Interventions Against Insulin Resistance in Pulmonary Arterial Hypertension
Phase: PHASE2
Conditions: Pulmonary Artery Hypertension
Sponsor: Vanderbilt University Medical Center

 
 
 
 
 
 
 
 
“Interventions Against Insulin Resistance in Pulmonary Arterial 
Hypertension” 
PI: Drs. Anna Hemnes, Robert Frantz, and Gustavo Heresi 
Vanderbilt University Medical Center 
 
NCT #: NCT03617458 
Most recent IRB Approval Date: 4/12/2024 
 
 
 
 

 
 
 
 
 
Interventions Against Insulin Resistance in Pulmonary 
Arterial Hypertension 
 
 
 
 
Date: 
December 26, 2021  
 
 
Version: 
6.1 
Principal 
Investigator: 
Anna R. Hemnes, MD 
T1218 Medical Center North 
1161 21st Ave South 
Nashville, Tennessee 37232 
Phone: +1 615-343-8227 
Fax: 
+1 615-343-3480 
Email: anna.r.hemnes@vanderbilt.edu 
 
Confidential Information 
 
 
 
Revision History: 
Version 1.0 
 
 
1/12/2018 
Version 1.1 
 
 
5/30/2018 
Version 2.1 
 
 
7/25/2018 – Sub study revisions 
Version 3 
2/22/2019 – 1. Change of PFT exclusion criteria, Change of visit 
window for week 12, medication clarification 
Version 3.1 
May 31, 2019 - Addition of muscle fatigue language and change of 
eGFR exclusion criteria. Addition of econsent use. 
Version 3.2 
10/29/2019  Clarification of inclusion/exclusion criteria and 
addition of Redcap Clinical Data Pull verbiage.  
Version 3.3 
Fix version error (V3.2 footer still said “version 2”.) 
Version 4 
Inclusion/Exclusion criteria changes 
Version 5 
Addition of language to include ability to contact patients via EMR 
and by email 
Version 6 
eGFR exclusion criteria change & Scleroderma inclusion criteria 
addition 
Version 6.1 
12.26.2021 - Amend “Scleroderma” inclusion/exclusion criteria to 
read, “connective tissue disease – associated PAH” to broaden 
inclusion 
 
 

mHealth+Met PAH                                                                                                              Protocol 
Protocol Version #: 6.1 
 
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Protocol Date: 12.26.21 
 
 
 
 
 
 
 
 
Protocol Summary 
OBJECTIVES: 
The primary objective of this study is to determine the 
impact of two interventions against insulin resistance 
on the composite endpoint of 10% improvement in 
baseline six minute walk distance or improvement in 
WHO functional class.  
Secondary objectives include: 
• To assess the effect of an mHealth intervention or 
no intervention and/or metformin or placebo on 
body weight at week 12. 
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
BMI at week 12. 
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
absolute 6MWD at week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
Borg Dyspnea Score at week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
emPHasis-10 quality of life survey score at week 
12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
WHO functional classification at week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
the average daily step count at week 12. 
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
frequency of daily goal attainment at week 12. 

mHealth+Met PAH                                                                                                              Protocol 
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Protocol Date: 12.26.21 
 
 
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
daily aerobic time at week 12. 
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
total daily activity at week 12. 
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
resting heart rate at week 12. 
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
HOMA-IR at week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
urine and plasma estradiol at week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
urine and plasma estrogen metabolites at week 
12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
plasma lipid profiles at week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
plasma free fatty acid profiles at week 12. 
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
plasma acylcarnitine profiles at week 12. 
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
plasma BNP at week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
quadriceps skeletal muscle triglyceride content at 
week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
change in quadriceps skeletal muscle fatigue at 
week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
quadriceps skeletal muscle strength at week 12.  

mHealth+Met PAH                                                                                                              Protocol 
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Protocol Date: 12.26.21 
 
 
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
quadriceps skeletal muscle contractile tissue 
cross-sectional area at week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on RV 
myocardial muscle triglyceride content at week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
tricuspid annular plane systolic excursion (TAPSE) 
at week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on RV 
and LV ejection fraction at week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on RV 
fractional area change at week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
tricuspid annular velocity (S’) at week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
tricuspid regurgitant (TR) velocity at week 12. 
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
estimated RV and RA pressure at week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on RV 
and LV diastolic function at week 12.  
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on RV 
free wall longitudinal strain at week 12.  
• To compare and define the screening clinical 
characteristics of responders and non-responders 
to mHealth intervention or no intervention and/or 
metformin at week 12.  
• To compare and define the screening plasma 
metabolomics profiles, including all amino acids 
and lipidomics, of responders and non-responders 
to mHealth intervention or no intervention and/or 
metformin at week 12.  

mHealth+Met PAH                                                                                                              Protocol 
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Protocol Date: 12.26.21 
 
 
• To assess the capacity of metabolomics profiles 
and clinical features at screening to predict 
response to the mHealth intervention or no 
intervention and/or metformin or placebo groups at 
week 12.  
• To assess the capacity of change in metabolomics 
profile and clinical features from screening to 
predict response to the mHealth intervention or no 
intervention and/or metformin or placebo groups at 
week 12. 
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
safety and tolerability in PAH subjects over 12 
weeks. 
• 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 or 
no intervention and/or metformin or placebo on 
patient satisfaction at week 12 
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
dropout rates over 12 weeks. 
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
PAH-related hospitalizations over 12 weeks. 
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
medication regimen escalation/reduction over 12 
weeks. 
• To assess the effect of a mHealth intervention or 
no intervention and/or metformin or placebo on 
incidence of death over 12 weeks. 
STUDY DESIGN: 
 
A 2x2 factorial randomized, blinded trial testing 
metformin versus placebo and an mHealth 
intervention (mHealth) versus usual care for 12 
weeks.  
STUDY POPULATION:      
 
 
Inclusion criteria: 

mHealth+Met PAH                                                                                                              Protocol 
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Protocol Date: 12.26.21 
 
 
• Adults aged 18 or older. 
• Diagnosed with idiopathic, heritable, connective 
tissue disease – associated PAH , or drug- or 
toxin-associated pulmonary arterial hypertension 
(PAH) according to World Health Organization 
consensus recommendations.  
• Repaired simple congenital heart disease or 
unrepaired ASD 
• 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. Adjustments in IV 
prostacyclin for side effect management are 
allowed.  
• Subjects must own a Bluetooth capable modern 
smartphone capable of receiving and sending text 
messages and an active data plan. 
• FEV1> or = 60% predicted and no more than mild 
abnormalities on lung imaging 
• WHO Functional Class I-III 
• Ambulatory 
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, connective tissue disease – associated 
PAH, or associated with drugs or toxins 
• Drug and toxin associated PAH patients with 
active drug use 
• WHO Functional class IV heart failure 
• FEV1< 60% predicted with more than mild 
abnormalities on lung imaging 
• Requirement of > 1 diuretic adjustment in the 
prior 30 days 
• Preferred form of activity is not measured by an 
activity tracker (swimming, ice skating, stair 

mHealth+Met PAH                                                                                                              Protocol 
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Protocol Date: 12.26.21 
 
 
master, or activities on wheels such as bicycling 
or rollerblading) 
• Type I diabetes mellitus 
• Prior diagnosis of cirrhosis 
• Untreated hypo- or hyper-thyroidism 
• eGFR by MDRD <40mL/min                                                  
PRIMARY ENDPOINT: 
 
• Composite endpoint of 10% or greater 
improvement in six minute walk distance over 
baseline or improvement of at least one WHO 
functional class at week 12.  
SECONDARY ENDPOINTS: 
 
• Difference in body weight between mHealth 
intervention or no intervention and/or metformin 
or placebo groups at week 12. 
• Difference in BMI between mHealth intervention 
or no intervention and/or metformin or placebo 
groups at week 12. 
• Difference in absolute 6MWD between mHealth 
intervention or no intervention and/or metformin 
or placebo groups at week 12. 
• Difference in Borg Dyspnea Score between 
mHealth intervention or no intervention and/or 
metformin or placebo groups at week 12.  
• Difference in emPHasis-10 quality of life survey 
score between mHealth intervention or no 
intervention and/or metformin or placebo groups 
at week 12. 
• Difference in WHO functional classification 
between mHealth intervention or no intervention 
and/or metformin or placebo groups at week 12.  
• Difference in average daily step count between 
mHealth intervention or no intervention and/or 
metformin or placebo groups at week 12.  
• Difference in frequency of daily goal attainment 
between mHealth intervention or no intervention 
and/or metformin or placebo groups at week 12. 
• Difference in daily goal aerobic time between 
mHealth intervention or no intervention and/or 
metformin or placebo groups at week 12. 

mHealth+Met PAH                                                                                                              Protocol 
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Protocol Date: 12.26.21 
 
 
• Difference in total daily activity between mHealth 
intervention and/or metformin and no intervention 
and/or metformin or placebo groups at week 12. 
• Difference in resting heart rate between mHealth 
intervention or no intervention and/or metformin 
or placebo groups at week 12. 
• Difference in HOMA-IR between mHealth 
intervention or no intervention and/or metformin 
or placebo groups at week 12. 
• Difference in urine and plasma estradiol between 
mHealth intervention or no intervention and/or 
metformin or placebo groups at week 12. 
• Difference in urine and plasma estrogen 
metabolites between mHealth intervention or no 
intervention and/or metformin or placebo groups 
at week 12. 
• Difference in plasma lipid profiles between 
mHealth intervention or no intervention and/or 
metformin or placebo groups at week 12. 
• Difference in plasma free fatty acid profiles 
between mHealth intervention or no intervention 
and/or metformin or placebo groups at week 12. 
• Difference in plasma acylcarnitine profiles 
between mHealth intervention or no intervention 
and/or metformin or placebo groups at week 12. 
• Difference in plasma BNP between mHealth 
intervention or no intervention and/or metformin 
or placebo groups at week 12. 
• Difference in quadriceps skeletal muscle 
triglyceride content between mHealth intervention 
or no intervention and/or metformin or placebo 
groups at week 12. 
• Difference in change of quadriceps skeletal 
muscle fatigue between mHealth intervention or 
no intervention and/or metformin or placebo 
groups at week 12. 
• Difference in quadriceps skeletal muscle strength 
between mHealth intervention or no intervention 
and/or metformin or placebo groups at week 12. 
• Difference in quadriceps skeletal muscle 
contractile tissue cross-sectional area between 
mHealth intervention or no intervention and/or 
metformin or placebo groups at week 12. 

mHealth+Met PAH                                                                                                              Protocol 
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Protocol Date: 12.26.21 
 
 
• Difference in RV myocardial muscle triglyceride 
content between mHealth intervention or no 
intervention and/or metformin or placebo groups 
at week 12. 
• Difference in tricuspid annular plane systolic 
excursion (TAPSE) between mHealth intervention 
or no intervention and/or metformin or placebo 
groups at week 12. 
• Difference in RV and LV ejection fraction between 
mHealth intervention or no intervention and/or 
metformin or placebo groups at week 12. 
• Difference in RV fractional area change between 
mHealth intervention or no intervention and/or 
metformin or placebo groups at week 12. 
• Difference in tricuspid annular velocity (S’) 
between mHealth intervention or no intervention 
and/or metformin or placebo groups at week 12. 
• Difference in tricuspid regurgitant (TR) velocity 
between mHealth intervention or no intervention 
and/or metformin or placebo groups at week 12. 
• Difference in estimated RV and RA pressure 
between mHealth intervention or no intervention 
and/or metformin or placebo groups at week 12. 
• Difference in estimated RV and LV diastolic 
function between mHealth intervention or no 
intervention and/or metformin or placebo groups 
at week 12. 
• Difference in RV free wall longitudinal strain 
between mHealth intervention or no intervention 
and/or metformin or placebo groups at week 12. 
• Difference in screening clinical characteristics 
between responders and non-responders to 
mHealth intervention or no intervention and/or 
metformin or placebo groups at week 12. 
• Difference in screening plasma metabolomics 
profiles, including all amino acids and lipidomics, 
between responders and non-responders to the 
mHealth intervention or no intervention and/or 
metformin or placebo groups at week 12. 
• Capacity of metabolomics profiles and clinical 
features at screening to predict response to the 
mHealth intervention or no intervention and/or 
metformin or placebo groups at week 12. 

mHealth+Met PAH                                                                                                              Protocol 
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Protocol Date: 12.26.21 
 
 
• Capacity of change in metabolomics profile and 
clinical features from screening to predict 
response to the mHealth intervention or no 
intervention and/or metformin or placebo groups 
at week 12. 
• Difference in safety and tolerability between 
mHealth intervention or no intervention and/or 
metformin or placebo groups in PAH subjects 
over 12 weeks.  
• Difference in fidelity of data collection and text 
transmission of the mHealth intervention over 12 
weeks. 
• Difference in patient satisfaction between 
mHealth intervention or no intervention and/or 
metformin or placebo groups at week 12.  
• Difference in dropout rates between mHealth 
intervention or no intervention and/or metformin 
or placebo groups over 12 weeks. 
• Difference in PAH-related hospitalizations 
between mHealth intervention or no intervention 
and/or metformin or placebo groups over 12 
weeks.  
• Difference in medication regimen 
escalation/reduction between mHealth 
intervention or no intervention and/or metformin 
or placebo groups over 12 weeks.  
• Difference in incidence of death between mHealth 
intervention or no intervention and/or metformin 
or placebo groups over 12 weeks.  
STUDY OBSERVATIONS: 
 
 
• Subjects will be evaluated in person at screening 
(-2 weeks) and 12 weeks.  
• Subjects will have telephone follow-up at weeks 
1, 3, 6, and 9. 
• HOMA-IR, estradiol and estrogen metabolites, 
lipid profiles, free fatty acids, acylcarnitine 
profiles, BNP levels, and other biomarkers will be 
assessed at screening and 12 weeks.  
• Subjects will have six minute walk testing at 
screening and 12 weeks. 
• Subjects will have a transthoracic 
echocardiogram at screening and 12 weeks. 

mHealth+Met PAH                                                                                                              Protocol 
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Protocol Date: 12.26.21 
 
 
• Subjects will answer quality of life questionnaires 
at screening and 12 weeks.  
• Subjects at Vanderbilt will have cardiac and 
skeletal muscle MR spectroscopy screening and 
12 weeks.  
• Subjects at Vanderbilt will have muscle strength 
and function testing at screening and 12 weeks.  
SAMPLE SIZE AND POWER: 
 
 
The pivotal trial of Iloprost demonstrated that in the 
Iloprost arm nearly 40% had 10% improvement in 
6MWD, 50% had improved FC, and 17% had both1. 
From these data we calculate that 73% had either 
10% improvement in 6MWD or improved functional 
status. Assuming metformin or the exercise arm will 
have similar response rate, and the placebo group will 
have 40% response rate, thought to be due to training 
effect potentially, we need 35 per group to have 80% 
power at 0.05 type I error rate. For the metformin and 
exercise combination group, an additive or synergistic 
effect between the two interventions will put its 
response rate above 73%. Thus the combination vs. 
placebo comparison will have at least 80%, likely 
better power. From past experience coupled with the 
low risk, low side effect profile interventions, we 
estimate a dropout rate of less than 10%1. We will 
enroll 40 subjects to ensure 35 completed subjects 
per group. The total target enrollment is 160 over 4.5 
years. 
DATA ANALYSIS: 
The primary analyses will focus on metformin vs 
placebo, exercise vs placebo, and metformin + 
exercise vs placebo comparisons on the primary 
endpoint. Since the evaluation of metformin or 
exercise will be reported as if they were independent 
studies and the combination arm versus placebo 
comparison serves to corroborate findings of the two 
separate comparisons, in addition to evaluating an 
additive or synergistic effect, we will not adjust for 
multiple comparisons. For binary endpoints, the 
Pearson chi-square or Fischer’s exact test will be 
used to assess between treatment arms difference. 
Logistic regressions will be conducted to examine the 
treatment effect while adjusting for important 
covariates such as baseline 6MWD, functional status, 

mHealth+Met PAH                                                                                                              Protocol 
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Protocol Date: 12.26.21 
 
 
and age. Model over-fitting will be avoided by 
considering the number of parameters in the model 
and the number of responders in the sample.  
Continuous endpoints will be analyzed using either 
two-sample t-test or ANOVA, or non-parametric 
methods Wilcoxon Rank Sum test or Kruskal-Wallis 
test. Multivariable regressions (general linear models) 
will be conducted to examine the treatment effect 
while adjusting for important covariates such baseline 
6MWD, functional status, and age.  We have 
designed the study to minimize the potential for 
missing data. Subjects who drop out will be replaced 
up to a total of 35 per group.  Nevertheless, in the 
event we have missing data, a multiple-imputation 
procedure as implemented in the areglmpute function 
in the Hmisc package in R (R Package; Version 3.0-
10) will be used to assess the impact of missing data. 
The analyses with imputation will mainly serve as 
sensitivity analyses. 
 
 
 
 
Brief Table of Contents 
 
Background & Significance.................................................................................. 18 
 
Objectives and Specific Aims .............................................................................. 20 
 
Screening, Subject Selection, and Randomization .............................................. 23 
 
Study Designs ..................................................................................................... 24 
 
Data Collection .................................................................................................... 27 
 
Assessments of Efficacy and Outcome Measures .............................................. 31 
 
Statistical Considerations .................................................................................... 39 
 
Study Risks and Discomforts ............................................................................... 42 
 
Quality Control ..................................................................................................... 44 
 Data and Safety Monitoring and Reporting ......................................................... 45 
 Safety and Adverse Events ................................................................................. 47 
 Confidentiality of Study Data ............................................................................... 53 
 Ethical Considerations ......................................................................................... 55 

mHealth+Met PAH                                                                                                              Protocol 
Protocol Version #: 6.1 
 
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Protocol Date: 12.26.21 
 
 
 
 
 
 
 
 
 

mHealth+Met PAH                                                                                                              Protocol 
Protocol Version #: 6.1 
 
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Protocol Date: 12.26.21 
 
 
Contents 
Protocol Summary ........................................................................................................ 1 
Abstract ........................................................................................................................ 17 
 
Background & Significance .............................................................................. 18 
1.1 
Morbidity, mortality, and limitations of medical therapy in pulmonary arterial 
hypertension. ............................................................................................................. 18 
1.2 
Insulin resistance in PAH. ................................................................................ 18 
1.3 
Functional impairment and efficacy of exercise. ............................................... 18 
1.4 
Mechanisms of the beneficial effects of physical activity in PAH. ................ 19 
1.5 
Mobile health tools to promote behavioral change. ...................................... 19 
1.6 
Metformin in PAH ............................................................................................ 20 
 
Objectives and Specific Aims .......................................................................... 20 
2.1 
Objectives ........................................................................................................ 20 
Primary Aim: ...................................................................................................................................... 20 
Secondary Aims: .............................................................................................................................. 20 
 
Screening, Subject Selection, and Randomization ........................................ 23 
3.1 
Recruitment of Study Sample ........................................................................... 23 
3.2 
Inclusion/Exclusion Criteria .............................................................................. 23 
3.3 
Study Arm Assignment, Randomization, and Subject Retention ...................... 24 
 
Study Designs ................................................................................................... 24 
4.1 
Overview .......................................................................................................... 24 
4.2 
Monitoring Device ........................................................................................... 25 
4.3 
Fitbit Application and Data Management ......................................................... 25 
4.4 
mHealth Intervention ...................................................................................... 25 
4.5 
Run-in Period and Step Count Targets ......................................................... 26 
4.6 
Metformin or Placebo ..................................................................................... 26 
4.7 
Remuneration ................................................................................................... 26 
 
Data Collection .................................................................................................. 27 
5.1 
Consent ............................................................................................................ 27 
5.2 
Study Visits and Contacts ................................................................................ 27 
 
Screening Visit (-2 Weeks) .................................................................................................. 28 
 
Study Initiation – Phone Call 1 (Baseline or Time Point 0) .................................................. 29 
 
Phone Call - (Week 1, 3, 6, 9) .............................................................................................. 29 
 
Study Day – Visit 2 (Week 12) ............................................................................................. 29 

mHealth+Met PAH                                                                                                              Protocol 
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5.3 
Study Schedule of Endpoints and Procedures ................................................. 30 
 
Assessments of Efficacy and Outcome Measures ......................................... 31 
6.1 
Assessments of Efficacy .................................................................................. 31 
 
Response to Therapy........................................................................................................... 33 
6.2 
Secondary Outcome Measures ........................................................................ 33 
 
Body Weight and BMI ......................................................................................................... 33 
 
Six Minute Walk Distance ................................................................................................... 34 
 
The Borg Dyspnea Score ..................................................................................................... 34 
 
Quality of Life Questionnaire (emPHasis–10) ..................................................................... 34 
 
WHO Functional Class ......................................................................................................... 34 
 
Step Counts and Physical Activity ....................................................................................... 34 
 
Resting Heart Rate .............................................................................................................. 35 
 
Blood Biomarkers ................................................................................................................ 35 
 
Transthoracic Echocardiographic Measures ....................................................................... 36 
 
Proton Magnetic Resonance Spectroscopy (MRS) .............................................................. 36 
 
Skeletal Muscle Function .................................................................................................... 37 
 
Responders vs. Non-Responders. ....................................................................................... 38 
 
Fidelity of Data Collection and Text Transmission .............................................................. 38 
 
Other Feasibility Endpoints ................................................................................................. 39 
 
Medication Regimen Escalation/Reduction ........................................................................ 39 
 
Hospitalization for PAH progression or right-sided heart failure ....................................... 39 
 
Death ................................................................................................................................... 39 
 
Statistical Considerations ................................................................................ 39 
7.1 
Study design .................................................................................................... 39 
7.2 
Statistical Analysis ........................................................................................... 40 
7.3 
Missing Data and Dropouts ............................................................................ 40 
7.4 
Statistical Power ............................................................................................. 41 
7.5 
Interim Monitoring Guidelines ........................................................................... 41 
7.6 
Protocol Violations ........................................................................................... 41 
 
Study Risks and Discomforts ........................................................................... 42 
8.1 
Activity Tracking ............................................................................................... 42 
8.2 
Echocardiography ............................................................................................ 42 
8.3 
Venipuncture .................................................................................................... 42 
8.4 
MR Spectroscopy ............................................................................................. 42 

mHealth+Met PAH                                                                                                              Protocol 
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8.5 
Metformin ......................................................................................................... 42 
 
Boxed Warning .................................................................................................................... 43 
 
Iodinated Contrast .............................................................................................................. 43 
8.6 
Privacy ............................................................................................................. 43 
8.7 
Financial Risk ................................................................................................... 44 
 
Quality Control .................................................................................................. 44 
9.1 
Personnel Training ........................................................................................... 44 
9.2 
Coordinating Center (CC)................................................................................. 44 
9.3 
Data Quality ..................................................................................................... 45 
 Data and Safety Monitoring and Reporting ..................................................... 45 
10.1 
Consent ........................................................................................................ 45 
10.2 
Institutional Review Board process ............................................................... 45 
10.3 
Designated Medical Director ......................................................................... 45 
10.4 
Monitoring ..................................................................................................... 46 
10.5 
Data Safety Monitor Board (DSMB) .............................................................. 46 
 Safety and Adverse Events .............................................................................. 47 
11.1 
Definitions ..................................................................................................... 47 
 
Unanticipated Problem (UP) ............................................................................................... 47 
 
Adverse Event (AE) .............................................................................................................. 47 
 
Serious Adverse Event (SAE) ............................................................................................... 47 
 
Suspected Adverse Reaction ............................................................................................... 48 
 
Internal Adverse Event ........................................................................................................ 48 
 
External Adverse Event ....................................................................................................... 48 
11.2 
Classifying AEs ............................................................................................. 48 
 
Severity ............................................................................................................................... 48 
 
Expectedness ...................................................................................................................... 48 
 
Relatedness ......................................................................................................................... 49 
11.3 
Interpretation of Definitions ........................................................................... 49 
 
AE and UP Reporting Period ............................................................................................... 49 
 
Preexisting Condition .......................................................................................................... 49 
 
General Physical Examination Findings ............................................................................... 49 
 
Post-study AE ...................................................................................................................... 49 
 
Abnormal Laboratory Values .............................................................................................. 50 
 
Hospitalization, Prolonged Hospitalization or Surgery ....................................................... 50 

mHealth+Met PAH                                                                                                              Protocol 
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11.4 
Expedited Reporting Procedures .................................................................. 50 
 
Expedited Reporting Process .............................................................................................. 51 
 
Other Reportable Events:.................................................................................................... 52 
11.5 
Subject Withdrawal ....................................................................................... 53 
11.6 
Unblinding of Intervention Assignment .......................................................... 53 
 Confidentiality of Study Data ........................................................................... 53 
12.1 
Privacy/Confidentiality Issues ....................................................................... 54 
12.2 
Follow-up and Record Retention .................................................................. 55 
 Ethical Considerations ..................................................................................... 55 
References ................................................................................................................... 55 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Abstract 
 
Pulmonary arterial hypertension (PAH) is characterized by progressive 
pulmonary vascular obliteration, right heart failure and death. Despite several approved 
therapies, none are curative or address the primary molecular drivers of this highly 
morbid disease. Work by our group and others has highlighted the role of metabolic 
dysregulation such as mitochondrial dysfunction, insulin resistance and cardiac 
lipotoxicity in PAH. We have published that glucose intolerance is common in human 
PAH and impacts survival. We have also assessed the effects of insulin-mediated 
mitochondrial lipid metabolism on the right ventricle (RV) and demonstrated that lipid 
deposition may be a key feature of RV dysfunction in PAH. Important questions remain: 
do interventions against insulin resistance improve PAH? Are there specific patients 
most likely to benefit from interventions against insulin resistance? Drug therapy, e.g. 
metformin, and exercise are the major currently practical interventions against insulin 
resistance in PAH. Further, we and others have published that PAH patients are highly 
sedentary with reduced skeletal muscle function, suggesting that activity may be a 
modifiable feature of PAH. Exercise is known to be safe in PAH, but implementation in 
the US is limited by access to care. Our group recently showed that linking activity 
monitoring, e.g. fitbit, with automated, personalized text prompts to encourage activity 
led to a 300% increase in step counts. This approach may provide an innovative, 
inexpensive mechanism to increase activity in PAH, and thereby reduce insulin 
resistance. The mechanisms by which these insulin-sensitizing interventions may 
improve 6MWD and outcomes in PAH is unknown, however.  
 
 
We propose to test the hypothesis that interventions to improve insulin resistance 
will improve exercise capacity and WHO functional class in PAH. We propose three 
specific aims to test this 1) A prospective 2x2 factorial design 12-week clinical trial of 
metformin or placebo and activity intervention or usual care to assess effect on six 
minute walk and WHO functional class, 2) Assessment of the interventions in Aim 1 in a 
subset of patients on RV and peripheral muscle function and lipid content and markers 
of pulmonary vascular disease to define how these interventions may work in PAH and 
3) Identify and prospectively test peripheral blood markers of metformin response in 
PAH.  The broad goals of this work are to demonstrate the efficacy and mechanisms of 
interventions against insulin resistance in PAH and to identify which patients are most 
likely to benefit from these interventions, moving to precision medicine in 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. Recent work has demonstrated a key role for 
insulin resistance in PAH2-6, but whether interventions against insulin resistance 
improve outcomes, such as six 6MWD or NYHA Functional Class (FC), is presently 
unknown. These data highlight the need for additional interventions to improve 
clinical outcomes in PAH.  
1.2 Insulin resistance in PAH. 
Insulin resistance has been demonstrated to be common in PAH and associated with 
worse six minute walk distance and mortality, perhaps due to promotion of right 
ventricular dysfunction through lipotoxicity13-18.  It is presently unknown if interventions 
against insulin resistance may impact short- or long-term outcomes in PAH. Insulin 
resistance can be ameliorated by weight loss, exercise and medications.  Aside from 
bariatric surgery, weight loss is often difficult to achieve and PAH patients have 
increased mortality associated with surgery. Exercise and medical therapies aimed at 
insulin resistance have not been studied previously in PAH.   
1.3 Functional impairment and efficacy of exercise. 
Patients with PAH have severely reduced exercise capacity when measured by 6MWT 
distance or cardiopulmonary exercise testing9-12, 20-22. At diagnosis, most PAH patients 
are NYHA functional class III with symptoms of fatigue and shortness of breath with less 
than ordinary activity23. Although once thought to be potentially dangerous24, 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 therapy25. 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 PAH26-29. All of these studies have been performed in Europe where 

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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 States30. 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. 
1.4 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 disease25. 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 dysfunction1,13-14, 16, 32. 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 function2,33-36. Skeletal 
muscle dysfunction contributes to reduced functional capacity in PAH29,36. Physical 
activity improves skeletal muscle function in PAH29,37,38, 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. 
1.5 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 factor39, yet less than half of the US adult population meets the 
goal of at least 150 minutes per week of moderate activity40. A 2012 Cochrane 
review confirmed the efficacy of telephone and web-based interventions to increase 
physical activity41. 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 activity42-44. 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 

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in physical activity45. 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 activity46. 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 tracking44. 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 
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. 
1.6 Metformin in PAH 
We have nearly completed an 8 week open label dose escalation (max dose 1g BID) 
study of metformin. Thus far we have enrolled 16 patients. There have been no serious 
adverse events thought related to the metformin exposure. One patient needed 
adjustment of diuretics and all patients have complained of mild diarrhea, with two 
requiring dose adjustment of metformin. Only one patient did not eventually reach the 
goal dose.   In order to preserve the integrity of the study, we have not analyzed the 
primary endpoints aside from safety. In a preliminary review of MRS-quantified lipid 
content and found a numeric reduction in RV triglyceride content after treatment with 
metformin. These data suggest that RV lipid deposition may be reversed by metformin 
therapy and strongly support safety in a broad range of PAH patients with mild and 
severe disease. 
Objectives and Specific Aims 
1.7 Objectives 
This is a phase II, 2x2 factorial randomized, blinded trial testing metformin versus 
placebo and a mHealth intervention (mHealth) versus usual care of 12 weeks. Specific 
Aims: 
Primary Aim:  
1. To determine whether a mHealth intervention, metformin, or both combined in 
PAH patients achieve the composite endpoint of 10% or greater improvement in 
six minute walk distance over baseline or improvement of at least one WHO 
functional class at week 12.  
Secondary Aims:  
1. To determine whether mHealth, metformin, or both interventions combined 
affects body weight at week 12. 
2. To determine whether mHealth, metformin, or both interventions combined 
affects BMI at week 12. 

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3. To determine whether mHealth, metformin, or both interventions combined 
affects absolute 6MWD at week 12.  
4. To determine whether mHealth, metformin, or both interventions combined 
affects Borg Dyspnea Score at week 12.  
5. To determine whether mHealth, metformin, or both interventions combined 
affects emPHasis-10 quality of life survey score at week 12.  
6. To determine whether mHealth, metformin, or both interventions combined 
affects WHO functional classification at week 12.  
7. To determine whether mHealth, metformin, or both interventions combined 
affects average daily step count at week 12. 
8. To determine whether mHealth, metformin, or both interventions combined 
affects frequency of daily goal attainment at week 12. 
9. To determine whether mHealth, metformin, or both interventions combined 
affects daily aerobic time at week 12. 
10. To determine whether mHealth, metformin, or both interventions combined 
affects total daily activity at week 12. 
11. To determine whether mHealth, metformin, or both interventions combined 
affects resting heart rate at week 12. 
12. To determine whether mHealth, metformin, or both interventions combined 
affects HOMA-IR at week 12.  
13. To determine whether mHealth, metformin, or both interventions combined 
affects urine and plasma estradiol at week 12.  
14. To determine whether mHealth, metformin, or both interventions combined 
affects urine and plasma estrogen metabolites at week 12.  
15. To determine whether mHealth, metformin, or both interventions combined 
affects plasma lipid profiles at week 12.  
16. To determine whether mHealth, metformin, or both interventions combined 
affects plasma free fatty acid profiles at week 12. 
17. To determine whether mHealth, metformin, or both interventions combined 
affects plasma acylcarnitine profiles at week 12. 
18. To determine whether mHealth, metformin, or both interventions combined 
affects plasma BNP at week 12.  
19. To determine whether mHealth, metformin, or both interventions combined 
affects quadriceps skeletal muscle triglyceride content at week 12.  
20. To determine whether mHealth, metformin, or both interventions combined 
affects change in quadriceps skeletal muscle fatigue at week 12.  
21. To determine whether mHealth, metformin, or both interventions combined 
affects quadriceps skeletal muscle strength at week 12.  

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22. To determine whether mHealth, metformin, or both interventions combined 
affects quadriceps skeletal muscle contractile tissue cross-sectional area at 
week 12.  
23. To determine whether mHealth, metformin, or both interventions combined 
affects RV myocardial muscle triglyceride content at week 12.  
24. To determine whether mHealth, metformin, or both interventions combined 
affects tricuspid annular plane systolic excursion (TAPSE) at week 12.  
25. To determine whether mHealth, metformin, or both interventions combined 
affects RV and LV ejection fraction at week 12.  
26. To determine whether mHealth, metformin, or both interventions combined 
affects RV fractional area change at week 12.  
27. To determine whether mHealth, metformin, or both interventions combined 
affects tricuspid annular velocity (S’) at week 12.  
28. To determine whether mHealth, metformin, or both interventions combined 
affects estimated RV and RA pressure at week 12.  
29. To determine whether mHealth, metformin, or both interventions combined 
affects estimated RV and LV diastolic function at week 12.  
30. To determine whether mHealth, metformin, or both interventions combined 
affects RV free wall longitudinal strain at week 12.  
31. To determine screening clinical characteristics of responders and non-
responders to mHealth, metformin, or both interventions combined at week 12.  
32. To determine screening plasma metabolomics profiles, including all amino acids 
and lipidomics, of responders and non-responders to mHealth, metformin, or 
both interventions combined at week 12.  
33. To determine whether metabolomics profiles and clinical features at screening 
predicts response to mHealth, metformin, or both interventions combined at 
week 12.  
34. To determine whether change in metabolomics profile and clinical features from 
screening predicts response to mHealth, metformin, or both interventions 
combined at week 12. 
35. To determine whether mHealth, metformin, or both interventions combined 
affects safety and tolerability in PAH subject over 12 weeks. 
36. To determine fidelity of data collection and text transmission of mHealth, 
metformin, or both interventions over 12 weeks. 
37. To determine patient satisfaction of mHealth, metformin, or both interventions at 
week 12. 
38. To determine dropout rates of mHealth, metformin, or both interventions over 12 
weeks. 
39. To determine whether mHealth, metformin, or both interventions combined 
affects PAH-related hospitalizations over 12 weeks. 

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40. To determine whether mHealth, metformin, or both interventions combined 
affects medication regimen escalation/reduction over 12 weeks. 
41. To determine whether mHealth, metformin, or both interventions combined 
affects incidence of death over 12 weeks. 
Screening, Subject Selection, and Randomization 
1.8 Recruitment of Study Sample 
Patients will be recruited from the Center for Pulmonary Vascular Disease (CPVD) at 
Vanderbilt University Medical Center (Nashville, TN), the Pulmonary Hypertension Clinic 
at Mayo Clinic (Rochester, MN), and the Pulmonary Hypertension Program at Cleveland 
Clinic (Cleveland, OH). Study sites may be contacting, communicating, and recruiting 
participants by, 1) telephone, 2) email using their assigned institution email address or, 
3) through a secure patient portal and associated electronic medical record. 
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 in-person informed consent or e-consent before any study procedures are 
performed. 
1.9 ResearchMatch.org will also be utilized as a recruitment tool for this protocol. 
ResearchMatch.org is a national electronic, web-based recruitment tool that was 
created through the Clinical & Translational Science Awards Consortium in 2009 
and is maintained at Vanderbilt University as an IRB-approved data repository 
(see IRB #090207).Inclusion/Exclusion Criteria  
Inclusion criteria: 
• Adults aged 18 or older. 
• Diagnosed with idiopathic, heritable, connective tissue disease – associated 
PAH, or drug- or toxin-associated pulmonary arterial hypertension (PAH) 
according to World Health Organization consensus recommendations.  
• Repaired simple congenital heart disease or unrepaired ASD 
• 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. Adjustments in IV prostacyclin for side effect management are 
allowed.  
• Subjects must own a Bluetooth capable modern smartphone capable of 
receiving and sending text messages and an active data plan. 
• FEV1> or = 60% predicted and no more than mild abnormalities on lung 
imaging 
• WHO Functional Class I-III 
• Ambulatory 
 
Exclusion criteria: 

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• 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, connective tissue 
disease – associated PAH, or associated with drugs or toxins 
• Drug and toxin associated PAH patients with active drug use 
• WHO Functional class IV heart failure 
• FEV1< 60% predicted with more than mild abnormalities on lung imaging 
• Requirement of > 1 diuretic adjustment in the prior 30 days 
• Preferred form of activity is not measured by an activity tracker (swimming, ice 
skating, stair master, or activities on wheels such as bicycling or rollerblading) 
• Type I diabetes mellitus 
• Prior diagnosis of cirrhosis 
• Untreated hypo- or hyper-thyroidism 
• eGFR by MDRD <40mL/min     
                                              
1.10 Study Arm Assignment, Randomization, and Subject Retention 
Participants will be assigned to either intervention, both interventions, or no 
intervention arms after the run-in period in a random manner until 40 participants 
are enrolled into each arm. Permuted block randomization stratified by WHO 
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/or Co-PI. The Data Safety Monitoring Board will be notified as soon 
as possible. 
Study Designs 
1.11 Overview 
We propose a phase II, 2x2 factorial randomized, blinded trial testing metformin versus 
placebo and an mHealth intervention (mHealth) versus usual care of 12 weeks. 

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1.12 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. 
1.13 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. 
 
1.14 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, 
 
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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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. 
1.15 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 HR device 24 hours a day for seven days a week (excluding only 
bathing or showering) 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 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.   
1.16 Metformin or Placebo 
Subjects will receive metformin 500mg or equivalent placebo tablets via overnight 
shipment in adequate time for week 1. Patients will titrate the medication as follows: 
1 Every Day x 5 days, 1 BID x 5 days, 1 TID x 5 days, and then 2 BID for the 
duration of the trial. This titration schedule is based on the excellent tolerability from 
our pilot study. Patients in the placebo group will have matching sugar pills 
prepared by the research pharmacy at Vanderbilt University Medical Center. 
Medication should be taken by participants all the way up to their Visit #2 date.  
1.17 Remuneration 

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Subjects will have an option to receive $275 for completing the study or to keep the 
Fitbit Charge HR device and receive $175 after completing all study procedures. 
Subjects enrolled at Vanderbilt University Medical Center will receive an additional $175 
for completing MR spectroscopy and muscle function test.  
Data Collection 
1.18 Consent 
Written consent or e-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 or e-consent will be obtained at the screening 
visit or before.  
 
For e-consent, the patient consent process will be conducted using a REDCap-based 
electronic consent form.  The consent 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.  
Potential participants will participate in the consent process by either: 
1.)  Being approached in-person at a Vanderbilt Clinic and accessing the REDCap 
survey via iPad or other portable electronic device and/or 
2.) Self-initiated access of consent forms on personal portable electronic devices 
using posted QR codes or web-links on study posters, brochures, or websites.  
Self-initiated accessing of consent forms may occur in clinic or at home. 
During the in-person consent process, patients will be consented by a member of the 
key study personnel.  
For self-initiated consent, contact information will be provided (email and phone) for 
prospective patients to contact a member of the key study personnel with questions, 
prior to consent. 
Patient signatures will be obtained using a typed signature.  Upon completion of the 
consent, patients will be provided with a copy of their version of the consent document 
by printing a pdf copy of the consent form in clinic or at their screening visit.  
 
1.19 Study Visits and Contacts 
This study will consist of two visits: screening (-2 week) and week 12. The screening 
and week 12 visit are both estimated to take approximately 4-6 hours each. Patients will 
be consented by the PI, a clinical research coordinator, or a research nurse. Patient’s 
written consent and study procedures will take place at the Pulmonary Vascular 
Disease Clinic (CPVD), the Clinical Research Center (CRC), and Vanderbilt Institute of 
Imaging Science (VUIIS) at Vanderbilt University Medical Center, Nashville, TN; the 

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Pulmonary Hypertension Clinic or the Clinical Research and Trials Unit (CRTU) at Mayo 
Clinic, Rochester, MN; and the Pulmonary Hypertension Program or Clinical Research 
Unit (CRU) at Cleveland Clinic, Cleveland, OH. There will be no changes to a patient’s 
medication regimen. 
 
Participants at Vanderbilt Medical Center will have the opportunity to participate in a sub 
study that includes a cardiac and skeletal MR spectroscopy, a noninvasive test 
measuring fat in the heart and skeletal muscles, and a muscle strength and function test 
at screening and week 12. The visits will occur at Vanderbilt Institute of Imaging 
Science (VUIIS). The MR spectroscopy will be performed by an experienced MRI 
technologist and be overseen by a faculty level imagining scientist.  
 
 Screening Visit (-2 Weeks) 
This visit will last approximately 4 to 6 hours and occur at each site’s clinical research 
center or equivalent: CRC at VUMC, CRTU at Mayo Clinic, and CRU at Cleveland 
Clinic. Some procedures may also take place at the time of a regularly scheduled visit at 
each site’s pulmonary hypertension clinic or equivalent: Pulmonary Vascular Disease 
Clinic at VUMC, Pulmonary Hypertension Clinic at Mayo Clinic, and the Pulmonary 
Hypertension Program at Cleveland Clinic. In the sub study at VUMC, the visit will also 
occur Vanderbilt Institute of Imaging Science (VUIIS). At screening, written consent will 
be obtained from subjects after all questions are adequately answered. After 
consenting, subjects will be acquainted with 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. Screening information will be used to characterize the participants and to 
compare the experimental groups with regards to demographics and other variables. 
The following procedures will be performed: 
• written informed consent  
• review inclusion/exclusion criteria  
• review of medical history 
• demographic data 
• urine pregnancy test (if needed) 
• education on FitBit device 
• education on metformin side effects 
• review of current medications 
• WHO functional class 
• blood and urine collection 
• quality of life survey (emPHasis-10) 
• vital signs 
• physical exam 
• six minute walk test 
• transthoracic echocardiography 
• cardiac and skeletal MR spectroscopy (VUMC subjects in sub-study only) 
• muscle strength and function testing (VUMC subjects in sub-study only) 

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After fasting research labs have been drawn, the subject will have the opportunity to eat 
a snack. The investigator or research nurse will take a medical history, perform a 
physical examination including checking vital signs, and review current medications. 
The subject will perform the six minute walk test. An experienced research sonographer 
will perform the transthoracic echocardiography. The subject will then complete the 
emPHasis-10 quality of life survey. For VUMC patients participating in the sub-study an 
experienced research technologists and MRI technologist at the Vanderbilt Institute of 
Imaging Science will conduct MR imaging and spectroscopy studies and a muscle 
strength and function test. These tests will be performed under the oversight of a 
faculty-level skeletal muscle physiologist/imaging scientist. 
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. 
 Study Initiation – Phone Call 1 (Baseline or Time Point 0) 
Study drug or placebo will be shipped via overnight service to arrive on study day 1. 
Patients will be contacted by phone and instructed to begin the study medication.  
Eligibility criteria will be confirmed prior to randomization to treatment group. 
Participants displaying noncompliance to activity tracker during the run-in period will not 
be randomized. Subjects dropped after the run-in period will be informed why the study 
doctor has removed them from the study and provided directions for return of activity 
tracker. 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. 
 Phone Call - (Week 1, 3, 6, 9) 
The research coordinator will call the subject. Symptoms, potential side effects, 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 the screening visit will be repeated at the Week 12 Visit. The following 
procedures will be performed:  
• review of interim medical history 
• review of current medications 
• WHO functional class 
• blood and urine collection 
• quality of life survey (emPHasis-10) 
• vital signs 
• physical exam 
• six minute walk test 
• transthoracic echocardiography 
• cardiac and skeletal MR spectroscopy (VUMC subjects in sub-study only) 
• muscle strength and function testing (VUMC subjects in sub-study only) 

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After fasting research labs have been drawn, the subject will have the opportunity to eat 
a snack. The investigator or research nurse will take an interim medical history, perform 
a physical examination including checking vital signs, and review current medications. 
The subject will perform the six minute walk test. An experienced research sonographer 
will perform the transthoracic echocardiography. The subject will then complete the 
emPHasis-10 quality of life survey. For VUMC patients participating in the sub-study, 
experienced research technologists and MRI technologists at the Vanderbilt Institute of 
Imaging Science will conduct MR imaging and spectroscopy studies and a muscle 
strength and function test. These tests will be performed under the oversight of a 
faculty-level skeletal muscle physiologist/imaging scientist.  
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.  
1.20 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 
Follow 
Up 
Week 
-2 to -4 
Week 
-2 
Week 
-1 
Week
1 
Week
3 
Week
6 
Week
9 
Week
12 
Week
15 
Week 
17 
Visit # 
1 
 
 
 
 
 
 
2 
 
 
Telephone Call # 
 
 
 
1 
2 
3 
4 
 
5 
6 
Day# 
(-14 to -30 
days to Study 
Hour 0) 
-14 to  
-30 
-7 to 
-23 
0 
21 
± 3 
42 
± 3 
63 
± 3 
84 
± 5 
105 ± 
3 
119 ±  
3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Run-In  
 
X 
X 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
Wash-Out  
 
 
 
 
 
 
 
 
X 
 
Follow-Up 
 
 
 
 
 
 
 
 
 
X 
History And Physical Exam 
 
 
 
 
 
 
 
 
 
 
Medical/Interim History 
X 
 
 
 
 
 
 
X 
 
 
Symptom Assessment 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Medications 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
 
 
 
 
 
 
X 
 
 
Physical Exam 
X 
 
 
 
 
 
 
X 
 
 
WHO Functional Class 
X 
 
 
 
 
 
 
X 
 
 
Testing 
 
 
 
 
 
 
 
 
 
 
Phlebotomy 
X 
 
 
 
 
 
 
X 
 
 
Glucose & Insulin 
X 
 
 
 
 
 
 
X 
 
 
Free Fatty Acids & 
Acylcarnitine Profiles 
X 
 
 
 
 
 
 
X 
 
 
Lipid Profiles 
X 
 
 
 
 
 
 
X 
 
 
Estradiol & Estrogen  
Metabolites 
X 
 
 
 
 
 
 
X 
 
 
NT-proBNP 
X 
 
 
 
 
 
 
X 
 
 
Metabolomics 
X 
 
 
 
 
 
 
X 
 
 
Amino acids 
X 
 
 
 
 
 
 
X 
 
 

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HgbA1c 
X 
 
 
 
 
 
 
X 
 
 
CBC 
X 
 
 
 
 
 
 
X 
 
 
Comprehensive Panel 
X 
 
 
 
 
 
 
X 
 
 
Six Minute Walk Test 
X 
 
 
 
 
 
 
X 
 
 
emPHasis-10 Survey 
X 
 
 
 
 
 
 
X 
 
 
Echocardiogram 
X 
 
 
 
 
 
 
X 
 
 
Cardiac Proton MRS 
X 
 
 
 
 
 
 
X 
 
 
Skeletal Muscle Proton MRS 
X 
 
 
 
 
 
 
X 
 
 
Skeletal Muscle Strength & 
Function Test 
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 
 
 
Assessments of Efficacy and Outcome Measures 
1.21 Assessments of Efficacy  
Primary Endpoint: Composite endpoint of 10% or greater improvement in six minute 
walk distance over baseline or improvement of at least one WHO functional class at 
week 12.  
Secondary Endpoints: There are several secondary objectives of this study. They 
include: 
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on body weight at week 12. 
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on BMI at week 12. 
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on absolute 6MWD at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on Borg Dyspnea Score at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on emPHasis-10 quality of life survey score at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on WHO functional classification at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on the average daily step count at week 12. 
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on frequency of daily goal attainment at week 12. 
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on daily aerobic time at week 12. 
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on total daily activity at week 12. 

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• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on resting heart rate at week 12. 
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on HOMA-IR at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on urine and plasma estradiol at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on urine and plasma estrogen metabolites at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on plasma lipid profiles at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on plasma free fatty acid profiles at week 12. 
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on plasma acylcarnitine profiles at week 12. 
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on plasma BNP at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on quadriceps skeletal muscle triglyceride content at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on change in quadriceps skeletal muscle fatigue at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on quadriceps skeletal muscle strength at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on quadriceps skeletal muscle contractile tissue cross-sectional area at 
week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on RV myocardial muscle triglyceride content at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on tricuspid annular plane systolic excursion (TAPSE) at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on RV and LV ejection fraction at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on RV fractional area change at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on tricuspid annular velocity (S’) at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on tricuspid regurgitant (TR) velocity at week 12. 
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on estimated RV and RA pressure at week 12.  
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on RV and LV diastolic function at week 12.  

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• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on RV free wall longitudinal strain at week 12.  
• To compare and define the screening clinical characteristics of responders and 
non-responders to mHealth intervention or no intervention and/or metformin at 
week 12.  
• To compare and define the screening plasma metabolomics profiles, including all 
amino acids and lipidomics, of responders and non-responders to mHealth 
intervention or no intervention and/or metformin at week 12.  
• To assess the capacity of metabolomics profiles and clinical features at screening 
to predict response to the mHealth intervention or no intervention and/or metformin 
or placebo groups at week 12.  
• To assess the capacity of change in metabolomics profile and clinical features from 
screening to predict response to the mHealth intervention or no intervention and/or 
metformin or placebo groups at week 12. 
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on safety and tolerability in PAH subject over 12 weeks. 
• 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 or no intervention and/or metformin 
or placebo on patient satisfaction at week 12 
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on dropout rates over 12 weeks. 
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on PAH-related hospitalizations over 12 weeks. 
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on medication regimen escalation/reduction over 12 weeks. 
• To assess the effect of a mHealth intervention or no intervention and/or metformin 
or placebo on incidence of death over 12 weeks. 
 Response to Therapy 
Response to therapy bot in will be classified as a binary yes or no response to therapy. 
A responder is defined by 10% or greater improvement in 6MWD over screening or 
improvement of at least one FC at week 12. 
1.22 Secondary Outcome Measures 
 Body Weight and BMI 
a. Body Weight 
b. Body Mass Index (BMI)  
                          BMI = weight in kilogram/(height in meters)2 

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 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 
walked which is reliable and valid49. Standardized test methods and scripted and timed 
statements have been established in prior studies of PAH3,9-12,20-22.The 6MWT will be 
administered according to the Thoracic Society guidelines23,49. The 6MWT will be 
performed at screening and 12 weeks visits. 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. 
 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 
screening and week 12 visits. This score is a measure the physical activity intensity 
level based on the subject's perceived exertion. Subjects will rate at resting and peak 
exercise. 
 Quality of Life Questionnaire (emPHasis–10) 
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. Subjects will complete the 
emPHasis-10 survey at screening and week 12 visits.  
 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 screening and week 12 visits. 
 Step Counts and Physical Activity  
Wearable accelerometers can provide accurate measurements of steps and activity in 
three dimensions. 
Accelerometry 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 

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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 14 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) 
 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.  
 Blood Biomarkers 
a. 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 screening and 12 weeks.  
b. Lipid Metabolism 
Altered lipid metabolism reflects insulin resistance.  Fasting plasma lipid metabolites 
will be evaluated via non-targeted metabolomics screen. Mass spectroscopy of 
approximately 300 metabolites across all major metabolic pathways will be 
performed at screening and 12 weeks.  
c. Fatty Acid Metabolism  
Elevated circulating fatty acids and acylcarnitines contribute to RV lipotoxicity and 
indicate insulin resistance associated with pulmonary hypertension. 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 screening and 
12 weeks.  
d. Plasma and Urine Estradiol and Estrogen Metabolites 
Estrogen metabolites are associated with pulmonary hypertension in human PAH 
subjects. Estrogen metabolism we will be evaluated by measuring plasma estradiol (E2) 
and estrogen metabolites, including 2ME and 16αOHE, using mass spectrometry at 
screening and 12 weeks. 
e. 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 screening and 12 weeks.  
f. Amino Acids and Metabolomics 

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We and others have observed in cross-sectional studies that PAH is associated 
with insulin resistance and lipid abnormalities. Metabolites associated with insulin 
resistance and lipid metabolism have not been examined in the context of a clinical 
trial targeting insulin resistance. Changes in amino acids and metabolomic profiles 
with metformin and physical activity may provide insight into the mechanisms by 
which these interventions may improve insulin resistance (and outcomes) in 
patients with PAH. 
g. Safety Labs 
A comprehensive panel, complete blood count, hemoglobin A1c, and a urine 
pregnancy test will be assessed at screening and 12 weeks.  
 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. The 
following metrics will be obtained: 1) tricuspid annular plane systolic excursion (TAPSE); 
2) RV & LV ejection fraction51; 3) RV fractional area change; 4) tricuspid annular velocity 
(S’);  5) tricuspid regurgitant (TR) velocity; 6) RV systolic pressure (estimated from the 
equation: RV systolic pressure = 4(maximum TR velocity)2 + right atrial pressure); 7) 
right atrial pressure52; 8) RV & LV diastolic function53; 9) RV free wall longitudinal 
strain54-55. All measurements will be performed according to the American Society of 
Echocardiography guidelines51-53. 
 
Proton Magnetic Resonance Spectroscopy (MRS) 
a. Cardiac Proton MRS 
Patients will undergo cardiac metabolic assessment in the VUIIS using a Philips 3 Tesla 
system at screening and week 12 visits. Lipid content of right ventricle will be measured 
by proton MRS56. Electrocardiographic and respiratory gating are used at end-systole 
and end expiration to minimize motion artifact. A 2x1x3cm3 voxel is placed over the 
interventricular septum to avoid contamination from epicardial fat. Water (suppressed 
and unsuppressed) spectra are collected to serve as an internal reference for chemical 
shift offset and fat concentration97. PRESS spectra (echo time, 30 ms) with and without 
water suppression are performed to quantify fat measurements98. Peak amplitudes of 
water and fat are measured using spectral processing software (Spectroview; Philips 
Medical Systems). Lipid content is expressed as percent triglyceride (%TG) versus 
water content, using the formula: signal amplitude of triglyceride divided by signal 
amplitude of water x 100. The usual components of a cardiac MRI will also be obtained 
from the MRS scan. Data will be analyzed by a blinded observer (Brittain).  
b. Skeletal Muscle Proton MRI and MRS 
After a 4 to 6 hour fast, patients will undergo skeletal muscle metabolic assessment in 
the VUIIS using a Philips 3 Tesla system at screening and week 12 visits.  Subjects will 
lie supine in the magnet with their thigh placed in a 1H-MRS volume coil.  Transverse T1 
weighted MR images are obtained to permit accurate placement of the 1H-MRS voxel 

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and to calculate the quadriceps cross-sectional area. A 10x10x10mm3 voxel is placed in 
the quadriceps muscle and water and lipid spectra are obtained by a point-resolved 
spectroscopy sequence. Finally, whole-body fat-water images will be acquired. 
Lipid content and composition will be analyzed as described for the RV57-58. Lipid 
content is expressed as percent triglyceride (%TG) versus water content, using the 
formula: signal amplitude of triglyceride divided by signal amplitude of water x 100. To 
calculate the quadriceps contractile tissue cross-sectional area, the maximum cross-
sectional area will be calculated and adjusted by the fat percentage in the same slice. 
 
Skeletal Muscle Function 
After the MRI and MRS, the patients will undergo a skeletal muscle function test 
using a workout chair that will take place in VUIIS. Equipment used will 
include a leg-extension Ergometer chair including lumbar support and 
seatbelt straps, that will allow us to measure the strength of a patient’s leg 
kick. This device will solely be used for research purposes. It is not being 
used to diagnose or treat disease and is not intended to be marketed for 
commercial use. The muscle fatigue protocol has demonstrated the ability to 
induce fatigue in the quadriceps muscles in both patients and healthy 
controls. Key outcomes of the protocol include measures of absolute muscle 
strength (i.e. maximal knee extensor torque) before, during, and following 
exercise. Percent loss in maximal voluntary contraction magnitude during 
the fatigue protocol serves as the primary measure of fatigability.  
a. Strength  
We will assess leg extensor muscle strength using an isometric dynamometer as 
previously published29 , both at the screening and the week 12 visits.  
The test procedures are as follows: The subject will warm up with about 5 minutes of an 
activity involving the thigh muscles, such as self-paced walking, low-resistance 
pedaling, or low-resistance leg extension exercise. Then the subject will sit in a custom-
built strength testing exercise chair with the hip and knees at about 90 degrees of 
flexion, and the right leg fastened to a kick bar capable of measuring force. Two 
shoulder straps and a waist strap will be placed around the subject to minimize the use 
of muscles other than the knee extensors. We will train the subject to perform muscle 
contractions with the quadriceps muscles with good technique, including the avoidance 
of a Valsalva maneuver. This will involve about 5-10 submaximal or maximal 
contractions, each separated by up to 2 minutes of rest. The subjects will then perform 
3-5 maximum voluntary contractions (MVCs), each lasting 4 seconds and being 
separated by about 3 minutes of rest. The highest value recorded from three 
contractions performed using good technique and closely matched in force output will 
be used for the muscle strength endpoint. The total time required for strength testing 
procedures is expected to be about 60 minutes.  
 
b. Fatigue  
We will assess leg extensor muscle fatigue using a progressive, submaximal isometric 
exercise protocol, both at the screening and week 12 visits.  

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The test procedures are as follows: The fatigue protocol requires the subject to perform 
6 sets of submaximal contractions in which s/he matches the effort level to a target 
intensity. Training the subject to perform the effort-matching procedure will typically 
require about 5-10 trials for practice. Each trial will be separated by about 2 minutes of 
rest. After the subject is able to match his/her effort level to the target intensity, s/he will 
be allowed about 5 minutes of rest. During the fatigue protocol, the subject will perform 
6 sets of 12 contractions with a 40% duty cycle (4s contraction and 6s relaxation), and 
each set of contractions will be followed by an MVC. The initial submaximal target force 
will be 20% of the previously measured MVC (section 1.22.11.a) and will be 
incremented by 10% every set until 70% MVC. After the subject completes the fatigue 
protocol, s/he will perform a single MVC every 3 minutes through a total of 12 minutes 
of recovery time. The total time required for the fatigue protocol is expected to be 
between 45 and 60 minutes.  
Fatigue will be expressed as % drop in MVC during the fatigue protocol compared with 
the pre-fatigue MVC force. Recovery will be expressed as the % recovery of MVC force 
that was lost during the fatigue protocol at the 12 minute time point. Secondary 
analyses of force recovery will occur for the 3, 6, and 9 minute time points. 
 
Responders vs. Non-Responders. 
a. Definitions 
Patients enrolled in our ongoing metformin pilot study will be divided into responders 
and nonresponders based on the primary endpoint of Aim 1. Clinical differences will be 
compared between groups, e.g. age, sex, BMI, PAH subtype, prevalent comorbidities, 
6MWD, RV function and RV lipid content. Differences in molecular characteristics 
profiles will be compared between groups. Fasting plasma (before and after drug 
exposure) from our ongoing metformin pilot study will be used to perform metabolomic 
profiling via mass spectroscopy of approximately 300 metabolites across all major 
metabolic pathway, measuring all amino acids and including lipidomics.  
 
 
b. Predictive Capacity 
We will validate the metrics gathered from clinical and molecular characteristics of 
responders and non-responders. We will test predictive capacity in response to 
mHealth, metformin, or both interventions.   
 
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. 

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Other Feasibility Endpoints  
a. Drop Out Rates  
b. Patient Satisfaction: Patient satisfaction will be assessed using a 
customized survey developed for A Mobile Health Intervention in 
Pulmonary Arterial Hypertension trial and adapted for the PAH 
population.  
c. Side effects and tolerability of interventions including metformin. 
 
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 the Data and Safety Monitoring Board (DSMB), which is unrelated to the 
study. 
 
Death 
Cardiovascular Death: We define as cardiovascular death:  
1) sudden death 
2) death preceded by either one of the following: 
a) cardiogenic shock defined by either: 
i. 
hypotension resulting in a failure to maintain normal renal 
ii. 
 cerebral function for >15 minutes prior to death) 
b) heart failure symptoms or signs requiring one of the following: 
i. 
intravenous therapy or oxygen in the hospital  
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 
1.23 Study design 

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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, emPHasis-10, echo, proton MRS, muscle function test, 
and blood sampling will be performed at screening and 12 weeks. Disposition of 
subjects and screening comparisons will be reported.  
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. 
1.24 Statistical Analysis 
The primary analyses will focus on metformin vs placebo, exercise vs placebo, and 
metformin + exercise vs placebo comparisons on the primary endpoint. Since the 
evaluation of metformin or exercise will be reported as if they were independent 
studies and the combination arm versus placebo comparison serves to corroborate 
findings of the two separate comparisons, in addition to evaluating an additive or 
synergistic effect, we will not adjust for multiple comparisons. For binary endpoints, 
the Pearson chi-square or Fischer’s exact test will be used to assess between 
treatment arms difference. Logistic regressions will be conducted to examine the 
treatment effect while adjusting for important covariates such as baseline 6MWD, 
functional status, age, and study cite. Model over-fitting will be avoided by 
considering the number of parameters in the model and the number of responders 
in the sample.  Continuous endpoints will be analyzed using either two-sample t-test 
or ANOVA, or non-parametric methods Wilcoxon Rank Sum test or Kruskal-Wallis 
test. Multivariable regressions (general linear models) will be conducted to examine 
the treatment effect while adjusting for important covariates such as baseline 
6MWD, functional status, age, and study site.  We have designed the study to 
minimize the potential for missing data. Subjects who drop out will be replaced up to 
a total of 35 per group.  Nevertheless, in the event we have missing data, a 
multiple-imputation procedure as implemented in the areglmpute function in the 
Hmisc package in R (R Package; Version 3.0-10) will be used to assess the impact 
of missing data. The analyses with imputation will mainly serve as sensitivity 
analyses.  
1.25 Missing Data and Dropouts 
For all endpoints, the primary analysis will be intention-to-treat (ITT): 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. 
Subjects who stop study interventions at any point of the study but agree to come 
back for the final data collection will be invited to do so to facilitate the ITT analysis. 
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) and others 

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identified by a committee not related to the study (XXX usually the study team 
determines a list of protocol violators before data un-blinding, but this is a single 
blinded study and that Anna and Evan know who gets what and the endpoints, that 
complicates it a bit) .  
Subjects who drop out will be replaced up to a total of 35 per group. Built-in alerts 
will be triggered if there is a prolonged lapse in data transmission in real-time activity 
tracking. Protocols to email, then call subjects will be followed to determine the cause of 
missing data and find a solution. The Fitbit device will store data for 28 days so even if 
data is not being transmitted, it will not be lost. A stock of new devices will be kept on 
hand to overnight ship to subjects if the Fitbit device fails to capture data or stops 
working. 
In the event of missing data, 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. A multiple 
imputation procedure implemented in the aregImpute function in the Hmisc package 
in R (R Package; Version 3.0-10) will be used. The analysis with imputation will 
serve primarily as a sensitivity analysis. The potential drop-out is considered in the 
power calculation to minimize its impact. 
1.26 Statistical Power 
The pivotal trial of Iloprost demonstrated that in the Iloprost arm nearly 40% had 10% 
improvement in 6MWD, 50% had improved FC, and 17% had both1. From these data 
we calculate that 73% had either 10% improvement in 6MWD or improved functional 
status. Assuming metformin or the exercise arm will have similar response rate, and the 
placebo group will have 40% response rate, thought to be due to training effect 
potentially, we need 35 per group to have 80% power at 0.05 type I error rate. For the 
metformin and exercise combination group, an additive or synergistic effect between the 
two interventions will put its response rate above 73%. Thus, the combination vs. 
placebo comparison will have at least 80%, likely better power. From past experience 
coupled with the low risk, low side effect profile interventions, we estimate a dropout 
rate of less than 10%1. We will enroll 40 subjects to ensure 35 completed subjects per 
group. The total target enrollment is 160 over 4.5 years. 
1.27 Interim Monitoring Guidelines 
We have not planned 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.  
1.28 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 

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such violations. When known, the causes and circumstances of all violations will be 
documented for 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 
1.29 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. 
1.30 Echocardiography 
There are no risks to this ultrasound procedure aside from minor discomfort related to 
placement of the ultrasound probe on the chest. 
1.31 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. 
1.32 MR Spectroscopy 
A portion of the patients will have MR spectroscopy which is not associated with 
meaningful risk of harm to patients when patients with contraindications such as metal 
implants are excluded. Prior to undergoing the study procedure, enrollees will be 
queried about the potential presence of implanted metal by trained personnel and will 
not undergo this procedure if concerns arise. Claustrophobic subjects may be 
administered an anxiolytic if the subject has taken this medication in the past without 
concern. The muscle strength and function test have no known risks, but they may be 
lengthy, uncomfortable, or make subjects feel tired.  
1.33 Metformin   
This drug has been on the market for several decades and is considered first line 
therapy for diabetes mellitus type 2. Moreover, it has been used extensively in non-
hyperglycemic patients with polycystic ovarian disease. Additional studies of the safety 
of metformin in heart failure have been published. The pertinent risk of metformin is 
development of lactic acidosis. This risk has been reported primarily in patients with 
abnormal renal or hepatic function, thus we have chosen to exclude these populations 
from the study. Additional concerns include hypoglycemia, though this is a rare risk of 
this drug, and gastrointestinal distress.  Patients will be educated on the signs and 
symptoms of hypoglycemia and advised to contact study staff immediately if any arise.  
Several other potential side effects listed in the package insert that will be monitored at 

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study visits and through phone conversation if need arises. We will monitor patients at 
baseline, week 1, week 3, week 6, week, 9, week 12, week 15, and week 17 through 
either a visit or phone conversation. At these points, side effects that limit dose 
adjustment will be assessed. If patients report significant gastrointestinal effects, 
metformin will not be increased as would otherwise occur in the protocol. If symptoms 
persist further, the dose will be dropped by 500 mg daily to the highest tolerated dose.    
The most common adverse reactions experienced are:  
• >10% of patients: diarrhea (instant release tablet: 12% to 53%; extended release 
tablet: 10% to 17%), nausea/vomiting (instant release tablet: 7% to 26%; 
extended release tablet: 7% to 9%), flatulence (12%), Weakness (9%) 
• 1% to 10%: chest discomfort, flushing, palpitation, headache (6%), chills, 
dizziness, lightheadedness, rash, hypoglycemia, Indigestion (7%), abdominal 
discomfort (6%), abdominal distention, abnormal stools, constipation, dyspepsia/ 
heartburn, taste disorder, myalgia, dyspnea, upper respiratory tract infection, 
decreased vitamin B12 levels (7%), increased diaphoresis, flu-like syndrome, nail 
disorder 
• <1% (Limited to important or life-threatening): lactic acidosis, leukocytoclastic 
vasculitis, megaloblastic anemia, pneumonitis 
• Contraindications to the use of metformin are: hypersensitivity to metformin or any 
component of the formulation; renal disease or renal dysfunction (serum 
creatinine ≥1.5 mg/dL in males or ≥1.4 mg/dL in females) or abnormal creatinine 
clearance from any cause, including shock, acute myocardial infarction, or 
septicemia; acute or chronic metabolic acidosis with or without coma (including 
diabetic ketoacidosis) 
 Boxed Warning   
A boxed warning has been issued for metformin related to the risk of developing lactic 
acidosis.  The risk is increased in patients with acute congestive heart failure, 
dehydration, excessive alcohol intake, hepatic or renal impairment, or sepsis.  
Conditions that increase the risk of lactic acidosis on metformin treatment are all 
exclusion criteria for this study.  Based on our pilot trial with no lactic acidosis in 
enrollees thus far, we do not anticipate this to be a significant complication. If clinically 
significant lactic acidosis is diagnosed for clinical indications, the DSMB and IRB will be 
notified as per protocol. 
 Iodinated Contrast  
Metformin therapy will be discontinued prior to or at the time of intravascular 
administration of iodinated contrast media (potential for acute alteration in renal 
function) should a subject require contrast during the course of this study. Metformin will 
be withheld for 48 hours after the radiologic study and restarted only after renal function 
has been confirmed as normal.  Patients will be encouraged to delay any elective 
radiologic studies requiring iodinated contrast until the conclusion of the study.   
1.34 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 

mHealth+Met PAH                                                                                                              Protocol 
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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 
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. 
1.35 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. 
 
1.36 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 sIRB 
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). 
1.37 Coordinating Center (CC) 
The coordinating center (CC) will be Vanderbilt University Medical Center. The 
coordinating center will be the central site responsible for organizing and managing 
activities and logistics for all collaborative components of the study, including oversight, 
and coordination of the multi-site study design, evaluation of progress, and data 
storage. The coordinating center will develop standard operating procedures for how 
each site collects data, plans for project management, subject recruitment and 
retention, performance milestones, scientific conduct of the trial, and dissemination of 
results. 

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1.38 Data Quality 
The site 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 CC will create computer modules to identify discrepancies and 
incomplete data. These reports are tracked until each problem is resolved and corrected 
in the database. 
Periodic audits of each enrollment site will be conducted by the lead site.  The 
monitoring staff will review database forms and source documents to ensure that the 
information on the forms is complete and consistent with the source documents. All 
consent forms will be audited. All study personnel are required to read the consent form 
and protocol. 
Project team members at Vanderbilt listed as Key Study Personnel with existing 
electronic health record (EHR) system access rights will make use of REDCap Clinical 
Data Pull (CDP) tools. These tools are designed to enable transfer of relevant study-
related data from the Vanderbilt Research Derivative and/or directly from the EHR into 
REDCap. 
 
Data and Safety Monitoring and Reporting  
1.39 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.   
1.40 
Institutional Review Board process 
The CC and Field Centers will rely on a single IRB (sIRB) of record (Vanderbilt 
University Medical Center’s IRB) and obtain approval and reliance agreements.  When 
sIRB approval is obtained, site specific ICFs will be sent to the CC along with the notice 
of approval. These materials must be on file in the CC before a center can begin 
enrolling participants into the clinical trial.  
1.41 
Designated Medical Director 
Dr. Meredith Pugh will serve as the medical director for this trial. Dr. Pugh serves as an 
attending physician in the Vanderbilt Medical Intensive Care Unit, the inpatient consult 
service, and the pulmonary hypertension service.  Dr. Pugh has outpatient clinics where 
she sees a variety of general pulmonary diseases and pulmonary vascular disease. She 
will be invited to attend weekly meetings with the PI and study personnel. She will be 

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available to discuss adverse events with the PI and respond to safety concerns from 
subjects or study personnel.  
1.42 
Monitoring 
During phone calls and study visits, 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. 
1.43 
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 
will be determined by the University of Kentucky that will conduct these activities with 
the addition of an ad hoc content expert in pulmonary arterial hypertension. 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). All meetings of the University of Kentucky 
DSMB are in person with either teleconference of the PAH content expert or in person 
visit per the determination of the DSMB. The DSMB will aim to meet every 4 months to 
review safety data per their standing schedule. The need for additional meetings will be 
agreed upon by the DSMB during their initial meeting. The PI will attend all meetings via 
teleconference 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 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.   

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Safety and Adverse Events 
1.44 
Definitions 
 Unanticipated Problem (UP) 
 Any incident, experience, or outcome that meets all of the following criteria:  
i. 
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;  
ii. 
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  
iii. 
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: 
i. 
results in study withdrawal 
ii. 
is associated with a serious AE 
iii. 
is associated with clinical signs or symptoms 
iv. 
leads to additional treatment or to further diagnostic tests 
v. 
is considered by the investigator to be of clinical significance 
 Serious Adverse Event (SAE)  
Adverse reactions are classified as serious or non-serious.  A serious adverse event is 
any AE that is:  
i. 
fatal 
ii. 
life-threatening 
iii. 
requires or prolongs hospital stay 
iv. 
results in persistent or significant disability or incapacity 
v. 
a congenital anomaly or birth defect 
vi. 
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.  

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 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. 
 Internal Adverse Event  
Adverse events experienced by subjects enrolled by the investigator(s) at their own 
Field Center.  
 External Adverse Event  
Adverse events experienced by subjects enrolled by investigators at other Field Centers 
in the clinical trial.  
1.45 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. 
i. 
CTCAEv4 Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention is not indicated. 
ii. 
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). 
iii. 
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). 
iv. 
CTCAEv4 Grade 4: life-threatening consequences; urgent intervention is 
indicated. 
v. 
CTCAEv4 Grade 5: death due to an AE. 
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. 

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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: 
i. 
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 
ii. 
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. 
 Relatedness 
i. 
Definite: the AE is clearly related to the research procedures 
ii. 
Probably: the AE is likely related to the research procedures 
iii. 
Possible: the AE may be related to the research procedures 
iv. 
Unlikely: the AE is doubtfully related to the research procedures 
v. 
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.  
1.46 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 
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 

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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:  
i. 
The laboratory abnormality is not otherwise refuted by a repeat test to confirm 
the abnormality 
ii. 
The abnormality suggests a disease and/or organ toxicity 
iii. 
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 CC to the sIRB during yearly renewals and to the DSMB and 
NHLBI at scheduled or ad hoc meetings upon request. The Field Center 
Investigator/designee should keep originals or photocopies of all relevant 
documentation, including facsimile confirmations, and file them in the participant's file. 
All Field Center Investigators should ensure that all routine AE(s) are reported to ensure 
the CC has accurate data for periodic or annual reporting requirements to the sIRB. 
 
 
 
1.47 Expedited Reporting Procedures 
The Field Center Investigator should notify the CC, in an expedited manner, of those 
events listed in the table below related to study participation. The CC will then notify the 
sIRB, DSMB and NHLBI.  
 

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 Expedited Reporting Process 
Events will be reported to CC within 24 hours of knowledge of the event using a 
required form or as a written report of the event (including a description of the event with 
information regarding its fulfillment of the above criteria, follow-up/resolution and need 
for revision to consent form and/or other study documentation). Copies of each report 
and documentation of sIRB notification and receipt will be kept in the Field Center 
Investigators’ study file and the Trial Master File (TMF) maintained by the CC. The Field 
Center Investigator is expected to provide as much of the following information to the 
sIRB as is available for initial assessment and subsequent reporting will occur as 
outlined on the table. 
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 
 
 
Internal Event 
Local 
Investigator 
• CC 
Within 24 hours of initial receipt of 
information 
Internal/    
external event 
CC 
• sIRB 
Within 24 hours of initial receipt of 
information from Field Center 
sIRB 
determination 
sIRB 
• local IRB reporting 
event 
Within 3 business days of sIRB 
determination 
Site Specific 
Action plan (if 
applicable) 
Local IRB 
• sIRB 
Within 7 calendar days of sIRB 
determination 
All events 
CC 
sIRB 
• NHLBI, DSMB 
• local IRBs if applicable 
Within 7 calendar days  of Field Center’s 
initial receipt of information 
Non-fatal, non-life-
threatening 
unexpected, 
suspected serious 
adverse reactions 
  
Internal Event 
Local 
Investigator 
• CC 
Within 24 hours of initial receipt of 
information 
Internal/    
external event 
CC 
• sIRB 
Within 24 hours of initial receipt of 
information from Field Center investigator 
sIRB 
determination 
sIRB 
• local IRB reporting 
event 
Within 3 business days of sIRB 
determination 
Site Specific 
Action plan (if 
applicable) 
Local IRB 
• sIRB 
Within 7 calendar days of sIRB 
determination 
All events 
CC 
sIRB 
• NHLBI, DSMB 
• local IRBs if applicable 
Within 15 calendar days of Field Center’s 
initial receipt of information 
Unanticipated 
Problem that is not 
an SAE 
  
Internal Event 
Local 
Investigator 
• CC 
Within 2 business days of initial receipt of 
information 
Internal/    
external event 
CC 
• sIRB 
Within 2 business days of initial receipt of 
information from Field Center investigator 
sIRB 
determination 
sIRB 
• local IRB reporting 
event 
Within 3 business days of sIRB 
determination 
Site Specific 
Action plan (if 
applicable) 
Local IRB 
• sIRB 
Within 7 calendar days of sIRB 
determination 
All events 
CC 
sIRB 
• NHLBI, DSMB 
• local IRBs if applicable 
Within 14 calendar days of Field Center’s 
initial receipt of information 
All Unanticipated 
Problems 
All Events 
Local 
Investigator 
• CC 
Within 2 business days of initial receipt of 
information 
sIRB 
• local IRBs (if 
applicable) 
Within 3 business days of sIRB 
determination 
• OHRP 
Within 30 days of the sIRB’s receipt of the 
report 

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• 
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 Field Center Investigator will provide details about the AE to the CC as they 
become available. If additional information cannot be obtained for whatever reason, this 
will be documented. The Field Center Investigator should inform the CC when no other 
information is expected. The Field Center Investigator should provide the CC with a 
logical, complete, and accurate narrative description of the AE based upon the above 
information. The Field Center Investigator should promptly determine an assessment of 
causality.  
The CC will report this information to the sIRB for initial assessment and subsequent 
reporting will occur as outlined on the table. The sIRB will communicate to the CCC 
(and the local IRBs) if the event requires revisions to the informed consent form or other 
measures. The sIRB will work with the local IRB and CCC to determine if any corrective 
actions should be initiated as a result. A formal determination will be provided to the 
sIRB within 1 business week and the CCC will inform all Field Center Investigators of 
the corrective action (e.g., revision of informed consent form, protocol, CRF). The CCC 
will also report any qualifying events to the DSMB and NHLBI as noted in the schedule. 
The CCC and any Field Center Investigator should file copies of all correspondence 
with the sIRB in the appropriate section of the Trial Master File or site study regulatory 
file. 
 Other Reportable Events: 
The following events are also reportable to the sIRB: 
• 
Any AE that would cause the sponsor to modify the investigators brochure, 
protocol or informed consent form, or would prompt other action by the sIRB 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. 

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• 
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 sIRB 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. 
1.48 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. 
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.  
1.49 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 Field Center, 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.  

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The CC at the Vanderbilt University Medical Center 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 sIRB 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.  
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. 
1.50 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 

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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. 
1.51 Follow-up and Record Retention 
The duration of this study is estimated to be 5 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. 
Ethical Considerations 
This study is to be conducted in accordance with applicable US government regulations 
and international standards of Good Clinical Practice, and applicable institutional 
research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted sIRB in 
agreement with local legal prescriptions for formal approval of the study conduct.  The 
decision of the sIRB concerning the conduct of the study will be made in writing to the 
investigator and a copy of this decision will be provided to the NIH before 
commencement of this study.   
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study. This consent form will be submitted with the protocol for 
review and approval by the sIRB for the study (and to Field Center IRBs if necessary for 
local content review).  The formal consent of a subject, using the IRB-approved consent 
form, must be obtained before that subject undergoes any study procedure.  The 
consent form must be signed by the subject or legally acceptable surrogate, and the 
investigator-designated research professional obtaining the consent.  
 
 
 
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