT, SF-36, emPHasis-10, DXA scanning, and blood sampling 

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will be performed at baseline and 12 weeks. Disposition of subjects and baseline 
comparisons  
Summaries of all subjects screened, recruited, and randomized and the number who 
complete the week 12 visit post-randomization will be provided, according to the 
CONSORT guidelines. The treatment groups will be compared at baseline with respect 
to demographics and baseline measurements related to efficacy and safety without 
formal statistical testing. 
7.2 Statistical Analysis 
We will use standard graphing and screening techniques to detect outliers and to 
ensure data accuracy. We will assess continuous outcomes for normality. If non-
normal, we will apply data transformation or consider non-parametric analysis 
methods.We will examine the effects of tracking with and without smart texts on the 
primary endpoint using general linear models. The independent variables will 
include the baseline 6MWT distance, age, gender, and a treatment group indicator. 
If the normality of the dependent variable is in question, we will use a generalization 
of the Wilcoxon test – the proportional odds ordinal logistic model. The effects of the 
baseline value and age will be assumed to be smooth but not linear by using 
restricted cubic spline functions.  
 
7.3 Missing Data and Dropouts 
For all endpoints, the primary analysis will be intention-to-treat: all subjects 
randomized with a post-intervention endpoint measurement will be included. For 
endpoints based on measurements collected at the end of the study, individuals 
who do not complete follow-up cannot be included in analyses of those endpoints. A 
per-protocol analysis will be conducted as a secondary analysis for the primary 
endpoints. Any subject who is identified as a major protocol violator will not be 
included. Major protocol violators will be defined as subjects randomized but non- 
compliant with wearing the accelerometer (i.e. missing ≥ ½ of total days).  
A multiple imputation procedure implemented in the aregImpute function in the 
Hmisc package in R (R Package; Version 3.0-10) will be used to assess the impact 
of missing data. The analysis with imputation will serve primarily as a sensitivity 
analysis. We will conservatively impute missing data to perform analyses with and 
without imputed missing data to corroborate findings. Conservative imputation 
strategies could include assuming worst case scenario for subjects on the 
intervention, best case for subjects on the control, or assuming the observed mean 
of the control group for the subjects on the intervention. The potential drop-out is 
considered in the power calculation to minimize its impact. 
7.4 Statistical Power 
We need a sample size of 20 or 25 in each group to have 80% or 90% power, 
respectively, to detect a 25% difference using a t-test with a 0.05 two-sided 
significance level. In this calculation, we conservatively assumed no change for the 
control group (conservative because 6MWT distance often declines in placebo 

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groups in PAH trials) and a within subject correlation of 0.7. Assuming a 10% drop 
out rate, we plan to enroll 25 subjects per group so that we can have at least 22 
completed subjects to have 85% power. 
7.5 Interim Monitoring Guidelines 
We have not planned a formal interim analyses for efficacy and therefore there are no 
stopping rules for efficacy for this trial. This is a Phase II trial which will be useful in 
supporting future studies of the intervention even if null. This project will have a DSMB 
who may consider whether to stop the trial or not if there is an increased risk of adverse 
events or toxicity.  
7.6 Protocol Violations 
Serious protocol violations such as discontinuation of the intervention unrelated to AEs 
will be carefully recorded and regularly reviewed by the Principal Investigator. Remedial 
changes in procedure will be recommended where feasible to reduce the incidence of 
such violations. The causes and circumstances of all violations will be documented 
where known for purposes of future secondary analyses and interpretation. Because all 
primary analyses will be intent-to-treat, it is essential that violations be kept to a 
minimum especially where it is possible to influence their rate of occurrence. 
 Study Risks and Discomforts 
8.1 Activity Tracking 
Digital activity tracking and text messaging do not present any obvious medical risk. 
Participants will be told that the text messaging system does not substitute interaction 
with health care providers and cannot address emergency situations. The PI will report 
in a timely fashion to the IRB any unanticipated problem or major study deviation. 
8.2 Echocardiography 
There are no risks to this ultrasound procedure aside from minor discomfort related to 
placement of the ultrasound probe on the chest. 
8.3 Venipuncture 
The protocol requires patients to have blood drawn for research purposes. The risks of 
drawing blood are uncommon and may include bleeding, minor infection and bruising. 
Commonly, having blood drawn is painful, and rarely can lead to infection at the site of 
the blood draw. The amount of blood drawn is small, and represents an exceedingly 
small percentage of the amount of the total blood volume and will not represent a 
significant risk to the patient. 
8.4 Privacy 
As noted, we will advise participants to set their phone to password protected mode. 
Due to the nature of text messaging technology, there is a small potential privacy risk 
when communicating through text messages. Text message communications are not 
encrypted and therefore this information can be read if intercepted while in transit. 
Although we have a strict confidentiality policy and the technology system we use to 

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deliver text messages meets or exceed HIPAA standards, there is a possibility for the 
text messaging communications to be intercepted or accessed without the participant’s 
authorization. Once delivered to the participant’s mobile device, text messages are 
under his or her control and are his or her responsibility. By agreeing to participate in 
this study, participants accept this technology risk and release the research team, 
Vanderbilt, and Johns Hopkins from any liability arising from the use of text message 
communications in this program. 
 
8.5 Financial Risk 
Participants will only pay for text messages according to their mobile phone service 
plan. 
 
The intent of this study is to test the real world feasibility of this intervention in a PAH 
population across a range of disease severity. Therefore, there will be no early stopping 
rules. As stated in the consent form and reviewed at the time of enrollment, subjects 
may end participation at any time without prejudice. 
 Quality Control 
Design strategies and monitoring activities throughout the study will ensure the integrity 
and high quality of the data. Design strategies include randomization of treatment 
assignment and training and certification of personnel. The rigorous monitoring program 
includes data queries and performance monitoring over the time of the trial. 
9.1 Personnel Training 
Prior to randomization of the first subject in the study protocol, each site PI will ensure 
that staff has completed appropriate training and that all documentation including IRB 
approval (and local IRB approvals, if required) is completed and available. The purpose 
of training is to ensure that study personnel are carrying out the protocol in a consistent 
way and are adhering to good clinical practice guidelines. Staff will have current Human 
Subjects Training Certification on file. Before enrollment begins, study coordinators and 
research assistants who will perform the outcome assessments will be trained in all 
procedures, including completion of case-report forms (CRFs). 
9.2 Data Quality 
The PI and study coordinator will constitute the first line of monitoring of the safety of 
the human participants. They will perform continuous monitoring of data quality and 
completion of CRFs. Surveillance for AEs will consist of questioning subjects about 
potential AEs at every study contact, having subjects report any adverse event to the 
study team, and having subjects undergo vital sign checks and physical exams during 
each study visit. The research team will create computer modules to identify 
discrepancies and incomplete data. These reports are tracked until each problem is 
resolved and corrected in the database. 
All study personnel are required to read the consent form and protocol. 
 

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 Data and Safety Monitoring and Reporting  
10.1 Consent 
Written consent will be obtained for enrollment from participants. For each consent 
process, study personnel will discuss the details of the study, the risks and benefits, and 
the subject’s rights and responsibilities if they choose to participate in the trial and their 
right to refuse to participate.  It will be made clear that their clinical care will not be 
affected by their decision.  Subjects will be permitted to provide verbal consent over the 
phone prior to being scheduled for a screening visit. Documentation of verbal consent 
will be noted.  Written consent will be obtained at the screening visit or before.   
10.2 Designated Medical Director 
Dr. Anna Hemnes will serve as the medical director for this trial. Dr. Hemnes is co-
director of the Vanderbilt Center for Pulmonary Vascular Disease. She will attend 
weekly meetings with the PI and study personnel. She will be available to discuss 
adverse events with the PI and respond to safety concerns from subjects or study 
personnel.  
10.3 Monitoring 
During bi-weekly phone calls, study personnel will review a checklist of signs or 
symptoms to detect any evidence of over-exertion or disease progression. Subjects will 
also be given a list of symptoms with definitions in lay language that may be related to 
overexertion and will be instructed to contact study personnel if symptoms arise. The list 
will include questions about excessive breathlessness with exertion, dizziness, 
presyncope/syncope, excessive fatigue, muscle soreness, increased use of as needed 
diuretics, orthopnea, and paroxysmal nocturnal dyspnea. Any positive responses will be 
reviewed with the medical director who will discuss these concerns with the subject to 
determine whether the symptoms are related to the intervention. If symptoms are likely 
attributable to the intervention, we will record it as an adverse event and decrease the 
step count goal to a tolerable level, depending on the severity of the symptoms and the 
judgement of the medical director. All serious adverse events will be reported to the 
DSMB, Vanderbilt Institutional Review Board, and NIH as described in Section 10.5.4. 
10.4 Data Safety Monitor Board (DSMB) 
An independent Data Safety Monitor Board (DSMB) will monitor the trial. The aims of 
the DSMB are to safeguard the interests of the trial's participants, potential participants, 
and investigators, to ensure the safety of the trial's interventions, to monitor the trial's 
overall conduct, and protect the trial's validity and credibility. The DSMB membership 
consists of 5 individuals.  Members have been chosen because of their experience in 
clinical trials and/or clinical expertise, and have been approved by the PI and the team 
of Co-Investigators. The members are independent of the trial (e.g., not be involved with 
the trial in any other way or have any involvement that could impact the trial).The 
members of the DSMB are: Roham Zamanian, MD, FCCP (Chair), Steven Kawut, MD, 
MS, Paul Nietart, PhD, Joseph Fanning, PhD, and Mary Beth Brown, PT, PhD. The first 
meeting will be an organizational meeting via teleconference.  It will be left to the 
discretion of the DSMB whether to subsequently meet face-to-face or by 

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teleconference.  The DSMB will aim to meet every six months to review safety data.  
The need for additional meetings will be agreed upon by the DSMB during their initial 
meeting.  The PI will attend all meetings unless a closed session is requested by the 
DSMB Chair. The DSMB will be blinded to intervention group during open sessions and 
unblinded during closed sessions. The DSMB will report its recommendations in writing 
within 48 hours of the DSMB meeting to the PI.  Possible recommendations include 
continuation of trial as planned with no action needed or advice on and proposal of 
protocol changes. If the trial is to continue without modifications, then the report from 
the DSMB should include a summary paragraph suitable for distribution.  No interim 
analysis is planned. In addition to communicating its preliminary recommendations at 
the end of the meeting, the DSMB will report formally in writing to the PI within 1 week 
of said meeting.  Unless the DSMB is recommending that the trial protocol be changed 
in some way, the letter to the PI should not reveal any confidential information.   
 
 
 
 
10.5 Safety and Adverse Events 
 Definitions 
• 
Unanticipated Problem (UP): Any incident, experience, or outcome that meets 
all of the following criteria:  
1. unexpected (in terms of nature, severity, or frequency) given a) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
document; and b) the characteristics of the subject population being 
studied;  
2. related or possibly related to participation in the research (Possibly related 
to participation in the research means there is a reasonable possibility that 
the AE, experience, or outcome may have been caused by the procedures 
involved in the research); and  
3. suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized.    
 
• 
Adverse Event (AE):  Any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study.  Intercurrent illnesses or 
injuries should be regarded as AEs.  Abnormal results of diagnostic procedures 
are considered to be AEs if the abnormality: 
 results in study withdrawal 
 is associated with a serious AE 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 

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• 
Serious Adverse Event (SAE): Adverse reactions are classified as serious or 
non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
Important medical events are those that may not be immediately life threatening, but 
are clearly of major clinical significance. They may jeopardize the subject, and may 
require intervention to prevent one of the other serious outcomes noted above.  For 
example, drug overdose or abuse, a seizure that did not result in in-subject 
hospitalization or intensive treatment of bronchospasm in an emergency department 
would typically be considered serious.  
All AEs that do not meet any of the criteria for serious should be regarded as non-
serious AEs.  
• 
Suspected Adverse Reaction: Any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event.  For reporting 
purposes, "reasonable possibility" means there is evidence to suggest a causal 
relationship between the drug/investigational product and the adverse event. 
 Classifying AEs 
Severity 
The intensity of the AE is classified according to the Common Terminology Criteria for 
Adverse Events v4.0 (CTCAEv4.0).  Grade refers to the severity (intensity) of the AE:  
If the intensity of an AE worsens during study drug administration, only the worst 
intensity should be reported on the AE page. If the AE lessens in intensity, no change in 
the severity is required. 
CTCAEv4 Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention is not indicated. 
CTCAEv4 Grade 2: moderate; minimal, local, or noninvasive intervention is 
indicated; limiting to age-appropriate instrumental activities of daily living (ADL; 
instrumental ADL refers to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc). 
CTCAEv4 Grade 3: severe or medically significant but not immediately life 
threatening; hospitalization or prolongation of hospitalization is indicated; 
disabling; limiting to self-care ADL (self-care ADL refers to bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not bedridden). 
CTCAEv4 Grade 4: life-threatening consequences; urgent intervention is 
indicated. 
CTCAEv4 Grade 5: death due to an AE. 

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In this grading system, severity is not equivalent to seriousness.  For example, a SAE 
would be any event which was life-threatening or disabling (Grade 4) or fatal (Grade 5) 
or was moderate-severe (Grade 2-3) and required or prolonged hospitalization. 
Expectedness 
AEs must be assessed as to whether they were expected to occur or were unexpected, 
meaning not anticipated based on current knowledge found in the protocol, investigator 
brochure, product insert, or label. 
Expected: an AE known to be associated with the intervention or condition under study. 
OHRP defines an unexpected AE as any AE occurring in one or more subjects 
participating in a research protocol, the nature, severity, or frequency of which is not 
consistent with either: 
1) the known or foreseeable risk of AEs associated with the procedures involved in 
the research that are described in a) the protocol-related documents, such as the 
IRB-approved research protocol, any applicable investigator brochure, and the 
current IRB-approved informed consent document, and b) other relevant sources 
of information, such as product labeling and package inserts; or 
2) the expected natural progression of any underlying disease, disorder, or 
condition   of the subject(s) experiencing the AE and the subject’s predisposing 
risk factor profile for the AE. 
3) Relatedness 
 
1) Definite: the AE is clearly related to the research procedures 
 
2) Probably: the AE is likely related to the research procedures 
 
3) Possible: the AE may be related to the research procedures 
 
4) Unlikely: the AE is doubtfully related to the research procedures 
 
5) Unrelated: the AE is clearly not related to the research procedures 
 
Possibly related to participation in the research: There is a reasonable possibility 
that the adverse event, experience, or outcome may have been caused by the 
procedures involved in the research.   
For each identified AE, an AE entry on the appropriate form will be completed using the 
above classifications as soon as possible, updating as necessary. Reporting procedures 
should be started immediately (within 24 hours) upon learning of a SAE or UP.  
 Interpretation of Definitions 
AE and UP Reporting Period 
The study period during which AEs must be reported is normally defined as the period 
from the initiation of any study procedures to the end of the study treatment follow-up.  
For this study, the study treatment follow-up is defined as 21 days following the last 
administration of study treatment (week 15 phone call).  
Preexisting Condition 

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A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an AE if the frequency, intensity, or the character of the 
condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities 
that meet the definition of an AE must also be recorded and documented as an AE.  
Post-study AE 
All unresolved SAEs or AEs that are possibly, probably, or definitely related to the study 
or study drug should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the AE is otherwise explained.  At the last scheduled visit, 
the investigator should instruct each subject to report any subsequent event(s) that the 
subject, or the subject’s personal physician, believes might reasonably be related to 
participation in this study.   
 
Abnormal Laboratory Values 
Laboratories will not be drawn unless clinically indicated.  A clinical laboratory 
abnormality should be documented as an AE if any one of the following conditions is 
met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of 
dose, discontinuation of the drug, more frequent follow-up assessments, further 
diagnostic investigation, etc. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious AE unless specifically instructed otherwise in 
this protocol.  Any condition responsible for surgery should be documented as an AE if 
the condition meets the criteria for an AE. Neither the condition, hospitalization, 
prolonged hospitalization, nor surgery are reported as an AE in the following 
circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an AE if the purpose of the surgery was elective or diagnostic and the 
outcome was uneventful. 
AEs and SAEs which do not fall under the expedited reporting procedure requirements 
will be reported by the investigator to the IRB during yearly renewals and to the DSMB 
and NHLBI at scheduled or ad hoc meetings upon request. The Investigator/designee 
should keep originals or photocopies of all relevant documentation, including facsimile 
confirmations, and file them in the participant's file. The Investigator should ensure that 
all routine AE(s) are reported to ensure the IRB has accurate data for periodic or annual 
reporting requirements. 

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 Expedited Reporting Procedures 
The Investigator should notify the IRB, DSMB and NHLBI, in an expedited manner, of 
those events listed in the table below related to study participation. 
Expedited Reporting Process 
The PI will report the following information to the IRB for initial assessment and 
subsequent reporting will occur as outlined on the table. 
• 
Protocol name and number 
• 
Subject identifiers 
• 
Demographic data 
• 
Nature of the event 
• 
Severity of the event 
• 
Probable relationship (causality) of AE to study procedure 
• 
Date and time of AE onset 
• 
Date and time of AE resolution, if available 
• 
Concomitant medications that the participant was taking for an 
underlying medical condition or disease and the therapeutic agents 
used for the treatment of the adverse event 
• 
Clinical assessment of participant conducted at time of SAE/AE 
• 
Results of any laboratory and/or diagnostic procedures, and 
treatment 
• 
Follow-up plan 
• 
Outcome 
• 
Autopsy findings (if appropriate) 
 
The IRB will communicate to the PI if the event requires revisions to the informed 
consent form or other measures. The PI will also report any qualifying events to the 
DSMB and NHLBI as noted in the schedule. The PI will file copies of all correspondence 
with the IRB in the appropriate section of the Trial Master File or site study regulatory 
file.  
 
What Event is 
Reported 
Event 
By Whom is 
Event 
Reported 
To Whom is Event 
Reported 
When is Event Reported 
Fatal or life 
threatening 
unexpected, 
suspected serious 
adverse reactions 
 
 
Event 
 Investigator 
• IRB 
Within 24 hours of initial receipt of 
information 
IRB 
determination 
IRB 
• Investigator 
Within 3 business days of IRB 
determination 
All events 
Investigator 
IRB 
• NHLBI, DSMB 
Within 7 calendar days of investigator’s 
initial receipt of information 
Non-fatal, non-life-
threatening 
unexpected, 
suspected serious 
adverse reactions 
  
Event 
Investigator 
• IRB 
Within 24 hours of initial receipt of 
information 
IRB 
determination 
IRB 
• Investigator 
Within 3 business days of IRB 
determination 
All events 
Investigator 
IRB 
• NHLBI, DSMB 
Within 15 calendar days of investigator’s  
initial receipt of information 

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Unanticipated 
Problem that is not 
an SAE 
  
Event 
Investigator 
• IRB 
Within 2 business days of initial receipt of 
information 
IRB 
determination 
IRB 
• Investigator 
Within 3 business days of IRB 
determination 
All events 
Investigator 
IRB 
• NHLBI, DSMB 
Within 14 calendar days of investigator’s 
initial receipt of information 
All Unanticipated 
Problems 
All Events 
IRB 
• OHRP 
Within 30 days of the IRB’s receipt of the 
report 
Other Reportable Events: 
The following events are also reportable to the IRB: 
• Any AE that would cause the sponsor to modify the investigators brochure, 
protocol or informed consent form, or would prompt other action by the IRB to 
assure protection of human subjects. 
• Information that indicates a change to the risks or potential benefits of the 
research, in terms of severity or frequency. For example:  
– Safety monitoring indicates that a particular side effect is more severe, or 
more frequent than initially expected. 
– A paper is published from another study that shows that an arm of the 
research study is of no therapeutic value. 
• Change in FDA safety labeling or withdrawal from marketing of a drug, device, or 
biologic used in a research protocol. 
• Breach of confidentiality 
• Change to the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research participant. 
• Incarceration of a participant when the research was not previously approved 
under Subpart C and the investigator believes it is in the best interest of the 
subject to remain on the study. 
• Complaint of a participant when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
• Protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that in the opinion of the investigator placed one or more 
participants at increased risk, or affects the rights or welfare of subjects. 
 Subject Withdrawal  
A subject has the right to withdraw from the study entirely at any time for any reason 
without prejudice to future medical care by the investigator or other physician. The 
investigator also has the right to withdraw subjects from the study in the event of 
concurrent illness, AEs, or other reasons deemed to be in the subject’s best interest. 
A subject should be withdrawn from the study if there is: 
• Withdrawal of consent 
• PI determination that the subject should be withdrawn for safety 
In order to preserve the integrity of the intention-to-treat analysis, even if the subject is 
withdrawn from the treatment portion of the protocol (either due to subject, physician, or 
investigator decision), it is imperative to continue with the scheduled follow-up 
assessments both for the safety of the subject and for completeness of data collection. 

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This will be explained to potential subjects at the time of informed consent. The 
importance of compliance with study visits will be reinforced throughout the trial.  
 Unblinding of Intervention Assignment 
Unblinding of the PI for a specific subject will be considered, prior to the formal study 
unblinding, only if the following circumstances are met: 1) knowledge of the treatment 
assignment is required to initiate appropriate therapy for an AE or 2) if the safety of the 
subject is at serious risk if the treatment is continued without the knowledge of treatment 
assignment. The decision to unmask will be made by the Investigator and Medical 
Monitor. The DSMB must be notified of the decision as soon as possible.  
 Confidentiality of Study Data   
In this study, each patient will be assigned a unique Participant ID number (PID) when 
his/her demographic and race/ethnicity information is entered for the first time. Follow-
up data are subsequently entered as needed when a patient has a clinic visit. The 
unique PID number remains with each patient permanently and is matched with all new 
data entered. The PID number and patient identifiers are directly linked in the study 
database.  
The study coordinator will also generate a Global Unique Identifier (GUID) for each 
subject using a NIH tool client. This is an identifying code assigned to a single research 
participant so that data can be compiled between research studies without using 
personally identifiable information (PII), even if the data are collected at different 
locations or by different studies. The GUID is created using PII (including, current name, 
legal given name given at birth (first, middle, and last), date of birth, city of birth, state of 
birth, country of birth, and physical sex at birth). Data including the GUID (without other 
identifiers) is considered de-identified by the NIH and OHRP. Personal identifying 
information used to generate the GUID will be erased by the study staff after the GUID 
is created at the end of the study. 
The potential for data sharing has been included in the informed consent. Data releases 
to investigators for approved research purposes and analyses (after review and 
approval by the Publications and Presentations Committee and approval by IRB and 
execution of a Data Use Agreement) will be stripped of identifiers using a “Safe Harbor” 
approach. If an approved investigator has conducted a separate study in which a 
shared participant has also consented to the use of a GUID then this will be retained in 
the data release; however, for all other data releases the GUID will be removed.  
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the subject 
of the following:  
• What protected health information (PHI) will be collected from subjects in this 
study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  

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In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization. For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive) at the end of their scheduled study period. 
Several mechanisms will be in place to maintain confidentiality. All of the data will be 
reported in aggregate. Each subject in all phases of the study will be assigned a unique 
study Participant Identification (PID) number to be used on all data forms, study 
records, and blood samples. A list of patient names and code numbers will be 
maintained separately in locked file cabinets or on password protected computers. Only 
the investigators and project staff will have access to this information. No other 
personally identifiable information will be available. We will also obtain a Certificate of 
Confidentiality from the NIH for this study before consent of the first patient. 
 
 
11.1 Privacy/Confidentiality Issues 
Consent forms, medical history data, and study data are stored in secured files, either in 
locked file cabinets or in a locked room separate from medical records and coded such 
that all subject identifiers have been removed. As an additional precaution all HIPAA 
regulated information is stored in an electronic file separate from other study data. Only 
approved study staff (determined by the PI) will be given authorization to access the 
database. Bio-specimens are processed and labeled with barcode labels that include 
the subjects electronically generated study code and date of sample collection. The bio-
specimens are stored in locked freezers in the study Laboratory; only approved study 
staff has access to the keys for each freezer. Access to the electronic freezer inventory 
of the specimens is kept on a secure password protected computer. 
11.2 Follow-up and Record Retention 
The duration of this study is estimated to be 3 years. The duration of record retention 
will be at least 6 years after study completion, but the possibility exists for indefinite 
archival of study information via the REDCap database.  Should the outcome of this 
study prompt future investigations, the participants may be contacted to obtain follow-up 
information and invited to participate in additional studies. 
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