A Randomized Controlled Pilot Trial of a Structured Mobile Technology Based Lifestyle Program vs Usual Care for Patients With Non-alcoholic Fatty Liver Disease
Phase: NA
Conditions: Non-Alcoholic Fatty Liver Disease, Non-alcoholic Steatohepatitis
Sponsor: University of Michigan

 
 
A RANDOMIZED CONTROLLED PILOT TRIAL OF A STRUCTURED MOBILE 
TECHNOLOGY BASED LIFESTYLE PROGRAM VS USUAL CARE FOR 
PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE  
Protocol Number: HUM 00153750 
National Clinical Trial (NCT) Identified Number: TBA 
Principal Investigator: Monica Tincopa MD MSc 
Sponsor: University of Michigan 
Grant Title: American Association for the Study of Liver Diseases (AASLD) Clinical 
Translational and Outcomes Research Award (CTORA) 
NCT Number: NCT03839082 
Grant Number: AWD007197  
Funded by: AASLD 
Version Number:  3.0 
Version Approval Date: 12 November 2019 

<A Randomized Controlled Pilot trial of a Structured Mobile Technology Based Lifestyle Program Vs Usual Care for 
Patients with Non-Alcoholic Fatty Liver Disease > 
 
Version <3.0>  
Protocol <1> 
 
12 November 2019 
 
 
 
 
Summary of Changes from Previous Version: 
 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Section 1.2 
Goal total number of participant was increased 
from 100 to 120 subjects. Hence, the number 
of patient in each arm of the study will be 60.  
This change is necessary in order to ensure 
that we have more accurate mean values 
and provide smaller margin of error.   
Section 5.5 
Additional recruitment strategies were added. 
Potential patients will be identified through 
data direct, EMERSE as well as our general 
hepatology clinics.  
Potential participants identified via data direct 
and our general hepatology clinics will be 
recruited via phone and text.  
Changes will help increase efficiency and 
speed of recruitment. 
 
 
 

<A Randomized Controlled Pilot trial of a Structured Mobile Technology Based Lifestyle Program Vs Usual Care for 
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Table of Contents 
 
INVESTIGATOR’S SIGNATURE ............................................................................... Error! Bookmark not defined. 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 2 
1.3 
Schedule of Activities  ......................................................................................................................... 3 
2 
INTRODUCTION ............................................................................................................................................ 5 
2.1 
Study Rationale .................................................................................................................................... 5 
2.2 
Background  ......................................................................................................................................... 5 
2.3 
Risk/Benefit Assessment .................................................................................................................... 6 
2.3.1 
Known Potential Risks .................................................................................................... 6 
2.3.2 
Known Potential Benefits ................................................................................................ 6 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 6 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 6 
4 
STUDY DESIGN ............................................................................................................................................. 7 
4.1 
Overall Design ...................................................................................................................................... 7 
4.2 
Scientific Rationale for Study Design................................................................................................ 7 
4.3 
Justification for Intervention ............................................................................................................... 7 
4.4 
End-of-Study Definition ....................................................................................................................... 7 
5 
STUDY POPULATION .................................................................................................................................. 8 
5.1 
Inclusion Criteria .................................................................................................................................. 8 
5.2 
Exclusion Criteria ................................................................................................................................. 8 
5.3 
Lifestyle Considerations ...................................................................................................................... 9 
5.4 
Screen Failures .................................................................................................................................... 9 
5.5 
Strategies for Recruitment and Retention ........................................................................................ 9 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) .............................................. 9 
6.1 
Study Intervention(s) ........................................................................................................................... 9 
6.1.1 
Study Intervention or Experimental Manipulation Description ................................. 10 
6.2 
Fidelity ................................................................................................................................................. 10 
6.2.1 
Interventionist Training and Tracking .......................................................................... 10 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 11 
6.4 
Study Intervention/Experimental Manipulation Adherence.......................................................... 11 
6.5 
Concomitant Therapy ........................................................................................................................ 11 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ......................................................................................... 11 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ............................................. 11 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 11 
7.3 
Lost to Follow-Up ............................................................................................................................... 12 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 12 
8.1 
Endpoint and Other Non-Safety Assessments .............................................................................. 12 
8.2 
Safety Assessments .......................................................................................................................... 13 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 13 
8.3.1 
Definition of Adverse Events ........................................................................................ 13 
8.3.2 
Definition of Serious Adverse Events .......................................................................... 13 
8.3.3 
Classification of an Adverse Event .............................................................................. 13 

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Patients with Non-Alcoholic Fatty Liver Disease > 
 
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8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 14 
8.3.5 
Adverse Event Reporting .............................................................................................. 15 
8.3.6 
Serious Adverse Event Reporting  .............................................................................. 15 
8.3.9 
Reporting of Pregnancy  ............................................................................................... 15 
8.4 
Unanticipated Problems .................................................................................................................... 15 
8.4.1 
Definition of Unanticipated Problems .......................................................................... 15 
8.4.2 
Unanticipated Problems Reporting .............................................................................. 16 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 16 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 16 
9.1 
Statistical Hypotheses ....................................................................................................................... 16 
9.2 
Sample Size Determination .............................................................................................................. 17 
9.3 
Populations for Analyses ..................................................................... Error! Bookmark not defined. 
9.4 
Statistical Analyses............................................................................................................................ 17 
9.4.1 
General Approach .......................................................................................................... 17 
9.4.2 
Analysis of the Primary Endpoint(s) ............................................................................ 17 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 17 
9.4.4 
Safety Analyses .............................................................................................................. 17 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 17 
9.4.6 
Planned Interim Analyses ................................................ Error! Bookmark not defined. 
9.4.7 
Sub-Group Analyses ..................................................................................................... 18 
9.4.8 
Tabulation of Individual Participant Data .................................................................... 18 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 18 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 18 
10.1.1 
Informed Consent Process ........................................................................................... 18 
10.1.2 
Study Discontinuation and Closure ................................ Error! Bookmark not defined. 
10.1.3 
Confidentiality and Privacy ........................................................................................... 18 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 19 
10.1.5 
Key Roles and Study Governance .............................................................................. 19 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 19 
10.1.9 
Data Handling and Record Keeping ............................................................................ 20 
10.1.10 
Protocol Deviations   ...................................................................................................... 20 
Abbreviations and Special Terms ....................................................................................................................... 21 
10.2 
Protocol Amendment History ........................................................................................................... 22 
11 
REFERENCES ............................................................................................................................................. 23 

< A Randomized Controlled Pilot trial of a Structured Mobile Technology Based Lifestyle Program Vs Usual Care for 
Patients with Non-Alcoholic Fatty Liver Disease> 
 
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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
A Randomized Controlled Pilot trial of a Structured Mobile Technology 
Based Lifestyle Program Vs Usual Care for Patients with Non-Alcoholic 
Fatty Liver Disease  
Grant Number: 
AWD007197 
Study Description: 
Lifestyle interventions remain first line therapy for the treatment of 
non-alcoholic fatty liver disease (NAFLD). In clinical practice, it is 
challenging for patients to initiate and maintain these changes. In this 
randomized clinical pilot trial, we will evaluate impact of a structured 
mobile technology-based lifestyle intervention program compared to 
usual care to among patients with NAFLD.  We hypothesize individuals 
randomized to the intervention arm will have significantly improved 
outcomes compared to usual care, and that the intervention will be 
feasible, low cost and amenable to large scale implementation. 
Objectives: 
 
Primary objective: compare the effectiveness of usual care to a mobile 
technology based lifestyle intervention on change in liver and 
metabolic related parameters. 
Secondary objectives: identify predictors associated with reduction in 
hepatic steatosis and weight loss.  
Endpoints: 
Primary Endpoint: change in amount of hepatic steatosis 
Secondary Endpoints: change in weight, change in physical activity 
Study Population: 
120 adult patients with NAFLD including steatosis only, non-alcoholic 
steatohepatitis (NASH) and NAFLD-related compensated cirrhosis seen 
in the Michigan Medicine Hepatology clinic. 
Phase or Stage: 
N/A 
Description of 
Sites/Facilities Enrolling 
Participants: 
 
 
Michigan Medicine Hepatology Clinics, and patient identified through 
Data Direct and EMERSE in various local clinics 
Description of Study 
Intervention/Experimental 
Manipulation: 
 
Personalized adaptive lifestyle intervention program that includes 
physical activity and nutritional feedback compared to usual care 
Study Duration: 
18 months 
Participant Duration: 
13 months 
 
 
 
 
 
 
 

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1.2 
SCHEMA  
Pre-Screening 
 
Visit 1 
Time 0 
 
 
 
 
 
 
 
 
 
 
3-Month Phone  
Call 
Day 84 ± 7 
 
 
Visit 2 
Day 168 ± 7 
 
 
 
 
 
 
 
 
9-Month Phone  
Call 
Day 252 ± 7 
 
 
Visit 3 
Day 336 ± 7 
 
 
Figure 1.  All participants will be enrolled in the study for ~12 months and will complete 3 study visits.  Individuals randomized 
to the Intervenetion arm will have 6 months of intervention followed by 6 months of follow-up to asssess for behavior change 
maintenance.  Individuals randomized to the Usual Care Waitlist will be followed for 6 months, after which they will start a 6-
month intervention period.   
 
 
 
Total N: 120 
Obtain informed consent. Screen potential participants by inclusion and exclusion criteria 
Conduct informed consent process. Perform baseline assessments. 
                                            (See Section 1.3, Schedule of Activities) 
Randomize
Review results. Nutritional assessment and overall feedback on physical activity for those 
in intervention arm. 
Usual Care 
N = 60  
Review results. Nutritional assessment and overall feedback on physical activity for those 
in intervention arm. 
Data collection on endpoints (see Section 1.3, Schedule of Activities) 
Transition from Usual Care to Intervention Arm and Intervention Arm to Usual Care. 
 
Post-Intervention assessments 
Intervention 
N = 60  
Usual Care 
N = 60  
Intervention 
N = 60  

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1.3 
SCHEDULE OF ACTIVITIES  
 
Table 1 - Arm 1 - active intervention w/follow up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OnCore Calendar Segment 
Pre-study 
Consented 
OnStudy 
OnArm/OnTreatm
On treatment 
On FollowUp 
OffStudy 
Study Timeline 
Pre-screening 
(Pre-consent) 
 
Visit 1 
Day 1 
Phone Call- 
Intervention Arm 
Day 84 ±7 
Visit 2 
Day 168 ±14 
Visit 3 
Day 336 ±21 
EMR Review Eligibility 
X 
 
 
 
 
Informed Consent 
 
X 
 
 
 
Demographics 
 
X 
 
 
 
Clinical history 
 
X 
 
 
 
Randomization 
 
X 
 
 
 
Provide FitBit and Instruction to Intervention 
Arm 
 
X 
 
X 
 
Outcome Evaluation 
 
 
 
 
 
Vitals + Anthropometrics: blood pressure, 
height, weight, waist and hip circumference 
 
X 
 
X 
X 
Blood Work:1 hepatic panel, platelets, A1c, 
fasting insulin, glucose, lipid panel 
 
X 
 
X 
X 
6MWT 
 
X 
 
X 
X 
Hand Grip Strength 
 
X 
 
X 
X 
Quality of Life Questionnaire 
 
X 
 
X 
X 
Physical Activity Survey (IPAQ) 
 
X 
 
X 
X 
Motivation to Change Questionnaire 
 
X 
 
X 
X 
Dietary Survey 
 
X 
X 
X 
X 
Dietician Assessment2 
 
X 
 
 
 
VCTE 1 
 
X 
 
X 
X 
MRE11,3 
 
X 
 
X 
 
Exit Interviews 
 
 
 
X 
X 
Adverse Events Reporting 
 
         X 
X 
X 
X 
 
 
 
 
 

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Table 2. Arm II - wait list control; receives intervention after visit 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Baseline results can be abstracted from medical record if performed within prior 6 months and <5% weight 
change since that time. Otherwise, VCTE will be performed +/- 14 days from enrollment. Hepatic panel and platelet 
count are standard of care measures. Remainder of imaging and laboratory data will be research costs. 
2Can be done +/- 14 days from enrollment in person or via telephone 
3 Only done in half of patients due to cost, determined by computer randomization with stratification according to 
liver disease stage (cirrhosis) 
 4 If not enough time during enrollment, participants will be sent a link via email to complete the surveys within 14 
days from enrollment date. 
EMR, electronic medical record; 6MWT, 6 minute walk test; IPAQ, International Physical activity Questionnaire; 
VCTE, vibration controlled transient elastography; MRE, magnetic resonance elastography 
 
OnCore Calendar Segment 
Pre-Study 
Consented 
OnStudy 
OnTreatment 
Off Study 
Study Timeline 
Pre-screening 
(Pre-consent) 
 
Visit 1 
Day 1 
Visit 2 
Day 168 ±7 
Phone Call- 
Intervention Arm 
Day 252 ±14 
Visit 3 
Day 336 ±21 
EMR Review Eligibility 
X 
 
 
 
 
Informed Consent 
 
X 
 
 
 
Demographics 
 
X 
 
 
 
Clinical history 
 
X 
 
 
 
Randomization 
 
X 
 
 
 
Provide FitBit and Instruction to Intervention 
Arm 
 
X 
X 
 
 
Outcome Evaluation 
 
 
 
 
 
Vitals + Anthropometrics: blood pressure, 
height, weight, waist and hip circumference 
 
X 
X 
 
X 
Blood Work:1 hepatic panel, platelets, A1c, 
fasting insulin, glucose, lipid panel 
 
X 
X 
 
X 
6MWT 
 
X 
X 
 
X 
Hand Grip Strength 
 
X 
X 
 
X 
Quality of Life Questionnaire 4 
 
X 
X 
 
X 
Physical Activity Survey (IPAQ) 4 
 
X 
X 
 
X 
Motivation to Change Questionnaire 4 
 
X 
X 
 
X 
Dietary Survey 4 
 
X 
X 
X 
X 
Dietician Assessment2 
 
X 
 
 
 
VCTE 1 
 
X 
X 
 
X 
MRE11,3 
 
X 
X 
 
 
Exit Interviews 
 
 
X 
 
X 
Adverse Events Reporting 
 
         X 
X 
X 
X 
 
 
 
 
 

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2 
 
INTRODUCTION 
2.1 
STUDY RATIONALE  
The only proven curative therapy for non-alcoholic fatty liver disease (NAFLD) is improvement in nutrition 
and increased physical activity targeted to weight loss. In clinical practice, the majority of patients have 
limited success with making these behavior changes and sustaining them. There is a critical knowledge 
gap related to the optimal design of lifestyle interventions for NAFLD patients and predictors of response 
to specific types of treatment interventions. This study aims to evaluate the impact of a mobile 
technology-based lifestyle intervention program compared to usual care for patients with NAFLD.  
2.2 
BACKGROUND  
NAFLD is a highly prevalent form of chronic liver disease that is caused by fat build-up in the liver. This 
condition is associated with obesity and underlying metabolic syndrome, and is estimated to affect 25% 
of adults worldwide. Over time, the fat deposition in the liver can cause inflammation, liver injury and the 
development of fibrosis (scar tissue) that can progress to cirrhosis and end-stage liver disease.  Additional 
significant associated morbidity and mortality includes development of hepatocellular carcinoma, 
increased risk of cardiovascular events, and poor health-related quality of life (HRQOL).(1-3) Thankfully, 
there is a proven curative therapy for NAFLD. A 3-5% reduction in body weight decreases steatosis; a 10% 
reduction can resolve steatosis, inflammation and fibrosis.(4) Exercise alone, independent of weight loss, 
has also been shown to reduce steatosis.(5) As a result, lifestyle changes, improved nutrition and physical 
activity, are first line therapy for NAFLD.(1) Despite the liver and multi-system benefit of this approach 
and the consequences of untreated NAFLD, the uptake and maintenance of lifestyle interventions is 
extremely limited in practice. The precise barriers to and reasons for limited uptake of lifestyle changes 
among individuals with NAFLD are poorly understood.  Relatedly, there is an important knowledge gap 
regarding the optimal design of structured lifestyle programs that would have real-world effectiveness 
and are low cost, sustainable and scalable tailored to patients with NAFLD. This lack of a standardized 
approach for lifestyle interventions also has implications for pharmacotherapy trials where variable 
“placebo effects” stemming from heterogeneous control group implementation of diet and exercise 
recommendations confound the interpretation of efficacy of these medications.(6)   
While highly regimented lifestyle programs have shown to be efficacious, they are often costly, not 
accessible to many patients, and not amenable to long term sustainability and scalability.(7) Data from 
the obesity literature indicates that programs that remove logistical barriers (time constraints, cost) and 
increase the frequency of interactions/ follow-up with real-time feedback have a higher likelihood for real 
world effectiveness. Mobile technology based lifestyle programs encompass many of these features and 
have proven to be effective for weight loss among cohorts with similar phenotypes.(8) Preliminary data 
from our initial pilot trial of a mobile technology-based lifestyle program among NAFLD patients suggest 
feasibility and efficacy in terms of positive impact on weight loss, physical function, HRQOL and liver and 
metabolic parameters. Data from a small cohort of NAFLD patients also demonstrated a mobile 
technology program (text messaging) was effective in promoting weight loss (mean decrease 11-lb 
compared to none in control group).(9) 
In order to assess outcomes of interest, we will employ validated non-invasive biomarkers to assess 
changes in hepatic steatosis and fibrosis. This includes VCTE, an ultrasound based test that can capture 
both amount of steatosis via controlled attenuation parameter (CAP) and fibrosis via liver stiffness 

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measurements. More recently, MRI based imaging tests, MR elastography (MRE) has been shown to have 
excellent accuracy for assessment of both fibrosis (elastography) and hepatic steatosis (via proton density 
fat fraction – PDFF). (10)  Lifestyle interventions in the general obesity literature and among NAFLD 
cohorts have been shown to have excellent safety profile with no to minimal adverse events, with primary 
concern being falls or other musculoskeletal related injuries.  
 
2.3 
RISK/BENEFIT ASSESSMENT  
2.3.1 KNOWN POTENTIAL RISKS  
The risks related to dietary changes and increase in physical activity are minimal, with overall systemic 
benefit improvements likely far outweighing any potential risks. So long as dietary restriction does not 
involve > 30% reduction in total caloric intake per day, risks to calorie restriction should be minimal. (11) 
Regarding physical activity, the overwhelming majority of individuals will be able to partake in a walking 
program with minimal to no risk. More vigorous exercise will be implemented based on baseline fitness 
and other factors that may impact potential to achieve higher METS. Potential, but unlikely risks include 
falls or other musculoskeletal injuries resulting from physical activity, or cardiac events among individuals 
with cardiac disease who engage in overly ambitious exercise regimens in an unsupervised setting. In 
terms of survey instruments, these risks are also minimal and rare, but include the potential for feelings 
of discomfort or anxiety related to answering personal questions. Participants will be able to opt out of 
answering questions that are discomforting to them. For participants completing MREs, there is a risk of 
feeling anxious or claustrophobic, transient changes in hearing due to clanging of the machine (rare), and 
risk related to indwelling metal that can be impacted by the machinery, but this will be addressed with 
proper screening. Lastly there is a risk of breach of confidentiality and privacy associated with being in the 
study, including potential breach of the FitBit app. 
2.3.2 KNOWN POTENTIAL BENEFITS  
Incorporating healthy eating and exercise has been demonstrated to improve HRQOL and multiple 
systemic metabolic diseases. (12) 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
The potential risks are minimal as outlined above and are far outweighed by possible benefits.  
 
3 
OBJECTIVES AND ENDPOINTS  
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Compare the effectiveness of usual 
care to a mobile technology based 
lifestyle intervention on change in 
liver and metabolic related 
parameters. 
 
Reduction in amount of hepatic steatosis 
(≥5% overall reduction in CAP score) at 6 
months.  
 
Hepatic steatosis is a liver 
specific outcome that has been 
shown to improve with diet and 
exercise and is associated with 
risk of downstream clinical 
outcome such as development 
of NASH and  cirrhosis. 
Secondary  
 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Improvements in other liver-specific 
and metabolic outcomes  
 
weight loss, increase in total physical 
activity (based on step counts) 
Weight 
loss 
has 
been 
associated 
with 
histologic 
improvements in NAFLD and 
NASH. Physical activity has been 
shown to improve fibrosis, liver 
enzymes, 
metabolic 
parameters and HRQOL.  
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This randomized clinical pilot trial will compare a mobile technology-based lifestyle intervention to a wait-
list control group receiving usual care for adult patients with NAFLD. The intervention will use FitBit to 
track and promote physical activity through tailored longitudinal feedback. Patient will also receive 
nutritional counseling with serial nutritional assessments. The primary endpoint will be change in amount 
of hepatic steatosis. Secondary outcomes include changes in weight and physical activity (assessed by 
trend in step counts). A wait-list control design will be applied. 60 Patients will be randomized to the 
intervention arm for 6 months and 60 to usual care (the wait-list control). Those initially randomized to 
the intervention arm will then transition to a 6-month post intervention monitoring period to assess 
maintenance of behavior change and sustainability of impact on outcomes of interest. Individuals initially 
randomized to usual care, will transition to the intervention at month 6 for a total of 6 months. 
 
The intervention arm will receive tailored physical activity and nutritional counseling, and the waitlist 
control arm which will follow usual and customary care for NAFLD patients attending our Heptology clinic 
for 6 months and then receive the 6-month intervention.    
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This trial will incorporate a wait-list control that will allow us to maximize our ability to assess the 
primary outcome (by using a pre-post intervention analysis). The 6-month post-intervention follow-up 
among those initially randomized to the intervention will allow us to assess maintenance of behavior 
change. 
4.3 
JUSTIFICATION FOR INTERVENTION 
Multiple studies in general obesity research and specifically among patients with NAFLD have shown 
that patients should aim to achieve ≥150 min/week of moderate intensity physical activity. For diet, the 
majority of studies have recommended a total caloric reduction of 30% in obese and overweight 
patients in order to achieve weight loss. We will track total amount of physical activity time and change 
in nutritional content as part of this intervention. 
4.4 
END-OF-STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 1.3. 

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The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial 
globally. 
5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
3. Age 18 or older 
4. Diagnosis of NAFLD or NASH based on:  liver biopsy (within past 24 months) or imaging 
[ultrasound (US), vibration controlled transient elastography (VCTE), cat scan (CT), or magnetic 
resonance imaging (MRI)] within past 24 months 
5. Ability to communicate in English as their primary language. 
6. Access to mobile phone/tablet/ or computer compatible with FitBit application and ability to use 
said device and application. 
7. Ability to participate in physical activity (reports ability to walk at least several blocks 
unassisted). 
 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Other causes of liver disease: Alcohol related liver disease (defined as an average 14 or more 
drinks per week in men and 7 or more drinks per week in women over the past 12 months); viral 
hepatitis, autoimmune liver disease, hereditary forms of liver disease, etc. 
2. Medications known to cause hepatic steatosis or other alternative causes of hepatic steatosis: 
mediations include steroids, tamoxifen, amiodarone, highly active anti-retroviral therapy 
(HAART), valproate, methotrexate. Other causes of hepatic steatosis include chronic total 
parenteral nutrition (TPN), severe rapid weight loss.  
3. Current or prior history of decompensated cirrhosis: variceal bleeding, ascites, hepatic 
encephalopathy, or hepatocellular carcinoma. 
4. Inability to make dietary modifications due to significant medical co-morbidity (including but not 
limited to severe, uncontrolled diabetes). 
5. Participation in a pharmacologic clinical trial for NAFLD/NASH. 
6. Plans for invasive procedures or other regimented lifestyle programs for weight reduction (i.e. 
bariatric surgery, other structured nutrition or exercise program such as University Metabolic 
Fitness Program, University of Michigan Medical Weight Loss Program, Weight Watchers, etc) 
7. Current use of weight reduction medications or supplements. 
8. Active substance abuse or psychiatric disease which limits patient’s ability to follow study 
protocol. 
9. Recent cardiovascular event (within last 3 months) including myocardial infarction, 
percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), cerebrovascular 

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accident (CVA), transient ischemic attack (TIA), severe cardiac valve disease, complex 
arrhythmias, class II-IV New York Heart Association (NYHA) heart failure 
10. Pregnancy based on self-report 
11. Individuals randomized to MRE cannot have non-MRI compatible metal in their body or severe 
claustrophobia. 
5.3 
LIFESTYLE CONSIDERATIONS 
 
During this study, participants will be asked to partake in the lifestyle intervention as outlined in detail in 
the study protocol.  They are to refrain from starting any of the following treatments while enrolled in 
the study: 
• 
Any new lifestyle or non-pharmacologic therapy for weight loss 
• 
Any new exercise program 
• 
Any medication or supplement for weight loss or appetite control 
 
Participants are asked to let the study team know about any new lifestyle or non-pharmacologic 
therapies started for other reasons, e.g. physical therapy for knee pain or osteoarthritis.  Likewise, 
participants should tell the study team about any new medications that might affect weight (e.g. 
metformin or some SSRIs, etc.) 
 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria.   
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a lack of 
biopsy or imaging evidence of NAFLD within the designated time frame may be rescreened. Rescreened 
participants should be assigned the same participant number as for the initial screening. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Potential participants will be identified through Data Direct, EMERSE or via screening of patients with 
NASH/NAFLD in our general hepatology clinics. Eligible participants will be recruited via phone, text or 
from our general hepatology clinics at the time of a routinely scheduled outpatient clinic appointment. 
Individuals who complete the entire study will receive $75, with $25 provided after the completion of 
each study visit and associated data collection for that visit.  
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
6.1 
STUDY INTERVENTION(S)  
 

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6.1.1 STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION 
This is a randomized trial comparing a structured mobile technology-based lifestyle intervention 
compared to usual care.  
 
Intervention 
-Education: Patients in the intervention arm will receive our NAFLD educational folder with an overview 
of contents by study staff. The folder includes: 1) NAFLD disease information including diagnosis, clinical 
manifestations, natural history and treatments; 2) NAFLD nutritional recommendations including sample 
menus; 3) NAFLD physical activity recommendations including walking programs and physical activity logs; 
4) weight tracking logs; and 5) resources for diet and exercise programs. 
 
-Physical Activity: All participants in the intervention arm (N=60) will receive a FitBit Zip for monitoring of 
step counts. The Fitbit wirelessly syncs data from the tracker to the Fitbit software or app. Study staff will 
assist with downloading the software and will instruct participants to wear their FitBit during waking hours 
every day.  At any time if the participant has questions or problems regarding the use of the FitBit, a study 
staff member can be contacted. Study staff will retrieve users’ step count data for analysis weekly and will 
provide subject with personalized feedback on physical activity with tailored step count goals (10% 
increase per week with max increase 800 steps per week to a maximum of 10,000 steps/week) and 
motivational messaging via e-mail. Patients with consecutive days without data recorded or with other 
signs of low FitBit usage (days with minimal step counts) will be contacted by study staff via e-mail or 
phone if necessary to encourage use. Feedback will occur weekly for the first 3 months of the intervention 
and then transition to biweekly for the last 3 months.  Participants will also complete the short-version 
IPAQ for physical activity at enrollment, 6 month and 12 month follow-up visits.  
 
-Nutrition: Patients in the intervention arm will have a nutritional assessment by a GI nutritionist 
specializing in NAFLD either at the enrollment visit if time allows, or in a separate in person or phone 
assessment within the first 2 weeks of enrollment. All patients will also complete the “Starting the 
Conversation” nutritional questionnaire for patients with metabolic disease at enrollment, 6 month and 
12 month follow-up visits.(15) 
 
Usual Care  
At our center, patients with NAFLD /NASH without decompensated cirrhosis are seen every 6-12 months. 
Visits are approximately 15-20 minutes and consist of review of BMI/weight, recent hepatic panel and 
Fibroscan if ordered. Management typically consists of a breif overview of lifestyle changes including 
improvements in nutrition and physical actiity. Vitamin E is prescribed In a small proportion of patients. A 
similarly small proportion of patients are formally referred to and subsequently evaluated by a 
nutritionist. 
 
6.2 
FIDELITY 
 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
The dieticians are RDs with specific expertise in caring for patients with liver disease. Study staff will be 
trained on how to provide tailored feedback on physical activity (step count goals). They had 
demonstrated proficiency in following standard procedures.  

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6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Participants in this trial will be randomized to either the intervention arm (tailored physical activity and 
nutritional counseling) or a wait-list control arm that receives usual care for 6 months, after which they 
will receive the intervention (for 6 months).  Neither participants nor interventionists are blinded to 
study arm.   
6.4 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
 
Adherence will be assessed by the following: 
-Completion of all study visits and data collection elements 
-Percentage of days with valid FitBit data (>300 steps per day as defined in behavioral health literature). 
Step count data will be assessed weekly for each participant.  
6.5 
CONCOMITANT THERAPY 
Participants can continue any treatments that are not listed as part of the exclusion criteria for this 
study.  
 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
Discontinuation from study intervention does not mean discontinuation from the study, and remaining 
study procedures should be completed as indicated by the study protocol.  If a clinically significant 
finding is identified (including, but not limited to changes from baseline) after enrollment, the 
investigator or qualified designee will determine if any change in participant management is needed. 
Any new clinically relevant finding will be reported as an adverse event (AE). 
 
The minimum data to be collected at the time of study intervention discontinuation will include the 
following: 
• 
Weight and anthropometrics, laboratory studies, HRQOL and VCTE if possible.  
• 
Download of all available Fitbit data 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
• 
Pregnancy 
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
Disease progression which requires discontinuation of the study intervention 

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• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant unable to receive study intervention for 30 days/4 weeks 
• 
Start of new therapy/program that is not allowed while enrolled in this study 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
appropriate CRF. Subjects who sign the informed consent form and are randomized but do not receive 
the study intervention may be replaced.  Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, or are withdrawn or 
discontinued from the study, will not be replaced. 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for 1 scheduled study visit 
and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The study team will attempt to contact the participant and reschedule the missed visit within 2 
weeks and counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the study team will make every effort to 
contact with the participant (where possible, 3 telephone calls, emails or text messages). These 
contact attempts should be documented in the participant’s research record.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
-Baseline & Outcome Assessments 
1) Demographics and Medical History: alcohol use, components of metabolic syndrome, diabetes, thyroid 
disease, depression, cirrhosis, NAFLD vs NASH. 
2) Physiologic Measures: blood pressure, weight, BMI, waist circumference, waist to hip ratio  
3) Physical Function and Frailty Measures: 6 Minute Walk Test (6MWT) to assess baseline physical 
function (validated among patients with chronic liver disease)(13) and hand grip strength;(14) 
4) HRQOL and Stages of Change: CLDQ-NAFLD for HRQOL and the validated motivation to change 
behavior questionnare.(16)  
5) Laboratory studies: hepatic panel, platelet count, lipid panel, glucose and hemoglobin A1c (abstracted 
if obtained within the last 6 months; otherwise ordered at time of clinic visit). If laboratory studies are 
ordered for study purposes, blood for hepatic panel, lipid panel and glucose will be obtianed in 1 serum 
separator tube (SST) (3mL). One lavender tube will be used to collect specimen for platelet count (3mL), 
and another 1 lavender tube will be used for hemoglobin A1c. The total amount of blood drawn from 
patients will not exceed 20 mL, and will be kept within the IRB restrictions. 
6) Hepatic Imaging: all patients will complete a fibroscan to assess liver stiffness and CAP measurements 
unless performed within prior 6 months. Historical results for prior testing will only be used if patients had 
not had >5% weight loss in prior 12 months. Due to cost limitations, a total 50 patients will have MRE with 

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PDFF. MRE exams will be evenly assigned by computer randomization with stratification according to liver 
stage (cirrhosis, no cirrhosis) and subcategory (NAFLD vs NASH) in each arm.  
 
Phone Call: Patients receiving the intervention will receive a phone call to review baseline data results 
after 3 months of intervention. They will also complete a second nutritional questionnaire. Patients will 
also be given detailed feedback and recommendations on step counts and nutrition thus far. 
 
8.2 
SAFETY ASSESSMENTS 
 
In order to screen for potential study participants, our clinical research staff with review the electronic 
health record (EHR) in compliance with HIPPAA protocol.  
 
Individuals enrolled in the study will complete the following procedures/evaluations to monitor clinical 
status and occurrence of adverse events: 
• 
Physical examination:  weight, waist and hip circumference.  
• 
Vital signs: blood pressure  
• 
Radiographic or other imaging assessments: VCTE and MRE 
• 
Biological specimen collection and laboratory evaluations: Platelet count, hepatic panel, lipid 
panel (fasting), hemoglobin A1c, fasting insulin 
• 
Assessment of adverse events:  to be assessed at 3-month phone call, 6 and month follow-up 
visits. Patients will also be asked to self-report AEs of interest (with focus on falls and other 
activity-related musculoskeletal injuries) during weekly eHealth communications. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of the PI, it 
results in any of the following outcomes: death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the participant and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 

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The following guidelines will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
All AEs must have their relationship to study intervention assessed by the PI.  She will evaluate the event 
based on temporal relationship of the event to the study intervention or research procedures, and her 
clinical judgment. The degree of certainty about causality will be graded using the categories below.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
results, occurs in a plausible time relationship to participation in the study intervention and 
cannot be explained by other factors (e.g. concurrent disease, other treatments or activities or 
action).  
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The event occurs within a reasonable time relative to participation in the 
study intervention, is unlikely to be attributed to concurrent disease or other factors. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time relative to participation in the study intervention).  However, 
other factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event whose temporal relationship to participation in the 
study intervention makes a causal relationship improbable (e.g., the event did not occur within a 
reasonable time after administration of the study intervention) and in which underlying disease 
or other factors provide a plausible explanation for the event occurrence. 
• 
Not Related – The event is completely independent of the study intervention, and/or evidence 
exists that the event is definitely related to another reason.  
 
8.3.3.3 EXPECTEDNESS  
The primary investigator will be responsible for determining whether an AE is expected or unexpected.  
An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information previously described for the study intervention. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an AE or SAE may come to the attention of the study team during study visits and 
routine study participant contact throughout their participation in the study. 

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All AEs including (including SAEs) will be captured on the appropriate CRF. Information to be collected 
includes event description, date of onset, PI’s assessment of severity, relationship to study intervention, 
and time of resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition related to their 
NAFLD/NASH deteriorates at any time during the study, it will be recorded as an AE. Changes in 
condition in unrelated medical issues with be documented but not reported. 
 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events 
will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
Adverse event reporting will follow the protocol outlined above. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
The 
PI 
will 
follow 
the 
IRBMED 
standard 
reporting 
schedule 
for 
SAEs 
(https://az.research.umich.edu/medschool/guidance/adverse-event-reporting). We will report any 
serious adverse event considered study intervention related.  
 
All SAEs will be followed until satisfactory resolution or until the PI deems the event to be chronic or the 
participant is stable.  
 
8.3.7 REPORTING OF PREGNANCY  
If participant becomes pregnant during study period, participation will end at that time. 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the protocol and informed consent 
document; and (b) the characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 

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For guidance on Michigan Medicine UaP guidelines, refer to 
https://az.research.umich.edu/medschool/guidance/adverse-events-aes-other-reportable-information-
and-occurrences-orios-other . 
 
8.4.2  UNANTICIPATED PROBLEMS REPORTING  
 The investigator will report unanticipated problems (UaP) to IRBMED 
(https://az.research.umich.edu/medschool/guidance/adverse-events-aes-other-reportable-information-
and-occurrences-orios-other) and will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the HUM number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to IRBMED according to the standard 
reporting schedule (within 7-14 days depending on whether it’s life threatening serious event vs. 
other serious adverse event: https://az.research.umich.edu/medschool/guidance/adverse-
event-reporting)  
• 
Any other UP will be reported to IRBMED within 14 days of the investigator becoming aware of 
the problem.  
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Any UaP that results in a change to the study design, procedures or risks will be addressed as necessary 
in an amended consent document.  Participants will be asked sign the new consent document as indicated.   
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
Primary Efficacy Endpoint:  
We hypothesize that participants who complete the lifestyle intervention (as defined by completing the 
6 month return visit and data collection) will achieve reduction in amount of hepatic steatosis ( ≥5% 
reduction in CAP), with those achieving higher percentage weight loss having larger reductions in 
amount of steatosis.  
 
Secondary Efficacy Endpoints: 
We hypothesize that subjects in the intervention arm will be more likely to achieve weight loss and 
increase their level of physical activity at 6-month compared to usual care.  
 

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9.2 
SAMPLE SIZE DETERMINATION 
Sample size calculations will be made based on the total N for the cohort. Enrollment of 120 patients in 
the intervention should provide adequate power to assess for parameters associated with ≥5% 
reduction in steatosis and weight loss using 80% power, alpha 0.05. We anticipate a dropout rate of up 
to 20%.  
 
9.3 
STATISTICAL ANALYSES 
 
9.3.1 GENERAL APPROACH 
Categorical data will be presented as percentages. Continuous data will be presented as medians with 
interquartile range. 
 
For inferential tests, the p-value of 0.05 will be considered significant; 95% confidence intervals for 
statistical significance (Type I error) and two-tailed tests will be used. 
 
Nonparametric tests will be used to analyzed any non-normative data.  
 
9.3.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
The primary outcome is change in steatosis. This will be assessed by VCTE controlled attenuation 
parameter (CAP).  A ≥5% reduction in CAP score at 6-months and maintenance at 12 months as this has 
been associated with clinically meaningful improvements in outcomes.   
 
For individuals with missing data (participants who do not complete follow-up imaging), we will analyze 
as modified intention to treat and a separate analysis among those who completed all data collection 
elements. 
 
Subjects will be analyzed according to a modified intention to treat analysis. Individuals who were 
randomized but never provided FitBit data will not be included in the final analysis 
 
9.3.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Analysis of secondary endpoints are not dependent on findings of primary endpoint.  
 
-% weight loss: at month 6 
-Physical activity: ≥10% increase in total minutes/week of physical activity based on IPAQ at month 6 
 
9.3.4 SAFETY ANALYSES 
A summary statistic of any adverse events will be provided.  
 
9.3.5 BASELINE DESCRIPTIVE STATISTICS 
Baseline descriptive statistics of demographics, clinical characteristics, laboratory and imaging tests will 
be performed. 

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9.3.6 SUB-GROUP ANALYSES 
The primary endpoint will also be analyzed according to presence of NASH and cirrhosis.  
 
9.3.7 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Individual patient data will be listed by measure and time point to allow for a pre-post comparison.  
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT 
AND 
OTHER 
INFORMATIONAL 
DOCUMENTS 
PROVIDED 
TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.   
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Consent forms will be IRBMED-approved 
and the participant will be asked to read and review the document. The study team will explain the 
research study to the participant and answer any questions that may arise. A verbal explanation will be 
provided in terms suited to the participant’s comprehension of the purposes, procedures, and potential 
risks of the study and of their rights as research participants.  Participants will have the opportunity to 
carefully review the written consent form and ask questions prior to signing. The participants should have 
the opportunity to discuss the study with their family or others, or think about it prior to agreeing to 
participate. The participant will sign the informed consent document prior to any procedures being done 
specifically for the study. Participants must be informed that participation is voluntary and that they may 
withdraw from the study at any time, without prejudice. A copy of the informed consent document will 
be given to the participants for their records. The rights and welfare of the participants will be protected 
by emphasizing to them that the quality of their medical care will not be adversely affected if they decline 
to participate in this study. 
 
10.1.2 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the study team. This confidentiality is 
extended to cover all lab tests and study procedures, and study interactions.  Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. No 

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information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor and/or consent of the participant.  
 
All research activities will be conducted in as private a setting as possible. 
 
Authorized representatives of the sponsor, representatives of IRBMED and other regulatory committees 
may inspect all documents and records required to be maintained by the investigator, including but not 
limited to, research and medical records (office, clinic, or hospital) for the participants in this study.  
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by our eResearch application and IRBMED. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at Michigan Medicine.  Participant contact information and study data will 
be maintaind in a HIPAA compliant study database (REDCap).  Individual research records will be identified 
by a unique study identification number. The study data entry and study management systems used by 
research staff will be secured and password protected. After publication of the primary manuscript, all 
study databases will be de-identified and archived at University of Michigan. 
 
10.1.3 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored at the University of Michigan.  After the study is 
completed, the de-identified, archived data will be stored at the University of Michigan for use by the 
research team. Permission to store data will be included in the informed consent.  
 
 
10.1.4 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Monica Konerman , MD MSc, 
Clinical Lecturer 
University of Michigan  
1500 E. Medical Center Drive 
Ann Arbor, MI 48109 
734-936-4000 
Konerman@med.umich.edu 
 
10.1.5 QUALITY ASSURANCE AND QUALITY CONTROL 
We will perform internal quality management of study conduct and data.  An individualized quality 
management plan will be developed to describe a site’s quality management. 
 

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Quality control procedures will be implemented beginning with the data entry system and data QC checks 
that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the PI for clarification/resolution. 
• 
The study team will self-monitor for data integrity 
• 
Regular data audits will occur throughout each year of the project, roughly once a quarter 
• 
The REDCap database will be configured with data validation rules 
 
10.1.6 DATA HANDLING AND RECORD KEEPING  
 
10.1.6.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the study staff under the supervision of the PI who is ultimately 
responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. 
 
All study documents should be completed in a neat, legible manner to ensure accurate interpretation of 
data.   
 
Hardcopy CRFs will be filed in individual study records and electronic data capture will occur within the 
REDCap database (a 21 CFR Part 11-compliant data capture system).  All study data whether captured on 
a paper CRF or electronically will stored in the study database.  It uses the same login credentials as the 
EMR, and is password protected.  We will incorporate internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered 
directly from the EMR, study CRFs or other sources. 
 
10.1.7 PROTOCOL DEVIATIONS   
A protocol deviation is any noncompliance with the study protocol. The noncompliance may be either on 
the part of the participant or the study team.  Protocol deviations can be inadvertent (i.e. participant 
forgot to fill out a survey so data is missing) or deliberate (e.g. study team elected not to do 6MW because 
participant reports not being up to the task). 
 
Deviations related to increased participant risk or major impact on data integrity be reported to IRBMED.       
 
It is the responsibility of the study team and PI to follow the protocol and document deviations.  Reporting 
of protocol deviations within 7-14 days (https://az.research.umich.edu/medschool/guidance/protocol-
deviations-exceptions-violations).   
 
 

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ABBREVIATIONS AND SPECIAL TERMS 
 
AE 
Adverse Event 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
HIPAA 
Health Insurance Portability and Accountability Act  
ICMJE 
International Committee of Medical Journal Editors 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intention-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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10.2 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
2.0 
10-31-2019 
Change of Principal Investigator’s name 
N/A 
2.0 
10-31-2019 
Extended the time frame in which the 
VCTE can be done up to 14 days from 
enrollment date. 
 
If not enough time during enrollment, 
participants will be sent a link via email 
to complete the surveys within 14 days 
from enrollment date. 
Extending the time frame in which 
participants can have the VCTE up 
to two weeks from their enrollment 
into the study will make 
participation in the study more 
convenient for subjects by 
shortening the length of the visit. 
Additionally, in the instances 
where VCTE is not available on the 
days or times subjects are enrolled 
into our study, this will give us the 
flexibility to schedule them in for a 
different day. 
 
Allowing participants to complete 
the surveys online will help 
increase efficiency and speed of 
enrollment. 
 
 

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