Clinical trial NCT03467217
Conditions: NAFLD - Nonalcoholic Fatty Liver Disease
Keywords: Losartan Nonalcoholic Fatty Liver Disease
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Start date: 2018-10-02; Completion date: 2020-06-30
Enrollment: 83 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A multicenter, randomized, double masked, placebo-controlled, parallel treatment groups phase 2 trial of losartan for pediatric nonalcoholic fatty liver disease (NAFLD).

Detailed description:
Children ages 8-17 years weighing between 70 -149 kilograms will be enrolled and treated with losartan (100 mg orally once per day) or matching placebo for 24 weeks. The hypothesis is that losartan will improve serum alanine aminotransferase (ALT) in children with pediatric NAFLD.

Arms: arm 1: Dose will be one 50 mg capsule of losartan per day for one week and then increased to two capsules of 50 mg of losartan per day (100 mg total) for 23 weeks patients with baseline weight ≥ 70 kg to \<150 kg. arm 2: Dose will be one 50 mg capsule of placebo losartan per day for one week and then increased to two capsules of 50 mg of placebo losartan per day (100 mg total) for 23 weeks for patients with baseline weight ≥ 70 kg to \<150 kg.
Interventions: intervention 1: Losartan potassium intervention 2: Placebo losartan capsule
Intervention descriptions: intervention 1: Losartan potassium is an angiotensin II receptor blocker acting on the AT 1 receptor subtype intervention 2: Matching placebo losartan oral capsule

Protocol documents:
ICF_002.pdf: 
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STOP-NAFLD.ChildAssent_21May18
National Institutes of Health (NIH) 
Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) 
ASSENT FORM FOR STUDIES INVOLVING CHILDREN 
 
Study Title: Losartan for the Treatment of Pediatric NAFLD (STOP-NAFLD): A Phase 2, 
Randomized, Placebo-Controlled Clinical Trial 
 
Principal Investigator:   
IRB No.:   
PI Version Date:  21 May 2018 
 
Purpose of the study 
 
We want to tell you about a research study we are doing. Research allows us to collect 
information from people to help us answer questions about health.  We would like to find out 
more about testing a treatment for a liver problem in children called Nonalcoholic Fatty Liver 
Disease (NAFLD).  Your liver is an organ, inside your body near the stomach area. This problem 
happens when too much fat stays in parts of your liver.   
 
Why you are being asked to join the study 
You have been asked to join because you have this liver problem.  The reason for this study is 
see if a medicine called losartan will make this liver problem better.  We hope to include about 
110 other children like you in this study. 
 
Procedures 
If you agree to join this research study, you will be asked to make 7 visits to this research 
center over the next 10 months.  At these visits you will do the following: 
ͻŶƐǁĞƌƋƵĞƐƚŝŽŶƐĂďŽƵƚǇŽƵƌŚĞĂůƚŚĂŶĚĨĞĞůŝŶŐƐ͘ 
ͻ,ĂǀĞĂƉŚǇƐŝĐĂůĞǆĂŵŝŶĂƚŝŽŶƚŽĐŚĞĐŬǇŽƵƌďŽĚǇŝŶĐůƵĚŝŶŐǇŽƵƌůŝǀĞƌ͘ 
ͻ&ŝůůŽƵƚĨŽƌŵƐĂďŽƵƚǁŚĂƚǇŽƵdrink, how you feel about your life, and how you are 
feeling.  
ͻdĂŬĞone capsule of medication each morning for one week, then take two capsules of 
medication or “sugar pills” (called a placebo) for this study once a day for 24 weeks. 
There is a 50/50 chance of getting the placebo. 
ͻ>ŝƐƚĞŶƚŽĂĚǀŝĐĞĂďŽƵƚŶƵƚƌŝƚŝŽŶĂŶĚĞǆĞƌĐŝƐĞĂŶĚĂƐŬƋƵĞƐƚŝŽŶƐŝĨǇŽƵŚĂǀĞĂŶǇ͘ 
ͻ'ŝǀĞďůŽŽĚƐĂŵƉůĞƐ͘ 
 
 
 


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STOP-NAFLD.ChildAssent_21May18
Risks 
There are some risks to being in the study: 
Blood draw: 
You will feel a pinch from the needle when you get your blood drawn and you may get a bruise 
where the needle was poked into your arm. 
 
Study medication (losartan potassium): 
The study medication may cause you to:  
x
have low blood pressure; 
x
feel dizzy; 
x
have a headache; 
x
have a fast heartbeat; 
x
feel anxiety;  
x
have a runny nose; 
x
have a sore throat;  
x
have to urinate more often 
 
Risk to a baby:  
There are risks to an unborn baby if you become pregnant during the STOP-NAFLD Trial. Use of 
the study drug losartan during pregnancy can cause injury and death to the developing baby. 
Potential negative effects to the baby include incomplete development of the skull and lungs 
(skull and lung hypoplasia), the baby’s kidneys do not make urine (anuria), low blood pressure 
(hypotension), kidney failure, and death. If you decides to take part in this study, and have 
periods, you must be as sure as possible that you are not pregnant. It is important that you 
contact the study doctor right away if you think you may be pregnant, if you have missed a 
period or if it is late, or if you have had a change such as heavier bleeding than usual or 
bleeding between periods. If you become pregnant during the study, you will stop taking the 
study drug. 
 
Benefits  
We do not know if being in this study will help you, but we hope to learn something that will 
help other children with liver disease.  
 
Voluntary participation 
You do not have to join this study. It is up to you.  You can say okay now, and you can change 
your mind later.  All you have to do is tell us. No one will be mad at you if you change your 
mind.  
 
 


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STOP-NAFLD.ChildAssent_21May18
Do you have any questions? 
 
 
If you want to be in this study, please sign your name. You will get a copy of this form to keep 
for yourself. 
 
_________________________________________               ____________________________                                
              (Sign your name here) 
 
 
 
 
 
 (Date) 
 
_________________________________________               ____________________________                                
         (Signature of Person Obtaining Assent)  
 
 
       
(Date)

Prot_SAP_000.pdf: 
Losartan for the Treatment of Pediatric NAFLD (STOP-
NAFLD):  A Phase 2, Randomized, Placebo-Controlled 
Clinical Trial  
 
Protocol Number: 9 
IND# 139098 
National Clinical Trial (NCT) Identified Number:  NCT03467217 
Principal Investigators: Miriam B. Vos and Joel Lavine 
IND Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)   
Funded by: NIDDK Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) 
FDA Version Number:  1.3 
18 February 2019 
Summary of Changes from Previous Version: 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
Section 1.1, 
Synopsis: 
Changed HbA1c time window to 60 days  
Changed to allow 60-day time window for all 
laboratory measurements except ALT. 
Section 1.3, Data 
Collection Schedule  
Removed Focused Physical Examination from the 
data collection at the randomization visit.  
A brief physical is required to determine if 
the patient is well on the day of 
randomization, but the Focused Physical 
Examination form is not completed. 
Section 8.1.2, 
Screening Visits: 
Protocol text changed to allow 60-day time 
window for all laboratory measurements except 
ALT 
 
ALT measurement must be completed within 
30 days of randomization; additional lab tests 
for screening must be completed within 60 
days of randomization 
Section 12.3, Blood 
Collection 
Schedule: 
CBC + WBC and uric acid added to blood 
collection at the f36 visit, to align with the Data 
Collection Schedule and visit procedures specified 
in the protocol. 
The total blood volume collected at f36 
corrected from 35mL to 42mL. 
 
 


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STOP-NAFLD Protocol Version 1.3 
ii 
 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................ 4 
1 
PROTOCOL SUMMARY .............................................................................................................................. 4 
1.1 
Synopsis ............................................................................................................................................... 4 
1.2 
Schema ................................................................................................................................................ 8 
1.3 
Schedule of Activities (SoA) .............................................................................................................. 9 
2 
INTRODUCTION ......................................................................................................................................... 10 
2.1 
Study Rationale ................................................................................................................................. 10 
2.1.1 
Definitions ....................................................................................................................... 10 
2.1.2 
Significance of NAFLD ................................................................................................. 10 
2.1.3 
Pathogenesis of NASH ................................................................................................. 11 
2.1.4 
Limitations of Current Treatment of NAFLD .............................................................. 12 
2.2 
Background ........................................................................................................................................ 14 
2.3 
Risk/Benefit Assessment ................................................................................................................. 20 
2.3.1 
Known Potential Risks .................................................................................................. 20 
2.3.2 
Known Potential Benefits ............................................................................................. 20 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................. 20 
3 
OBJECTIVES AND OUTCOMES.............................................................................................................. 22 
4 
STUDY DESIGN .......................................................................................................................................... 23 
4.1 
Overall Design ................................................................................................................................... 23 
4.2 
Scientific Rationale for Study Design ............................................................................................. 23 
4.3 
Justification for Dose ........................................................................................................................ 24 
4.4 
End of Study Definition ..................................................................................................................... 25 
5 
STUDY POPULATION ................................................................................................................................ 25 
5.1 
Inclusion Criteria ............................................................................................................................... 25 
5.2 
Exclusion Criteria .............................................................................................................................. 25 
5.3 
Lifestyle Considerations ................................................................................................................... 26 
5.3.1 
Standard treatment recommendations ....................................................................... 26 
5.4 
Screen Failures ................................................................................................................................. 27 
5.5 
Strategies for Recruitment and Retention ..................................................................................... 28 
5.5.1 
Recruitment .................................................................................................................... 28 
6 
STUDY INTERVENTION ............................................................................................................................ 28 
6.1 
Study Intervention(s) Administration .............................................................................................. 28 
6.1.1 
Study Intervention Description From FDA Package INsert ..................................... 28 
6.1.2 
Dosing and Administration ........................................................................................... 34 
6.2 
Preparation/Handling/Storage/Accountability ............................................................................... 35 
6.2.1 
Acquisition and accountability ..................................................................................... 35 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................... 35 
6.2.3 
Product Storage and Stability ...................................................................................... 35 
6.2.4 
Preparation ..................................................................................................................... 35 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................................... 36 
6.4 
Study Intervention Compliance ....................................................................................................... 36 
6.5 
Concomitant Therapy ....................................................................................................................... 37 
6.5.1 
Rescue Medicine ........................................................................................................... 37 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL 37 


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7.1 
Discontinuation of Study Intervention ............................................................................................ 37 
7.2 
Participant Discontinuation/Withdrawal from the Study .............................................................. 39 
7.3 
Lost to Follow-Up .............................................................................................................................. 39 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 39 
8.1 
Efficacy Assessments ...................................................................................................................... 39 
8.1.1 
Visit schedule overview ................................................................................................ 39 
8.1.2 
Screening and baseline data collection ..................................................................... 40 
8.1.3 
Randomization visit ....................................................................................................... 41 
8.1.4 
Follow-up visits .............................................................................................................. 42 
8.1.5 
Standardized questionnaires ....................................................................................... 43 
8.2 
Safety and Other Assessments ...................................................................................................... 44 
8.3 
Adverse Events and Serious Adverse Events .............................................................................. 44 
8.3.1 
Definition of Adverse Events (AE) .............................................................................. 45 
8.3.2 
Definition of Serious Adverse Events (SAE) ............................................................. 45 
8.3.3 
Classification of an Adverse Event ............................................................................. 45 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................... 46 
8.3.5 
Adverse Event Reporting ............................................................................................. 46 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 47 
8.3.7 
Reporting Events to Participants ................................................................................. 47 
8.3.8 
Events of Special Interest ............................................................................................ 47 
8.3.9 
Reporting of Pregnancy ................................................................................................ 47 
8.4 
Unanticipated Problems ................................................................................................................... 47 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................ 47 
8.4.2 
Unanticipated Problem Reporting ............................................................................... 48 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 48 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 48 
9.1 
Statistical Hypotheses ...................................................................................................................... 48 
9.2 
Sample Size Determination ............................................................................................................. 49 
9.3 
Populations for Analyses ................................................................................................................. 50 
9.4 
Statistical Analyses ........................................................................................................................... 50 
9.4.1 
General Approach ......................................................................................................... 50 
9.4.2 
Analysis of the Primary Efficacy OUTCOME(s) ........................................................ 50 
9.4.3 
Analysis of the Secondary OUTCOME(s) ................................................................. 50 
9.4.4 
Safety Analyses ............................................................................................................. 50 
9.4.5 
Baseline Descriptive Statistics .................................................................................... 51 
9.4.6 
Planned Interim Analyses ............................................................................................ 51 
9.4.7 
Sub-Group Analyses ..................................................................................................... 51 
9.4.8 
Tabulation of Individual participant Data .................................................................... 51 
9.4.9 
Exploratory Analyses .................................................................................................... 51 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 52 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .......................................................... 52 
10.1.1 
Informed Consent Process .......................................................................................... 52 
10.1.2 
Study Discontinuation and Closure............................................................................. 53 
10.1.3 
Confidentiality and Privacy ........................................................................................... 53 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 54 
10.1.5 
Key Roles and Study Governance .............................................................................. 54 
10.1.6 
Safety Oversight: Data and Safety MOnitoring BOard ............................................ 54 
10.1.7 
Clinical Monitoring ......................................................................................................... 55 


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10.1.8 
Quality Assurance and Quality Control ...................................................................... 56 
10.1.9 
Data Handling and Record Keeping ........................................................................... 56 
10.1.10 
Protocol Deviations ....................................................................................................... 57 
10.1.11 
Publication and Data Sharing Policy .......................................................................... 57 
10.1.12 
Conflict of Interest Policy .............................................................................................. 58 
10.2 
Additional Considerations ................................................................................................................ 58 
10.3 
Abbreviations ..................................................................................................................................... 58 
10.4 
Protocol Amendment History .......................................................................................................... 61 
11 
REFERENCES ............................................................................................................................................. 62 
12 
APPENDIX .................................................................................................................................................... 68 
12.1 
Participating Centers ........................................................................................................................ 68 
12.2 
Blood collection schedule (amounts in mL) .................................................................................. 69 
 
 
 


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STATEMENT OF COMPLIANCE 
 
(1) The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical Practice 
(ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR 
Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for the 
conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects Protection and 
ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to 
the Institutional Review Board (IRB) for review and approval.  Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will require review 
and approval by the IRB before the changes are implemented to the study.  In addition, all changes to the 
consent form will be IRB-approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent using a previously approved consent form. 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Losartan for the treatment of Pediatric NAFLD (STOP-NAFLD): A Phase 2, 
Randomized, Placebo-Controlled Clinical Trial  
Study Description: 
This is a multicenter, randomized, double masked, placebo-controlled, 
parallel treatment groups phase 2 trial of losartan for pediatric NAFLD. 
Children ages 8-17 years will be enrolled for 24 weeks and treated with 
losartan (100 mg orally once per day) or matching placebo.  The primary 
outcome of the study is improvement in alanine aminotransferase (ALT) 
from baseline to 24 weeks.  The hypothesis is that losartan will improve 
ALT in children with pediatric NAFLD.   
 
Objectives: 
 
Primary Objective:  To determine whether 24 weeks of treatment with 
losartan compared to treatment with placebo improves measures of 
nonalcoholic fatty liver disease (NAFLD) as determined by improvement in 
serum ALT from baseline. 
 
 
 
Secondary Objectives:  To determine safety of losartan in children with 
pediatric NAFLD over 24 weeks and to measure other biomarkers of 
response to losartan.   
 
Outcomes: 
Primary Outcome Measure:  
• 
Change in serum alanine aminotransferase (ALT) from baseline to 
24 weeks.  
 
• 
Secondary outcome measures (24 weeks of treatment with losartan 


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compared to treatment with placebo): 
o Relative change in ALT at 24 weeks compared to baseline ALT 
o Proportion of patients achieving normalization of ALT at 24 
weeks  
o Change in serum aspartate aminotransferase (AST) at 24 
weeks compared to baseline AST 
o Change in gamma-glutamyl transpeptidase (GGT) at 24 weeks 
compared to baseline GGT 
o Change in ALT at 12 weeks compared to baseline ALT 
o Change in Homeostatic Model Assessment of Insulin 
Resistance (HOMA-IR) at 24 weeks compared to baseline. 
o Change in anthropometric measurements (weight, waist to hip 
ratio, waist circumference) and BMI z-score at 24 weeks 
compared to baseline 
o Change in serum lipid profiles at 24 weeks compared to 
baseline 
o Change in C-reactive protein (serum marker of inflammation), 
from screening to 24 weeks 
o Change in Pediatric Quality of Life (Ped-QoL) scores at 24 
weeks compared to baseline 
o Change in frequency of adverse events compared to baseline 
 
Exploratory: 
• 
Change in peripheral proinflammatory cytokine levels (including IL-
6, TNF, TGF-beta) from baseline to 24 weeks  
• 
Change in NMR MetaboProfile Analysis (LP4) from baseline to 24 
weeks. 
 
Study Population: 
The study population will be 110 children ages 8-17 years with a history of 
biopsy-proven NAFLD, boys and girls, located in the United States.   
 
Phase: 
Phase 2 
 
Description of 
Sites/Facilities Enrolling 
Participants: 
Participants will be enrolled at 10 pediatric NASH CRN sites located 
throughout the United States.   
 
Description of Study 
Intervention: 
 
The dose for patients with baseline weight ≥ 70 kg to <150 kg will be one 
50 mg capsule of losartan or matching placebo per day for one week, then 
two capsules of 50 mg of losartan or matching placebo per day (100 mg 
total) for weeks 2-24. This dosing scheme is based on the recommended 
starting dose of 0.7 mg/kg/day and the maximum dose of 1.4 mg/kg/day. 
 
Total Study Duration: 
• 
Recruitment phase: 12 months  
 
• 
Follow-up phase: 24 months  


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• 
Expected rate of recruitment is 11 per clinical center; approximately 1 
per month  
 
 
Participant Duration: 
• 
Screening phase is 60 days; randomization must occur within 730 days 
of liver biopsy.  
• 
24-week treatment period; 12-week post–treatment follow-up; 
• 
10 months total 
 
 
Inclusion Criteria: 
 
• 
Age 8-17 years at initial screening interview 
• 
Histological evidence of NAFLD with or without fibrosis and a NAFLD 
activity score (NAS) of ≥3, on a liver biopsy obtained no more than 730 
days prior to enrollment  
• 
Serum ALT at screening ≥ 50 IU/L 
 
Exclusion Criteria: 
 
• 
Body weight less than 70 kg or greater than 150 kg at screening 
• 
Significant alcohol consumption or inability to reliably quantify alcohol 
intake 
• 
Use of drugs historically associated with NAFLD (amiodarone, 
methotrexate, systemic glucocorticoids, tetracyclines, tamoxifen, 
estrogens at doses greater than those used for hormone replacement, 
anabolic steroids, valproic acid, other known hepatotoxins) for more 
than 2 consecutive weeks in the past year prior to randomization 
• 
New treatment with vitamin E or metformin started in the past 90 
days or plans to alter the dose or stop over the next the 24 weeks.  A 
stable dose is acceptable.     
• 
Prior or planned bariatric surgery 
• 
Uncontrolled diabetes (HbA1c 9.5% or higher within 60 days prior to 
enrollment) 
• 
Presence of cirrhosis on liver biopsy 
• 
History of hypotension or history of orthostatic hypotension  
• 
Stage 2 Hypertension or >140 systolic or >90 diastolic at screening 
• 
Current treatment with any antihypertensive medications including all 
angiotensin converting enzyme (ACE) inhibitors or aliskiren; 
• 
Current treatment with potassium supplements or any drug known to 
increase potassium 
• 
Current daily use of nonsteroidal anti-inflammatory drugs (NSAIDs) 
• 
Current treatment with lithium  
• 
Platelet counts below 100,000 /mm3 
• 
Clinical evidence of hepatic decompensation (serum albumin < 3.2 
g/dL, international normalized ratio (INR) >1.3, direct bilirubin >1.3 
mg/dL, history of esophageal varices, ascites, or hepatic 
encephalopathy) 
• 
Evidence of chronic liver disease other than NAFLD: 
- 
Biopsy consistent with histological evidence of autoimmune 
hepatitis 
- 
Serum hepatitis B surface antigen (HBsAg) positive. 
- 
Serum hepatitis C antibody (anti-HCV) positive. 
- 
Iron/total iron binding capacity (TIBC) ratio (transferrin saturation) 
> 45% with histological evidence of iron overload 


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- 
Alpha-1-antitrypsin (A1AT) phenotype/genotype ZZ or SZ 
- 
Wilson’s disease   
• 
Serum alanine aminotransferase (ALT) greater than 300 IU/L 
• 
History of biliary diversion 
• 
History of kidney disease and/or estimated glomerular filtration rate 
(eGFR) < than 60 mL/min/1.73 m2  using Schwartz Bedside GFR 
Calculator for Children isotope dilution mass spectroscopy (IDMS)-
traceable 
• 
Known Human Immunodeficiency Virus (HIV) infection 
• 
Active, serious medical disease with life expectancy less than 5 years  
• 
Active substance abuse including inhaled or injected drugs, in the year 
prior to screening 
• 
Pregnancy, planned pregnancy, potential for pregnancy and 
unwillingness to use effective birth control during the trial, breast 
feeding 
• 
Participation in any clinical/investigational trial within the prior 150 
days and during the STOP-NAFLD Trial. 
• 
Any other condition which, in the opinion of the investigator, would 
impede compliance or hinder completion of the study 
• 
Inability to swallow capsules 
• 
Known allergy to losartan potassium or other angiotensin receptor 
blocker 
• 
Failure of parent or legal guardian to give informed consent or subject 
to give informed assent 


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1.2 
SCHEMA 
 
Screening:  
Prior to  
Enrollment 
 
 
 
 
 
 
 
 
↓ 
 
Visit 1  
Day 0 
 
 
 
 
↓ 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
↓ 
Telephone visit 
Week 2      
  
↓ 
Visit 2 
Week 4  
 
 
 
 
 
 
 
 
↓ 
 
Visit 3 
Week 12  
 
 
 
 
 
 
 
 
↓ 
 
Visit 4 
Week 24  
 
 
 
 
 
 
 
 
↓ 
Visit 5 
36 week 
 
 
 
 
 
Total 110:  Obtain informed consent. Screen potential participants by inclusion 
and exclusion criteria; obtain history, CMP, CBC, plasma, serum, anthropometrics, 
and questionnaires, perform baseline assessments. Document eligibility. 
Follow-up assessments of study objectives and adverse effects, physical exam, 
metabolic and hepatic panel, pregnancy test (See 1.3 Schedule of Activities) 
 
Arm 2 = 
PLACEBO 
(N=55) 
Arm 1 = 
LOSARTAN 
(N=55) 
Review dosing instructions, blood pressure log, physical exam, adverse effects, 
metabolic and hepatic panel, pregnancy test (See 1.3 Schedule of Activities) 
12-week post treatment wash out period 
Assessments: See 1.3 Schedule of Activities) 
Follow-up assessments of study objectives and adverse effects, physical exam, 
metabolic and hepatic panel, pregnancy test (See 1.3 Schedule of Activities) 
Randomize and Dispense losartan or placebo 
Review dosing instructions, blood pressure log, and any adverse effects 


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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Screening
visits 
 
Follow-up visits- 
Weeks from Randomization 
 
Assessment/Procedure 
 
 
RZ 
f02-
Phone 
 
f04 
 
f12 
 
f24 
 
f36 
Consent, HIPAA authorization, demographics 
X 
. 
. 
. 
. 
. 
. 
Baseline medical history 
X 
. 
. 
. 
. 
. 
. 
Follow-up medical history 
. 
. 
. 
X 
X 
X 
X 
Review for adverse effects 
. 
. 
X 
X 
X 
X 
X 
Review for concomitant medications 
X 
X 
. 
X 
X 
X 
X 
Alcohol questionnaire AUDIT (A) if interim (I) 
A 
. 
. 
I 
I 
I 
I 
Detailed (D) or focused (F) physical exam 
D 
 
. 
F 
F 
D 
F 
Liver biopsy review 
X 
A 
. 
A 
A 
A 
A 
Pediatric quality of life questionnaire (Peds-QL) 
X 
. 
. 
. 
. 
X 
X 
Beverage intake questionnaire (BEV-Q) 
X 
. 
. 
. 
. 
X 
X 
Standard of care materials provided 
. 
X 
. 
. 
. 
. 
. 
Eligibility confirmation 
. 
X 
. 
. 
. 
. 
. 
Study drug dispensing 
. 
X 
. 
. 
. 
. 
. 
Review of study drug adherence 
. 
. 
X 
X 
X 
X 
. 
Blood pressure log 
 
X 
X 
X 
. 
. 
. 
Labs: 
Complete blood count +WBC 
X 
 
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Basic metabolic panel + eGFR 
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Uric acid 
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Complete Case Report Forms (CRFs) 
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Closeout form 
 
 
 
 
 
 
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Detailed physical exam: anthropometric assessments (body weight [kg], body height [cm], waist circumference [cm], and hip 
circumference [cm]); vital signs (temperature, heart rate, respiratory rate, blood pressure), organ systems (skin, chest, lungs, heart, 
abdomen, nervous) and liver signs  
A= as available 
Focused physical exam: anthropometric assessments (body weight [kg], body height [cm], waist circumference [cm], and hip 
circumference [cm]); vital signs (temperature, heart rate, respiratory rate, blood pressure) and liver signs 
Metabolic panel: glucose, calcium, sodium, potassium, CO2 (carbon dioxide, bicarbonate), chloride, BUN, creatinine  
Hepatic panel: alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), bilirubin, albumin, 
total protein  
Etiologic tests as needed: Hepatitis B surface antigen, hepatitis C antibody, alpha-1-antitrypsin level, ceruloplasmin. Autoantibodies: 
(ANA, AMA ASMA), serum iron, ferritin and total iron binding capacity (TIBC) 
 


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INTRODUCTION 
 
2.1 
STUDY RATIONALE  
NAFLD has become the most common form of chronic liver disease in the developed world. It commonly occurs in 
the setting of obesity, insulin resistance and a sedentary lifestyle and it is often considered the liver manifestation of the 
metabolic syndrome. The primary form of treatment is optimization of lifestyle, including nutrition and exercise.  In the 
real world, success is limited by the difficulty of diet and exercise for many children, as well as the fact that NAFLD may 
not always respond to these lifestyle interventions even when fully implemented. Therefore, pharmacologic treatments 
have been sought but none has proved universally efficacious. This may be related to the fact that the histopathological 
changes seen on liver biopsy currently described as NASH may be the result of multiple pathogenetic mechanisms acting 
in concert to varying degrees. Based on the prevalence and risk of progression of NAFLD to cirrhosis and cancer, the 
burden of significant disease is large, and drug therapy to prevent or treat NAFLD is needed. While the pathologist’s 
approach to liver histology is not age-specific, histologic features differ in adults and children, therefore data from adult 
studies cannot be extrapolated to the pediatric population.[1] 
2.1.1 DEFINITIONS 
Nonalcoholic fatty liver disease (NAFLD) is defined by the presence of greater than "normal" amounts of fat in the 
liver. The pathologists' definition is based on observed steatotic droplets (triglyceride) exceeding 5% of surface area. This 
figure evolved from older studies showing that the normal liver was 5% lipid. In the largest population study of adults 
using MR spectroscopy, the threshold value for abnormal liver fat fraction was similar to these other assessments.[2] 
Nonalcoholic steatohepatitis (NASH) is the name applied to a constellation of biopsy abnormalities occurring in the 
presence of NAFLD that typically include hepatocyte ballooning with or without Mallory-Denk bodies, a mixed 
polymorphonuclear leukocyte and mononuclear inflammatory cell infiltrate in the lobules, chronic inflammation in the 
portal tracts, and sometimes zone 3 perisinusoidal fibrosis.[3] 
A name for NAFLD that is not NASH has not been universally established. Terms such as nonalcoholic fatty liver 
(NAFL), simple steatosis, benign steatosis, bland steatosis, and isolated steatosis have been used, but each has 
limitations that preclude general acceptance.[4] 
2.1.2  
SIGNIFICANCE OF NAFLD 
Prevalence 
In the Study of Child and Adolescent Liver Epidemiology (SCALE) for children ages 2-19 the standardized prevalence 
of NAFLD was 9.6% after adjusting for age, gender, race, and ethnicity.[5] Studies evaluating the prevalence of NASH in 
children vary greatly by setting. In hepatology clinics in San Diego 84% of children, and in Italy 86% with biopsy proven 
NAFLD were reported as having NASH.[6, 7] However, in the San Diego based SCALE study, only 23% of children with 
NAFLD showed evidence of NASH.[5] In the NASH CRN Database study, which included American children from various 
geographic locations, 38% had borderline steatohepatitis and 39% were found to have definite NASH.[8]  Among 
morbidly obese American adolescents undergoing bariatric surgery, intra-operative biopsy revealed 83% had NAFLD 
while only 20% had NASH.[9] 


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Progression to cirrhosis  
In studies of children undergoing liver biopsy for suspected NAFLD, rates of cirrhosis have been reported to range 
from 2 to 10%.[1, 7, 10] Of those patients without evidence of cirrhosis on their initial biopsy, the risk for developing 
cirrhosis may vary by histology and subtype. In adults with steatohepatitis, Matteoni et al reported that one in four 
patients went on to develop cirrhosis.[11] Longitudinal data are needed to further elucidate the risk of disease 
progression in pediatric NAFLD. 
Development of hepatocellular carcinoma  
Multiple cross-sectional studies suggest that NAFLD is a significant risk factor for the development of hepatocellular 
carcinoma (HCC).[12-14] It is estimated that roughly 1,000 cases of HCC in the United States each year can be attributed 
to NAFLD.[15] One prospective study of adult patients with NASH cirrhosis found HCC to develop in roughly 7% of 
patients over a 10 year period.[16] Little is known about the risk for HCC in children. However, the long duration of 
NASH may impact the development HCC for those who have NAFLD as children. 
Comorbidities  
Current data suggest that NAFLD confers an increased risk for the development of cardiovascular disease, 
particularly through its association with metabolic syndrome. The key components of metabolic syndrome include 
central obesity, impaired glucose tolerance, elevated blood pressure, and dyslipidemia.[17] A study demonstrated 
NAFLD to be more frequent among children with metabolic syndrome compared to children without metabolic 
syndrome.[18] Of the 300 children evaluated, those with biopsy-proven NAFLD had a significantly greater cardiovascular 
risk profile. Higher values for fasting glucose, insulin, low-density lipoprotein cholesterol, triglycerides, and systolic blood 
pressure were observed in the NAFLD group. In a Swedish cohort study, patients with a history of steatohepatitis had 
significantly higher rates of cardiovascular disease and mortality when compared to patients with isolated steatosis.[19] 
Identification of NAFLD should prompt consideration of cardiovascular health and relative risk reduction through 
lifestyle changes. 
Children with NAFLD may have an increased risk for developing type 2 diabetes. In large studies of children with 
biopsy-proven NAFLD, 5 to 10% of children have type 2 diabetes at the time of diagnosis.[7, 20] Additionally, nearly 50% 
of children diagnosed with type 2 diabetes have suspected fatty liver based on ALT elevation.[21] Progression to 
diabetes is important to understand from both preventive and therapeutic standpoints. In adults, the risk for 
development of diabetes may be as high as 20 to 25% over 5 years.[22, 23] 
2.1.3 PATHOGENESIS OF NASH  
The majority of studies on the pathogenesis of NAFLD have been in the adult population. While pediatric and adult 
NAFLD share many characteristics, known differences between the two, including histological differences, indicate 
variation in the development of pediatric versus adult NAFLD.[24, 25] While our understanding of the pathogenesis is in 
its infancy, obesity, central adiposity, and insulin resistance are strongly associated with pediatric NAFLD and 
inflammation with progression to NASH. 
Insulin resistance may be defined as the state in which a given concentration of insulin is associated with a lower 
than normal uptake of glucose by tissues such as muscle and liver. Insulin resistance is associated with multiple 
metabolic abnormalities including metabolic syndrome, abnormal glucose metabolism, reproductive abnormalities in 


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women, and cutaneous abnormalities including acanthosis nigricans and skin tags.[26-28] Systemic insulin resistance is 
thought to be critical to the pathogenesis of pediatric NAFLD and has been demonstrated to be present in a majority of 
children with biopsy-proven NAFLD.[7] Studies in animals provide insight to the physiologic link between insulin 
resistance and fatty liver; hyperinsulinemia and insulin resistance result in increased adipose tissue lipogenesis and very 
low density lipoproteins (VLDL) uptake resulting in increased adipocyte fat sequestration and obesity.[29] Insulin 
resistance in both adipose and liver tissue may be integral to the development of NAFLD. 
Mechanisms of hepatocellular injury  
To the extent that mitochondrial dysfunction, ATP depletion, endoplasmic reticulum stress, and oxidant stress play a 
role in hepatocellular injury in NASH, putative mechanisms have been proposed to tie these processes to subsequent 
cell death.[30, 31] Because the fatty acid metabolites responsible for initiating lipotoxic injury are not fully known, how 
they promote cell injury and death has yet to be resolved.[32] A major mechanism of hepatocyte death in NASH is 
apoptosis.[33] 
Fibrosis and progression to cirrhosis  
Liver fibrosis results from hepatocyte injury as demonstrated by studies showing that the production of cytokines 
and lipid peroxidation species from stressed or dying hepatocytes promote proliferation and activation of hepatic 
stellate cells. The balance of extracellular matrix deposition versus degradation is thus disrupted in favor of net 
accumulation of fibrosis. This pathway has been challenged by recent data indicating that epithelial progenitor cells in 
the liver can undergo epithelial-mesenchymal transition (EMT) when stressed.[34] The relative roles of EMT versus 
activation of existing stellate cells in progression of NASH fibrosis to cirrhosis has yet to be established. 
2.1.4 LIMITATIONS OF CURRENT TREATMENT OF NAFLD 
2.1.4.1 LIFESTYLE MODIFICATION  
Because obesity, poor dietary habits, and a sedentary lifestyle predispose to the development of NAFLD, the 
standard of care therapeutic intervention is to address these factors through a combination of gradual and sustained 
weight reduction through a balanced, calorically appropriate diet composed of healthy food choices coupled with 
increased physical activity.[35] There are enough data to support this recommendation[36] for the typical NAFLD 
phenotype which includes conditions such as obesity and metabolic syndrome[37]. However, better data are needed on 
the histological response of children with NAFLD to standardized nutritional lifestyle interventions as recommended by 
the American Academy of Pediatrics. 
2.1.4.2  
METFORMIN 
Insulin resistance is believed to be central to the development of NAFLD. Therefore, several studies have evaluated 
metformin as a potential treatment for NAFLD in children. In the first study to use magnetic resonance spectroscopy as a 
measure of hepatic steatosis, 10 non-diabetic children with biopsy-proven NASH received 500 mg of metformin by 
mouth twice daily for 6 months in an open-label pilot trial.[38] At the completion of the study, ALT normalized in 40% 
and AST normalized in 50%. Hepatic fat fraction was significantly reduced in 9 of 10 subjects, decreasing from a baseline 
mean of 30 ± 11% to 23 ± 9% after 24 weeks of treatment.  


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An open-label, 2-year observational pilot study from Rome evaluated the effect of metformin on NAFLD in 
children.[39] Thirty children with biopsy-proven NAFLD and mildly elevated ALT were enrolled and treated with 1,500 
mg of metformin daily. All subjects also received lifestyle advice, including an individually tailored hypocaloric or 
isocaloric diet, physical activity recommendations, and monthly 1-hour sessions with a dietitian. Of those enrolled, 40% 
had a follow-up biopsy. In this subset, several histologic features, including steatosis, ballooning, and lobular 
inflammation were noted to have improved. However, there was no change in fibrosis. 
The Treatment of NAFLD in Children (TONIC) trial was a multicenter, randomized, double-masked, placebo-
controlled trial conducted by the NASH CRN[39].  A total of 173 children ages 7 to 17 years with biopsy-proven NAFLD 
were randomized to receive either metformin, vitamin E, or placebo for 96 weeks to assess the change in serum ALT and 
histology. The outcomes from the trial were published in March 2011.[40]  {see also 2.1.4.4} 
2.1.4.3 THIAZOLIDINEDIONES 
The thiazolidinediones (TZDs, glitazones) are a class of drugs developed to treat type 2 diabetes because of their 
insulin sensitizing effect in states of insulin resistance. Studies have shown that the benefits of TZDs are at least partly 
explained by their ability to improve insulin responsiveness in adipose tissue and reduce inappropriate peripheral 
lipolysis.[40, 41] As ligands for the nuclear transcription factor peroxisome proliferator-activated receptor gamma 
(PPARγ), this class of drugs has multiple complex effects. Improved insulin signaling has been attributed to the ability of 
TZDs to induce adipocyte differentiation and also prevent the inhibitory effect of c-Jun N-terminal kinases (JNKs) on 
post-receptor insulin signaling. Pilot studies indicated that the TZDs rosiglitazone and pioglitazone might improve the 
histology of NASH. Placebo controlled trials have had somewhat mixed results with the French FLIRT trial showing 
primarily improvement in steatosis[42, 43] and other trials showing improvement in inflammation as well.[44-46] The 
pioglitazone treated patients in the PIVENS trial did not achieve the pre-defined histological Outcome or demonstrate 
improved fibrosis, but did have significant improvements in steatosis, inflammation, and the presence of 
steatohepatitis.[47] Similar to findings in other trials of TZDs, the improvement in ALT occurred over 3-6 months and was 
not sustained when the drug was discontinued. Whether the histological improvement occurs in parallel with the ALT 
decrease is unknown since no trial has examined serial liver biopsies in TZD treated patients. The primary side effect of 
using TZDs over the typical 1-2 year time course of most trials is significant weight gain in some subjects. Exacerbation of 
congestive heart failure, osteoporosis with distal limb fractures, and rare idiosyncratic hepatotoxicity are additional side 
effects known to occur with the use of TZDs, but in general they have not been observed in the relatively small NASH 
trials. This class of medication has not yet been tested and proven safe in children. 
2.1.4.4 VITAMIN E 
Trials of antioxidant agents for the treatment of NASH have been undertaken because of the proposed role of 
oxidant stress in the pathogenesis of steatohepatitis.[48] Vitamin E (RRR-alpha-tocopherol) has been of particular 
interest. Pilot studies were inconclusive but the PIVENS trial demonstrated that 43% of patients treated for two years 
reached the desired histological outcome compared to 19% in the placebo group (P<0.01).[47] Improvement in fibrosis 
was not observed. Similar to the pioglitazone-treated patients, the ALT improved over a time period of 3-6 months. 
Unlike treatment with pioglitazone, weight gain was not observed, but neither was any improvement in insulin 
sensitivity. 
 
 


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The NASH Clinical Research Network performed the Treatment of NAFLD in Children (TONIC) trial (92); a 
multicenter, double-blind, double-placebo, randomized clinical trial in which 173 pediatric patients received metformin 
(500 mg twice daily), vitamin E (400 IU twice daily), or placebo twice daily for 96 weeks. All three groups received 
standardized recommendations regarding lifestyle modifications, use of other medications, alcohol avoidance, and 
management of comorbid illnesses. The primary outcome was sustained reduction in alanine aminotransferase (ALT) 
level defined as reduction in serum ALT levels to below 50% of the baseline values or into the normal range (40 U/L or 
less) during the last 48 weeks of treatment. Secondary histologic outcomes included changes in the total NAFLD activity 
score and individual histological features, and the resolution of NASH. Disappointingly, neither vitamin E nor metformin 
was superior to placebo in achieving sustained ALT reduction or in improving steatosis, lobular inflammation or fibrosis 
scores. The only histologic feature of NASH that improved with both medications was ballooning. Compared to placebo, 
only vitamin E significantly improved the NAFLD activity score and was associated with improved resolution of NASH on 
the repeat liver biopsy (58% vs. 28%; P value of 0.006). The authors suggested that vitamin E should be considered in a 
subset of children with biopsy-proven NASH, and incorporated into guidelines by the AGA, AASLD, and ACG. 
An open-label pilot study of vitamin E in 11 children with suspected NAFLD based on ultrasound showed 
improvement in serum aminotransferases in all subjects, without concomitant weight loss.  
2.1.4.5 CYSTEAMINE 
The NASH CRN recently published the results of a RCT (ClinicalTrials.gov no: NCT01529268) comparing Cysteamine 
bitartrate delayed release (CBDR) with placebo in 169 children. One year of CBDR did not reduce overall histologic 
markers of NAFLD compared with placebo in children. There was no significant difference between groups in the 
primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 
0.8–2.1; P = .34). However, children receiving CBDR had significant changes in pre-specified secondary outcomes: 
reduced mean levels of alanine aminotransferase (reduction, 53 ± 88 U/L vs 8 ± 77 U/L in the placebo group; P = .02) and 
aspartate aminotransferase (reduction, 31 ± 52 vs 4 ± 36 U/L in the placebo group; P = .008), and a larger proportion had 
reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1–2.9; P = .03). 
Summary 
NAFLD is a highly prevalent disease in children with adverse clinical outcomes documented in young adults.  While 
definitive longer term natural history data for clinical outcome data is still lacking, given the common occurrence of 
fibrosis in children, the high incidence of type II diabetes in children with fatty liver and the established natural history 
data for NAFLD in adults demonstrating early type II diabetes, cardiovascular disease and progression to cirrhosis in the 
setting of fibrosis, there is consensus that children with NAFLD and inflammation or fibrosis should be treated.  Current 
standard of care treatment is lifestyle changes and consideration of vitamin E, however only a minority of children 
(~30%) with NAFLD have histologic improvement with lifestyle changes alone.  Thus, treatments that have the potential 
to improve the liver and insulin resistance should be sought for children with NAFLD.  
 
2.2 
BACKGROUND  
Evidence for Use of Losartan Potassium in Adult Hypertension 
The antihypertensive effects of losartan potassium were demonstrated principally in 4 placebo-controlled, 6 to 12 week 
trials of dosages from 10 to 150 mg per day in patients with baseline diastolic blood pressures of 95 to 115 mmHg. The 
studies allowed comparisons of two doses (50 to 100 mg/day) as once-daily or twice-daily regimens, comparisons of 


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peak and trough effects, and comparisons of response by gender, age, and race. Three additional studies examined the 
antihypertensive effects of Losartan and hydrochlorothiazide in combination. 
 
The 4 studies of Losartan monotherapy included a total of 1,075 patients randomized to several doses of Losartan and 
334 to placebo. The 10 mg and 25 mg doses produced some effect at peak (6 hours after dosing) but small and 
inconsistent trough (24 hour) responses. Doses of 50, 100, and 150 mg once daily gave statistically significant 
systolic/diastolic mean decreases in blood pressure, compared to placebo in the range of 5.5 to 10.5/3.5 to 7.5 mmHg, 
with the 150 mg dose giving no greater effect than 50 to 100 mg. Twice-daily dosing at 50 to 100 mg/day gave 
consistently larger trough responses than once-daily dosing at the same total dose. Peak (6 hour) effects were uniformly, 
but moderately, larger than trough effects, with the trough-to-peak ratio for systolic and diastolic responses 50 to 95% 
and 60 to 90%, respectively. 
 
Addition of a low dose of hydrochlorothiazide (12.5 mg) to Losartan 50 mg once daily resulted in placebo-adjusted blood 
pressure reductions of 15.5/9.2 mmHg. 
 
Analysis of age, gender, and race subgroups of patients showed that men and women, and patients over and under 65, 
had generally similar responses. Losartan potassium was effective in reducing blood pressure regardless of race, 
although the effect was somewhat less in Black patients (usually a low-renin population). 
 
Evidence for Use of Losartan potassium in Pediatric Hypertension 
The antihypertensive effect of losartan was studied in one trial enrolling 177 hypertensive pediatric patients aged 6 to 
16 years old. Children who weighed <50 kg received 2.5, 25, or 50 mg of losartan daily and patients who weighed ≥50 kg 
received 5, 50, or 100 mg of losartan daily. Children in the lowest dose group were given losartan in a suspension 
formulation [see Dosage and Administration (2.1)]. The majority of the children had hypertension associated with renal 
and urogenital disease. The sitting diastolic blood pressure (SiDBP) on entry into the study was higher than the 95th 
percentile level for the patient’s age, gender, and height. At the end of three weeks, losartan reduced systolic and 
diastolic blood pressure, measured at trough, in a dose-dependent manner. Overall, the two higher doses (25 to 50 mg 
in patients <50 kg; 50 to 100 mg in patients ≥50 kg) reduced diastolic blood pressure by 5 to 6 mmHg more than the 
lowest dose used (2.5 mg in patients <50 kg; 5 mg in patients ≥50 kg). The lowest dose, corresponding to an average 
daily dose of 0.07 mg/kg, did not appear to offer consistent antihypertensive efficacy. When patients were randomized 
to continue losartan at the two higher doses or to placebo after 3 weeks of therapy, trough diastolic blood pressure rose 
in patients on placebo between 5 and 7 mmHg more than patients randomized to continuing losartan. When the low 
dose of losartan was randomly withdrawn, the rise in trough diastolic blood pressure was the same in patients receiving 
placebo and in those continuing losartan, again suggesting that the lowest dose did not have significant antihypertensive 
efficacy. Overall, no significant differences in the overall antihypertensive effect of losartan were detected when the 
patients were analyzed according to age (<, ≥12 years old) or gender. While blood pressure was reduced in all racial 
subgroups examined, too few non-White patients were enrolled to compare the dose-response of losartan in the non-
White subgroup. 
 
Animal model support for losartan potassium as a treatment for NAFLD 
A wide range of animal model work has demonstrated potential of losartan as a treatment for liver diseases.[50-63]  The 
renin-angiotensin system (RAS) is an enzymatic cascade in which renin cleaves angiotensinogen to form angiotensin I, 
which is then transformed to angiotensin II by angiotensin-converting enzyme (ACE). The contribution of RAS in NAFLD 
and NASH has been investigated extensively (reviewed in[64]) and may include effects on insulin receptors, effects on 


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adipogenesis, cytokine modulation and local hepatocellular regulation[64].  Both ACE inhibitors and angiotensin 
receptor blockers (ARBs) antagonize RAS and suppress angiotensin II.  For example, in a 12 week mice model 
experiment, both losartan and telmisartan benefited insulin resistance and decreased plasminogen activator inhibitor-1 
(PAI-1) gene expression.[57]    However, the data are somewhat mixed because in a choline-deficient diet model and the 
carbon tetrachloride model, losartan alone did not protect against liver injury or fibrogenic events.[50, 52]  A larger 
experiment using rats and choline deficient L-amino acid defined diet did show protection of the liver when combined 
with ursodeoxycholic acid.[65]  
 
Evidence for Utilization of losartan in NAFLD in Humans  
There are a number of studies and articles reporting on use of losartan in NAFLD.[61, 66-72]  In humans, ARBs, including 
losartan, appear to have a superior effect on insulin sensitivity and two meta-analyses have found that ARBs improved 
insulin sensitivity and reduced incidence of type II diabetes.[73, 74]  The data for liver disease are mixed.  A large 
retrospective review of diabetic patients treated with both ACEs and ARBs demonstrated a significant association with 
reduced fibrosis.[75] But in an RCT treating 137 subjects with biopsy proven NASH, the combination of rosiglitazone and 
losartan was not superior to rosiglitazone and metformin.[72]  The Fatty Liver Protection Trial by Telmisartan or Losartan 
Study (FANTASY) compared Telmistartan to losartan and neither improved ALT significantly.  However, ALT levels were 
relatively low at baseline and a low dose of losartan was utilized (50 mg once a day).[68]  A recently reported RCT in 
adults also proposed to test 50 mg of losartan daily compared to placebo however the trial was not completed due to 
difficulties with recruiting.[69]   
 
Plasminogen activator inhibitor-1 (PAI-1) modulation as the possible liver relevant target of losartan potassium  
Plasminogen activator inhibitor-1 (PAI-1) is an acute-phase protein that is found to be increased in insulin resistance 
state and inflammation and injury.[76] More recently, it has been linked to the initiation and progression of liver disease 
of various etiologies[77] including NAFLD. Our previous data and work by others have shown that PAI-1 is elevated in 
both adults and children with significant hepatic steatosis[78-80] and, furthermore, correlates with hepatic 
inflammation levels as well as fibrosis stages.[81]  The renin-angiotensin system (RAS) has been suggested to be involved 
in the pathways of liver damage and might play a critical role in the pathogenesis of NAFLD.[82] Importantly, blockage of 
the RAS significantly inhibits the expression of PAI-1 in the liver.[57] Angiotensin receptor blockers (ARB), a class of 
medications that antagonize the angiotensin receptor and suppress RAS, have been proposed as a novel treatment of 
NAFLD in part because they decrease PAI-1 but also because they improve insulin resistance. 
The underlying mechanisms of losartan in modulating lipid and insulin metabolism is only partially understood. One of the 
hypotheses is that the effect on insulin sensitivity is through the inhibition of PAI-1 production and consequently 
restoration of hepatocyte growth factor (HGF) activity. PAI-1 overexpression has been found in steatotic livers[78, 79] and 
upregulated PAI-1 may inhibit the maturation of pro-HGF to HGF, which fails to activate the HGF receptor (HGFR) and thus 
has two major downstream effects. First, disrupted HGF-HGFR interaction leads to decreased apolipoprotein (apoB) 
expression and microsomal triglyceride transfer protein (MTTP) activity in the liver, both of which are responsible for 
increased accumulation of triglyceride in the liver and a compensatory increase in very low density lipoprotein (VLDL) to 
shuttle the greater amount of triglyceride from hepatocytes into the circulation.[80] Second, inactivated HGF-HGFR axis 
is unable to interact with insulin substrate receptor thus inhibiting insulin signaling pathway and dysregulating glucose 
metabolism.[81] In a PAI-1 knockout mouse model, diet-induced hepatic steatosis was attenuated by ~50% and it was 
associated with a significant increase in HGFR activity, hepatic expression of apoB and activity of MTTP.[80] Losartan has 
been shown to reduce hepatic PAI-1 gene expression by ~42% and ameliorate fatty liver in an experimental model of 


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NAFLD.[57] Taken together, the effect of losartan on improving hypertriglyceridemia and insulin sensitivity that we found 
in the study participants may result from modulation of the activation of HGF through blockage of PAI-1.      
Safety Data of Losartan Potassium in Pediatric NAFLD  
Vos et al conducted a randomized, double-blind, placebo-controlled, crossover study (phase 1/2).  It was approved by 
the Emory University Institutional Review Board and listed on Clinical Trials.gov (NCT01913470). Adolescents with biopsy 
proven NASH, who failed to normalize liver enzymes with conventional therapy (lifestyle changes), were consented and 
assessed for enrollment eligibility at the screening visit (week -4). After a 4-week stabilization period, subjects were 
randomized to losartan or placebo for 8 weeks followed by a 6-week washout and then the alternate therapy for 8 
weeks. Participant’s study visits were at weeks 4, 8, 12, 14, 22, and 28 for safety monitoring as well as intermediate 
efficacy. Fasting blood samples were collected (typically between 7-9am) at weeks 0, 8, 14, and 22. All participants 
continued their usual healthy diet and exercise as recommended by their NAFLD physician and were asked not to make 
major changes during the study.  The inclusion criteria were age 11-19 years at enrollment; body weight ≥ 62.5 kg; BMI > 
85th percentile for age and gender; history of definite or borderline NASH based upon histology using NASH CRN 
criteria[82]; ALT ≥ 3 times normal (69 U/L for girls, 78 U/L for boys) at enrollment; and at least 2 months of attempted 
lifestyle changes after liver biopsy. Exclusion criteria were history of cirrhosis and liver synthetic dysfunction (INR ≥ 1.5); 
history of hypotension; diagnosis of diabetes (or fasting glucose > 125 mg/dl); renal insufficiency (GFR < 30); any other 
chronic disease requiring daily medication (except medications for acid reflux, allergies or asthma); acute illness within 
past 2 weeks prior to enrollment (fever > 100.4°F); and anti-oxidant therapy or supplement within past 4 weeks before 
enrollment. Patients started losartan or identical placebo pills at 25 mg per day for 1 week and 50 mg for 7 weeks, and 
then the alternate therapy for 8 weeks (25 mg daily for 1 week and 50 mg daily for 7 weeks) after a 6-week washout. 
The primary side effect associated with losartan is reduction of blood pressure. To ensure safety, parents were provided 
and taught to use an automated blood pressure cuff for home monitoring of blood pressure.       
 
The results of this pilot study were reported in abstract form at DDW 2016.[88]  In brief, the findings are as follows.  
Twelve children were enrolled with 9 subjects completing all study visits. One participant was lost to follow-up, one 
withdrew, and one was withdrawn due to noncompliance.  67% of subjects were Hispanic with mean age of 14 years 
and BMI z-score of 2.32. There were no serious adverse events reported and other adverse events are reported in Table 
1.  


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Analysis of this pilot study demonstrated that there was an unexpected, significant carry-over effect of losartan in the 
group that was randomized to losartan treatment first. However, importantly losartan had no safety issues and there were 
no changes in blood pressure observed within and between groups for the duration of the study (Table 2).  
 
Changes in ALT, AST and HOMA-IR over 8 weeks of treatment are shown for individual subjects with baseline and end 
values visualized in Figure 1.  
 


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Figure 1 (A-D):  During losartan treatment, more participants decreased ALT compared to during the placebo time 
period.   A similar pattern was seen in HOMA-IR. The change in PAI-1 from baseline to end of treatment was not 
different between treatment periods.  In conclusion, this pilot study of losartan potassium in children with NAFLD using 
a dose of 50 mg demonstrated safety and some signals of preliminary efficacy, however we suspect the dose was 
insufficient given the mean BMI z-score of 2.32. 
 
Importance of this Trial and Controversies in Pediatric NAFLD Treatment  
NAFLD has quickly become the most common liver disease in children and it is apparent that treatment with lifestyle 
alone is insufficient to resolve the condition in children with advanced disease.[37]  Thus, efficacious and safe 
medications are needed.  Losartan is a relatively inexpensive medication, widely available that has an established safety 
record in children and adults.  Further, there are preliminary safety data for losartan in children with NAFLD.   
 
There remains controversy regarding which children with NAFLD will require medications in addition to the standard of 
care treatment of healthy lifestyle.  It is uncertain at this point, due to a lack of long term data, which children are at 
higher risk of advancing to clinical outcomes such as type II diabetes, portal hypertension, cirrhosis and hepatocellular 
carcinoma.  In adults, it appears that fibrosis on liver biopsy is the most consistent risk factor for future liver related 
outcomes.[89] However, in children this has not been demonstrated.  In children, the most rapid clinical outcome is 
likely to be progression to type II diabetes which has been shown to be strongly associated with NAFLD.[90]  Thus, 
therapeutics that improve both insulin resistance and liver histologic damage are highly desirable.   


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A controversy in NAFLD clinical trials is the selection of the primary outcome because no surrogate markers are validated 
to predict future clinical outcomes of feeling, function, or survival.  Typically, either ALT or histology is used as the 
primary outcome and for shorter phase 2 trials, ALT is well accepted as a surrogate marker of improvement of liver 
inflammation in children with NAFLD. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
2.3.1 KNOWN POTENTIAL RISKS  
 
• 
Hypotension – Losartan is an antihypertensive approved in children and the children in the trial may or may not 
have elevated blood pressures.  This side effect is worse with co-treatment of other antihypertensives.  
• 
Hyperkalemia – is a rare reported side effect of losartan.  This side effect may be worse with co-treatment of 
other antihypertensives, with other drugs affecting renal function, or with use of potassium supplementation.  
• 
Acidosis – is a rare side effect of losartan also worse in the setting of co-treatment.  
• 
Renal function decline – is a rare reported side effect of losartan.  This is worse with co-treatment with other 
drugs affecting renal function.   
• 
Harm to unborn child 
• 
Blood draws 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Immediate potential benefits to individual participants in this trial are twofold.  First, all participants will receive lifestyle 
counseling at baseline which is the standard of care for pediatric NAFLD.  Lifestyle counseling will be standardized and 
based upon the established protocols of the NASH CRN.  Second, losartan is well established as a medication that 
improves insulin resistance in children, and insulin resistance is strongly associated with pediatric NAFLD; perhaps even 
fundamental in the mechanisms perpetuating the dysregulated lipid and inflammatory physiology driving NASH.  If 
losartan reduces insulin resistance, inflammation and PAI-1, this will improve the histologic injury and potentially reduce 
progression to type II diabetes in children with NAFLD.   
 
Long range potential benefits include to reduce progression to type II diabetes, cirrhosis, cardiovascular disease, and 
hepatocellular carcinoma in children with pediatric NAFLD.  If losartan is effective in improving ALT and insulin 
resistance, a longer term, histology-based trial will be planned to test effectiveness on histologic improvement.  If it is 
proven to be efficacious, this will benefit children across the world because losartan is a relatively inexpensive 
medication, available as a generic that is known to be safe for long term use in children with hypertension as well as 
other pediatric disorders.  This medication could be used to decrease the prevalence of progression to clinical outcomes 
in children with NAFLD.   
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Rationale for necessity of exposing participants to risk and minimization of risks: Risks to the patients in this study 
include that losartan potassium can rarely cause hyperkalemia, hypotension, acidosis, and renal function deterioration.  
Risks are minimized by avoiding other medications that increase risk of hyperkalemia, acidosis and renal deterioration, 
and hypotension and by close monitoring. Risks are also minimized in this trial by using ALT as a surrogate marker of 
histologic response, thus avoiding the need for liver biopsies in this phase 2 study.  The number of time points for blood 


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draws was minimized to decrease potential harm from blood draws and inconvenience to the families regarding missing 
work and school.   
 
• 
Hypotension:  All children will be monitored using blood pressure at the screening visit and randomization 
visit.  Each participant will be given a home blood pressure cuff and blood pressure log at the randomization 
visit.  They will be asked to check blood pressure each morning for the first 14 days (7 days after starting the 
initial dose and 7 days after increase to maximum dose.  The logs will be reviewed at each site and checked 
for hypotension.  Participants will be instructed to call for any blood pressures under 90/60 and for 
symptoms of hypotension (dizziness, fainting, lightheadedness).   
 
• 
Hyperkalemia: The risk of harm has been minimized by treating children with an established dose known to 
be safe in children with Marfan Syndrome, renal disorders and in children with hypertension.  Further, the 
protocol has been designed to assess potassium levels at 1 month, 3 months and at completion of the 
treatment phase (6 months).  Use of other medications that also increase potassium are prohibited in the 
trial.  Finally, the DSMB will review the potassium levels at each time point to assess differences between 
the treatment and placebo group to detect trends.  
 
• 
Acidosis: The risk of harm has been minimized by treating children with an established dose known to be 
safe in children with Marfan Syndrome, renal disorders, and in children with hypertension.  Further, the 
protocol has been designed to assess CO2 levels at 1 month, 3 months and at completion (6 months).  Use of 
other medications that also enhance acidosis are prohibited in the trial.  Finally, the DSMB will review the 
CO2 at each time point to assess differences between the treatment and placebo group to detect trends. 
 
• 
Renal function deterioration:  All children will be monitored closely using labs to follow renal function (using 
creatinine).  Methods to decrease risk include only enrolling children with normal renal function at baseline, 
excluding usage of other medications that can harm the kidneys, and encouraging good hydration.   
 
• 
Blood draws:  All children will be enrolled at experienced pediatric sites and established techniques will be 
used to minimize bleeding, infection, and pain/discomfort with blood draws.   
 
Justification of the risks: All children will receive standard of care as part of the trial and will potentially benefit if they 
are in the treatment group (losartan) by improvement in ALT and insulin resistance.  The value of the information is high 
because all of the children in the study have confirmed NAFLD and are in need of treatment beyond lifestyle changes.  
By conducting the trial and furthering the understanding of losartan for pediatric NAFLD, all of the children in the study 
stand to benefit in the future if losartan is proven to be effective.   
 


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3 
OBJECTIVES AND OUTCOMES 
OBJECTIVES 
OUTCOMES 
JUSTIFICATION FOR OUTCOMES 
Primary 
 
 
To determine whether 24 weeks of 
treatment with losartan compared 
to treatment with placebo 
improves measures of nonalcoholic 
fatty liver disease (NAFLD)  
Change in ALT from screening to 24 
weeks 
 
ALT is the most accepted short term 
(<12 months) surrogate marker for 
histologic improvement in NAFLD 
Secondary 
 
 
The secondary objective(s) have 
been selected to provide further 
information on whether 24 weeks 
of treatment with losartan 
compared to treatment with 
placebo improves measures of liver 
indices, insulin resistance, 
dyslipidemia and body size.   
 
Relative change in ALT from screening 
to 24 weeks 
Proportion of patients achieving 
normalization of ALT at 24 weeks 
Change in AST and GGT from screening 
to 24 weeks 
Mean ALT (12 and 24 weeks) compared 
to baseline 
Change in fasting markers of insulin 
resistance (HOMA-IR) from screening to 
24 weeks 
Change in anthropometric 
measurements (weight, BMI z-score, 
waist to hip ratio, waist circumference) 
from screening to 24 weeks 
Change in serum lipid profiles from 
screening to 24 weeks 
Change in C-reactive protein (serum 
marker of inflammation)  from 
screening to 24 weeks 
Change in Health-related Quality of Life 
(HR-QoL) scores from screening to 24 
weeks 
Change in frequency of adverse events 
from screening to 24 weeks 
These outcomes were selected 
because they measure important co-
morbidities of NAFLD and are useful 
for determining if losartan improves 
other features commonly associated 
with NAFLD.  Safety and quality of life 
outcomes are also included.   
 
Tertiary/Exploratory  
Change from screening to 24 weeks: 
 
Tertiary/exploratory objective(s) 
were selected to serve as a basis for 
explaining or supporting findings of 
primary analyses and for 
suggesting further hypotheses for 
later research. 
Change in peripheral proinflammatory 
cytokine levels (including IL-6, TNF, 
TGF-beta) from baseline to 24 weeks. 
Change in NMR MetaboProfile Analysis 
(LP4) from baseline to 24 weeks. 
 
Inflammation and oxidative stress are 
considered major drivers of NAFLD 
and improvement in these would 
support further development of 
losartan for NAFLD.   
 
 


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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN 
• 
 The hypothesis of the trial is that 24 weeks of treatment with losartan potassium in children with NAFLD will 
improve the ALT compared to screening values.   
• 
 Phase 2a 
• 
A Multicenter, randomized, double-masked, placebo-controlled, parallel treatment groups phase 2a trial with 
24-week change from baseline in serum ALT as the primary outcome.  
• 
Methods to decrease bias will include placebo control, double masking and randomization.  
• 
Two study arms 
• 
Multisite  
• 
Study intervention is losartan potassium (100 mg orally once per day) or matching placebo. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The study design is a multicenter, randomized, double-masked, placebo-controlled, parallel treatment groups phase 2 
trial.  
Rationale for a Placebo Group: NAFLD is a highly variable disease with a high placebo response rate of 10-30%[91, 92], 
likely in part because of the ongoing standard of care treatment of diet and exercise during all trials. Because of this, it is 
important to have a placebo control group to allow discernment of treatment effect over and above lifestyle changes.  
Lifestyle interventions are considered the standard treatment for NAFLD, but are often not available to children with 
NAFLD due to both the lack of available care and limitations of insurance coverage for lifestyle interventions.  In this 
study we will provide all participants, including those receiving placebo with a standardized nutrition and exercise 
intervention consistent with the recommendations of the American Academy of Pediatrics.  Thus, all children will receive 
treatment. 
Currently, there are no FDA approved therapies for NAFLD in children. Medications that are being investigated for the 
treatment of NAFLD cannot be compared with an active alternative treatment arm.  In order to assess the efficacy of an 
agent in NAFLD, a placebo-arm is needed to determine its relative efficacy in improving liver histology beyond that 
achieved with a placebo.  Previous non-randomized and pilot studies have shown the efficacy of several agents such as 
ursodiol and betaine in the treatment of NAFLD, but follow-up randomized-placebo-controlled studies failed to show 
improvement in liver histology beyond that observed in placebo groups.[85, 86]  In order to have the highest quality of 
evidence to test our hypothesis, the STOP-NAFLD trial utilizes a randomized, double-masked, placebo-controlled study 
design (http://www.ahrq.gov/clinic/uspstf/grades.htm). As there is no proven pharmacologic therapy for NAFLD in 
children, using a placebo for comparative purposes is justified. 
The trial is double masked to prevent bias by investigators and participants.  The trial is 24 weeks because significant 
differences in ALT have been seen at 24 weeks in patients who go on to have histologic improvement[84], and thus ALT 
change at 24 weeks is widely accepted as a surrogate marker of future histologic benefit and future clinical benefit for 
patients.[91, 92]     
 
The CyNCh trial data below show improvements in ALT were evident as soon as 12 weeks and were even greater at 24 
weeks of treatment. 


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CyNCh Trial: Changes in ALT (U/L) at 12 and 24 weeks by treatment group  
Change in ALT (U/L) from 
baseline – mean (SD) 
Cysteamine 
(N=88) 
Placebo 
(N=81) 
Total 
(N=169) 
P 
12 weeks 
-54 (88) 
-9 (48) 
-30 (73) 
0.008 
24 weeks 
-55 (90) 
-10 (54) 
-32 (77) 
0.03 
 
 
Rationale for a two year (730 days) maximum duration between liver biopsy and enrollment:  Use of a historical liver 
biopsy (up to 730 days prior to enrollment) ensures that all patients have a liver biopsy based diagnosis.  The primary 
outcome is ALT, and this will be obtained at screening to ensure that it is elevated, suggesting ongoing inflammation in 
the liver.   
Treatment duration-rationale for 24 weeks:  An ideal duration of a treatment should only expose participants to a study 
drug long enough to show meaningful improvement in ALT if it is going to occur. This enables any positive findings to be 
reported as soon as possible. 
4.3 
JUSTIFICATION FOR DOSE 
The usual dose of losartan potassium in children is orally administered and a starting dose of 0.7 mg per kg daily (up to 
50 mg total for starting dose).  The upper limit is 1.4 mg/kg or 100 mg daily.  The doses proposed in this trial will range 
from 0.7 mg/kg/day to 1.4 mg/kg/day. The previous Vos pilot study of losartan potassium in children with NAFLD using a 
dose of 50 mg demonstrated safety and some signals of preliminary efficacy, however we suspect the dose was 
insufficient given the mean BMI z-score of 2.32.  
The table below illustrates the dose ranges proposed and the distribution of weights in patients who meet the biopsy 
eligibility criteria in the current NASH CRN Pediatric Database 2 study. 
Participant 
weight (kg) 
50 mg Dose 
100 mg Dose 
 
 
 
Eligibility Criteria 
Current biopsy eligible 
Pediatric DB2 participants 
N=79 
 
mg/kg/day 
mg/kg/day 
 
 
<40 
 
 
Exclude if <70 kg 
50 mg dose (0.8 mg/kg-1.3 mg/kg) 
 
 
N=25 
 
40 
1.3 
 
45 
1.1 
 
50 
1.0 
 
55 
0.9 
 
60 
0.8 
1.7 
65 
0.8 
1.5 
 
 
70 
0.7 
1.4 
 
 
 
 
 
 
75 
 
1.3 
80 
 
1.3 
85 
 
1.2 
90 
 
1.1 
95 
 
1.1 


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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. 
 
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 
• 
Age 8-17 years at initial screening interview 
• 
Histological evidence of NAFLD with or without fibrosis and a NAFLD activity score (NAS) of ≥3, on a liver biopsy 
obtained no more than 730 days prior to enrollment. 
• 
Serum ALT at screening ≥ 50 IU/L 
5.2 
EXCLUSION CRITERIA 
• 
Body weight less than 70 kg or greater than 150 kg at screening 
• 
Significant alcohol consumption or inability to reliably quantify alcohol intake 
• 
Use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic glucocorticoids, 
tetracyclines, tamoxifen, estrogens at doses greater than those used for hormone replacement, anabolic 
steroids, valproic acid, other known hepatotoxins) for more than 2 consecutive weeks in the past year prior to 
randomization 
• 
New treatment with vitamin E or metformin started in the past 90 days or plans to alter the dose or stop over 
the next the 24 weeks.  A stable dose is acceptable.     
• 
Prior or planned bariatric surgery 
• 
Uncontrolled diabetes (HbA1c 9.5% or higher) 
• 
Presence of cirrhosis on liver biopsy 
• 
History of hypotension or history of orthostatic hypotension  
• 
Stage 2 Hypertension or >140 systolic or >90 diastolic at screening 
• 
Current treatment with any antihypertensive medications including all angiotensin converting enzyme (ACE) 
inhibitors or aliskiren 
• 
Current treatment with potassium supplements or any drug known to increase potassium 
100 
 
1.0 
≥70 kg to <150 kg weight 
100 mg dose (0.7-1.4mg/kg) 
N=53 
 
105 
 
1.0 
110 
 
0.9 
115 
 
0.9 
120 
 
0.8 
125 
 
0.8 
130 
 
0.8 
135 
 
0.7 
140 
 
0.7 
145 
 
0.7 
150 
 
0.7 
>150 
 
 
Exclude if kg >=150  
N=1 


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• 
Current daily use of NSAIDs 
• 
Current treatment with lithium  
• 
Platelet counts below 100,000 /mm3 
• 
Clinical evidence of hepatic decompensation (serum albumin < 3.2 g/dL, INR >1.3, direct bilirubin >1.3 mg/dL, 
history of esophageal varices, ascites, or hepatic encephalopathy) 
• 
Evidence of chronic liver disease other than NAFLD: 
- 
Biopsy consistent with histological evidence of autoimmune hepatitis 
- 
Serum hepatitis B surface antigen (HBsAg) positive. 
- 
Serum hepatitis C antibody (anti-HCV) positive. 
- 
Iron/total iron binding capacity (TIBC) ratio (transferrin saturation) > 45% with histological evidence of iron 
overload 
- 
Alpha-1-antitrypsin (A1AT) phenotype/genotype ZZ or SZ 
- 
Wilson’s disease  
• 
Serum alanine aminotransferase (ALT) greater than 300 IU/L 
• 
History of biliary diversion 
• 
History of kidney disease and/or eGFR < than 60 mL/min/1.73 m2 using Schwartz Bedside GFR Calculator for 
Children IDMS-traceable (link) 
• 
Known Human Immunodeficiency Virus infection 
• 
Active, serious medical disease with life expectancy less than 5 years  
• 
Active substance abuse including inhaled or injected drugs, in the year prior to screening 
• 
Pregnancy, planned pregnancy, potential for pregnancy and unwillingness to use effective birth control during 
the trial, breast feeding 
• 
Participation in any clinical/investigational trial within the prior 150 days and during the STOP-NAFLD Trial. 
• 
Any other condition which, in the opinion of the investigator, would impede compliance or hinder completion of 
the study 
• 
Inability to swallow capsules 
• 
Known allergy to losartan potassium or other angiotensin receptor blocker 
• 
Failure of parent or legal guardian to give informed consent or subject to give informed assent 
 
5.3 
LIFESTYLE CONSIDERATIONS 
5.3.1 STANDARD TREATMENT RECOMMENDATIONS  
The use of prescription or non-prescription medicines or herbal remedies or dietary supplements, consumption of 
alcohol, and management of various co-morbid illnesses will be discussed with the patients. These recommendations 
have been prepared by the NASH CRN Pediatric Standard of Care Committee and are approved by the NASH CRN 
Steering Committee to be applied across all study sites. This will help ensure that the patients in both groups receive the 
same standard of care treatment for NAFLD. 
Enhanced Lifestyle Intervention 
All children, including those in the placebo group will receive an intervention in the form of standardized lifestyle 
intervention recommendations consistent with the latest recommendations from the American Academy of Pediatrics 
(AAP).  Assessing the impact of such an intervention on NAFLD will be important. Attaining a healthy weight is the 


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cornerstone of current treatment of pediatric NAFLD, given the lack of proven pharmaceutical therapy in this age group 
and the strong association of NAFLD with excess adiposity, in particular central adiposity.[87]  Weight loss has been 
associated with improvements in liver enzymes and histology in adults with NAFLD, while weight loss in children with 
NAFLD has been shown to improve serum aminotransferase levels in small pilot studies.[36, 88, 89] Therefore, lifestyle 
intervention through changes in diet and exercise will be encouraged for participants in both the placebo and active 
study drug treatment group of the STOP-NAFLD trial, as this represents the current standard of care for children.  
The standard of care lifestyle intervention designed for this trial will incorporate components of the AAP’s 2007 Expert 
Committee Recommendations Regarding the Prevention, Assessment, and Treatment of Child and Adolescent 
Overweight and Obesity that can be reproduced across the study sites.[90] STOP-NAFLD Trial participants will be given 
written materials that will include evidence-based strategies to achieve a healthier diet and increase physical activity, as 
endorsed by the American Academy of Pediatrics as well as the CDC and NIH.[90-92] A family-based, patient-centered 
and stepped approach to making lifestyle changes will be employed as recommended by the AAP.[90] Accordingly, the 
lifestyle materials will be reviewed with trial participants and their family members at each study visit and they will be 
encouraged to select 1-2 goals which they consider personally obtainable and that they can commit to pursuing in the 
interval until their next study visit.  
Topics to be covered in the materials will include: 
1)  Reduce fat intake and sugar intake to 0 servings per day 
2)  Reduce screen time to 2 hours or less per day 
3)  Increase physical activity to 1 hour or more per day 
4)  Increase fruits and vegetable intake to 5 or more servings per day  
5)  Reduce fast food intake and make healthier choices when eating out 
These topics and the specific strategies to be included in the lifestyle intervention materials are in accordance with 
healthy weight strategies currently recommended by the Centers for Disease Control and Prevention and the National 
Institutes of Health National Heart Lung and Blood Institute’s “We Can” program.[91-94] Therefore, we will also include 
references in the study’s lifestyle intervention materials to these freely accessible, federal government sponsored 
websites so that participants and their families can easily access additional information on these lifestyle changes and 
strategies to achieve them. 
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, and any serious adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a low ALT may be 
rescreened once. Rescreened participants should be assigned the same participant number as for the initial screening. 
 
 


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5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
5.5.1 RECRUITMENT 
Approximately 110 participants in 2 groups of equal size (55 per group) will be recruited at the ten participating clinical 
centers of the NASH CRN (averaging 11 patients per center) over a 12-month period. 
Eligible patients will be identified and recruited at the participating clinical centers subject to the inclusion and exclusion 
criteria. Clinics will be expected to recruit sufficient overall numbers of minorities and females so that results can be 
generalized to these populations. Each clinic will develop a recruitment plan. These plans will vary from clinic to clinic 
depending on the available pools of patients and local recruitment resources and referral patterns. 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION FROM FDA PACKAGE INSERT 
Losartan potassium tablets USP is an angiotensin II receptor blocker acting on the AT 1 receptor subtype. Losartan 
potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-[ p-( o-1 H-­tetrazol-5-ylphenyl) 
benzyl]imidazole-5-methanol monopotassium salt.  
Its molecular formula is C 22H 22ClKN 6O, and its structural formula is: 
 
 
Losartan potassium USP is a white to off-white free-flowing crystalline powder with a molecular weight of 461.01. It is 
freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as acetonitrile and 
methyl ethyl ketone. Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of 
Losartan. 
 
Losartan potassium is available as tablets for oral administration containing either 25 mg, 50 mg or 100 mg of Losartan 
potassium USP and the following inactive ingredients: Microcrystalline cellulose, lactose monohydrate, pregelatinized 
starch, magnesium stearate, Opadry white (hydroxypropyl cellulose, hypromellose, titanium dioxide). 
 
Losartan potassium 25 mg, 50 mg and 100 mg tablets contain potassium in the following amounts:  2.12 mg (0.054 
mEq), 4.24 mg (0.108 mEq) and 8.48 mg (0.216 mEq), respectively. 
 
Losartan - Clinical Pharmacology 
Mechanism of Action 
Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)] is a 
potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system, and an important component 


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in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its 
principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively 
blocking the binding of angiotensin II to the AT 1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal 
gland). There is also an AT 2 receptor found in many tissues but it is not known to be associated with cardiovascular 
homeostasis. Neither Losartan nor its principal active metabolite exhibit any partial agonist activity at the AT 1 receptor, 
and both have much greater affinity (about 1000-fold) for the AT 1 receptor than for the AT 2 receptor. In vitro binding 
studies indicate that Losartan is a reversible, competitive inhibitor of the AT 1 receptor. The active metabolite is 10 to 40 
times more potent by weight than Losartan and appears to be a reversible, non-competitive inhibitor of the AT 1 
receptor. 
 
Neither Losartan nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin 
II and degrades bradykinin), nor do they bind to or block other hormone receptors or ion channels known to be 
important in cardiovascular regulation. 
 
Pharmacodynamics 
Losartan inhibits the pressor effect of angiotensin II (as well as angiotensin I) infusions. A dose of 100 mg inhibits the 
pressor effect by about 85% at peak with 25 to 40% inhibition persisting for 24 hours. Removal of the negative feedback 
of angiotensin II causes a doubling to tripling in plasma renin activity and consequent rise in angiotensin II plasma 
concentration in hypertensive patients. Losartan does not affect the response to bradykinin, whereas ACE inhibitors 
increase the response to bradykinin. Aldosterone plasma concentrations fall following Losartan administration. In spite 
of the effect of Losartan on aldosterone secretion, very little effect on serum potassium was observed. 
 
The effect of Losartan is substantially present within one week but in some studies the maximal effect occurred in 3 to 6 
weeks. In long-term follow-up studies (without placebo control) the effect of Losartan appeared to be maintained for up 
to a year. There is no apparent rebound effect after abrupt withdrawal of Losartan. There was essentially no change in 
average heart rate in Losartan-treated patients in controlled trials. 
 
Pharmacokinetics 
Absorption: Following oral administration, Losartan is well absorbed and undergoes substantial first-pass metabolism. 
The systemic bioavailability of Losartan is approximately 33%. Mean peak concentrations of Losartan and its active 
metabolite are reached in 1 hour and in 3 to 4 hours, respectively. While maximum plasma concentrations of Losartan 
and its active metabolite are approximately equal, the AUC (area under the curve) of the metabolite is about 4 times as 
great as that of Losartan. A meal slows absorption of Losartan and decreases its C max but has only minor effects on 
Losartan AUC or on the AUC of the metabolite (~10% decrease). The pharmacokinetics of Losartan and its active 
metabolite are linear with oral Losartan doses up to 200 mg and do not change over time. 
 
Distribution: The volume of distribution of Losartan and the active metabolite is about 34 liters and 12 liters, 
respectively. Both Losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with 
plasma free fractions of 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range 
achieved with recommended doses. Studies in rats indicate that Losartan crosses the blood-brain barrier poorly, if at all. 
 
Metabolism: Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 
enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II 
receptor antagonism that follows Losartan treatment. About 14% of an orally-administered dose of Losartan is 
converted to the active metabolite. In addition to the active carboxylic acid metabolite, several inactive metabolites are 
formed. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of Losartan to 
its metabolites. 
 
Elimination: Total plasma clearance of Losartan and the active metabolite is about 600 mL/min and 50 mL/min, 
respectively, with renal clearance of about 75 mL/min and 25 mL/min, respectively. The terminal half-life of Losartan is 


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about 2 hours and of the metabolite is about 6 to 9 hours. After single doses of Losartan administered orally, about 4% 
of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion 
contributes to the elimination of Losartan and its metabolites. Following oral 14C-labeled Losartan, about 35% of 
radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of 14C-labeled 
Losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces. Neither Losartan nor its metabolite 
accumulates in plasma upon repeated once-daily dosing. 
 
Special Populations 
Pediatric: Pharmacokinetic parameters after multiple doses of Losartan (average dose 0.7 mg/kg, range 0.36 to 0.97 
mg/kg) as a tablet to 25 hypertensive patients aged 6 to 16 years are shown in Table 4 below. Pharmacokinetics of 
Losartan and its active metabolite were generally similar across the studied age groups and similar to historical 
pharmacokinetic data in adults.  The principal pharmacokinetic parameters in adults and children are shown in the table 
below. 
 
The bioavailability of the suspension formulation was compared with Losartan tablets in healthy adults. The suspension 
and tablet are similar in their bioavailability with respect to both Losartan and the active metabolite. 
 
Geriatric and Sex: Losartan pharmacokinetics have been investigated in the elderly (65 to 75 years) and in both genders. 
Plasma concentrations of Losartan and its active metabolite are similar in elderly and young hypertensives. Plasma 
concentrations of Losartan were about twice as high in female hypertensives as male hypertensives, but concentrations 
of the active metabolite were similar in males and females. No dosage adjustment is necessary. 
 
Race: Pharmacokinetic differences due to race have not been studied. 
 
Renal Insufficiency: Following oral administration, plasma concentrations and AUCs of Losartan and its active metabolite 
are increased by 50 to 90% in patients with mild (creatinine clearance of 50 to 74 mL/min) or moderate (creatinine 


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clearance 30 to 49 mL/min) renal insufficiency. In this study, renal clearance was reduced by 55 to 85% for both Losartan 
and its active metabolite in patients with mild or moderate renal insufficiency. Neither Losartan nor its active metabolite 
can be removed by hemodialysis. 
 
Hepatic Insufficiency: Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, 
plasma concentrations of Losartan and its active metabolite were, respectively, 5-times and about 1.7-times those in 
young male volunteers. Compared to normal subjects the total plasma clearance of Losartan in patients with hepatic 
insufficiency was about 50% lower and the oral bioavailability was about doubled. Use a starting dose of 25 mg for 
patients with mild to moderate hepatic impairment. Losartan potassium has not been studied in patients with severe 
hepatic impairment.  
 
Drug Interactions 
No clinically significant drug interactions have been found in studies of Losartan potassium with hydrochlorothiazide, 
digoxin, warfarin, cimetidine and phenobarbital. However, rifampin has been shown to decrease the AUC of Losartan 
and its active metabolite by 30% and 40%, respectively. Fluconazole, an inhibitor of cytochrome P450 2C9, decreased 
the AUC of the active metabolite by approximately 40%, but increased the AUC of Losartan by approximately 70% 
following multiple doses. Conversion of Losartan to its active metabolite after intravenous administration is not affected 
by ketoconazole, an inhibitor of P450 3A4. The AUC of active metabolite following oral Losartan was not affected by 
erythromycin, an inhibitor of P450 3A4, but the AUC of Losartan was increased by 30%. 
 
The pharmacodynamic consequences of concomitant use of Losartan and inhibitors of P450 2C9 have not been 
examined. Subjects who do not metabolize Losartan to active metabolite have been shown to have a specific, rare 
defect in cytochrome P450 2C9. These data suggest that the conversion of Losartan to its active metabolite is mediated 
primarily by P450 2C9 and not P450 3A4. 
 
Nonclinical Toxicology 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Losartan potassium was not carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 
and 92 weeks, respectively. Female rats given the highest dose (270 mg/kg/day) had a slightly higher incidence of 
pancreatic acinar adenoma. The maximally tolerated dosages (270 mg/kg/day in rats, 200 mg/kg/day in mice) provided 
systemic exposures for Losartan and its pharmacologically active metabolite that were approximately 160 and 90 times 
(rats) and 30 and 15 times (mice) the exposure of a 50 kg human given 100 mg per day. 
 
Losartan potassium was negative in the microbial mutagenesis and V-79 mammalian cell mutagenesis assays and in the 
in vitro alkaline elution and in vitro and in vivo chromosomal aberration assays. In addition, the active metabolite 
showed no evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro chromosomal 
aberration assays. 
 
Fertility and reproductive performance were not affected in studies with male rats given oral doses of Losartan 
potassium up to approximately 150 mg/kg/day. The administration of toxic dosage levels in females (300/200 
mg/kg/day) was associated with a significant (p<0.05) decrease in the number of corpora lutea/female, implants/female, 
and live fetuses/female at C-section. At 100 mg/kg/day only a decrease in the number of corpora lutea/female was 
observed. The relationship of these findings to drug-treatment is uncertain since there was no effect at these dosage 
levels on implants/pregnant female, percent post-implantation loss, or live animals/litter at parturition. In nonpregnant 
rats dosed at 135 mg/kg/day for 7 days, systemic exposure (AUCs) for Losartan and its active metabolite were 
approximately 66 and 26 times the exposure achieved in man at the maximum recommended human daily dosage (100 
mg). 
 
Contraindications 
Losartan potassium is contraindicated: 


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• 
In patients who are hypersensitive to any component of this product. 
• 
For co-administration with aliskiren in patients with diabetes. 
 
Warnings and Precautions 
Fetal Toxicity 
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal 
renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with 
fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, 
hypotension, renal failure, and death. When pregnancy is detected, discontinue Losartan potassium as soon as possible.  
 
Hypotension in Volume- or Salt-Depleted Patients 
In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being 
treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Losartan 
potassium. Correct volume or salt depletion prior to administration of Losartan potassium. 
 
Renal Function Deterioration 
Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin­-angiotensin system 
and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., 
patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be 
at particular risk of developing acute renal failure on Losartan potassium. Monitor renal function periodically in these 
patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal 
function on Losartan potassium. 
 
Hyperkalemia 
Monitor serum potassium periodically and treat appropriately. Dosage reduction or discontinuation of Losartan 
potassium may be required. 
 
Adverse Reactions 
Clinical Trials Experience 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical 
trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates 
observed in practice. 
 
Hypertension 
Losartan potassium has been evaluated for safety in more than 3300 adult patients treated for essential hypertension 
and 4058 patients/subjects overall. Over 1200 patients were treated for over 6 months and more than 800 for over one 
year. 
 
Treatment with Losartan potassium was well-tolerated with an overall incidence of adverse events similar to that of 
placebo. In controlled clinical trials, discontinuation of therapy for adverse events occurred in 2.3% of patients treated 
with Losartan potassium and 3.7% of patients given placebo. In 4 clinical trials involving over 1000 patients on various 
doses (10 to 150 mg) of Losartan potassium and over 300 patients given placebo, the adverse events that occurred in 
≥2% of patients treated with Losartan potassium and more commonly than placebo were: dizziness (3% vs. 2%), upper 
respiratory infection (8% vs. 7%), nasal congestion (2% vs. 1%), and back pain (2% vs. 1%). 
 
The following less common adverse reactions have been reported: 
 
Blood and lymphatic system disorders: Anemia. 
Psychiatric disorders: Depression. 


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Nervous system disorders: Somnolence, headache, sleep disorders, paresthesia, migraine. 
Ear and labyrinth disorders: Vertigo, tinnitus. 
Cardiac disorders: Palpitations, syncope, atrial fibrillation, CVA. 
Respiratory, thoracic and mediastinal disorders: Dyspnea. 
Gastrointestinal disorders: Abdominal pain, constipation, nausea, vomiting. 
Skin and subcutaneous tissue disorders: Urticaria, pruritus, rash, photosensitivity. 
Musculoskeletal and connective tissue disorders: Myalgia, arthralgia. 
Reproductive system and breast disorders: Impotence. 
General disorders and administration site conditions: Edema. 
 
Cough 
Persistent dry cough (with an incidence of a few percent) has been associated with ACE-inhibitor use and in practice can 
be a cause of discontinuation of ACE-inhibitor therapy. Two prospective, parallel-group, double-blind, randomized, 
controlled trials were conducted to assess the effects of Losartan on the incidence of cough in hypertensive patients 
who had experienced cough while receiving ACE-inhibitor therapy. Patients who had typical ACE-inhibitor cough when 
challenged with lisinopril, whose cough disappeared on placebo, were randomized to Losartan 50 mg, lisinopril 20 mg, 
or either placebo (one study, n=97) or 25 mg hydrochlorothiazide (n=135). The double-blind treatment period lasted up 
to 8 weeks. These studies demonstrate that the incidence of cough associated with Losartan therapy, in a population 
that all had cough associated with ACE-inhibitor therapy, is similar to that associated with hydrochlorothiazide or 
placebo therapy. Cases of cough, including positive re-challenges, have been reported with the use of Losartan in 
postmarketing experience. 
 
Hypertensive Patients with Left Ventricular Hypertrophy 
In the Losartan Intervention for Endpoint (LIFE) study, adverse reactions with Losartan potassium were similar to those 
reported previously for patients with hypertension. 
 
Nephropathy in Type 2 Diabetic Patients 
In the Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study involving 
1513 patients treated with Losartan potassium or placebo, the overall incidences of reported adverse events were 
similar for the two groups. Discontinuations of Losartan potassium because of side effects were similar to placebo (19% 
for Losartan potassium, 24% for placebo). The adverse events, regardless of drug relationship, reported with an 
incidence of ≥4% of patients treated with Losartan potassium and occurring with ≥2% difference in the Losartan group 
vs. placebo on a background of conventional antihypertensive therapy, were asthenia/fatigue, chest pain, hypotension, 
orthostatic hypotension, diarrhea, anemia, hyperkalemia, hypoglycemia, back pain, muscular weakness, and urinary 
tract infection. 
 
Postmarketing Experience 
The following additional adverse reactions have been reported in postmarketing experience with Losartan potassium. 
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to 
estimate their frequency reliably or to establish a causal relationship to drug exposure: 
 
Digestive: Hepatitis. 
General Disorders and Administration Site Conditions: Malaise. 
Hematologic: Thrombocytopenia. 
Hypersensitivity: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of 
the face, lips, pharynx, and/or tongue has been reported rarely in patients treated with Losartan; some of these patients 
previously experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schönlein 
purpura, has been reported. Anaphylactic reactions have been reported. 
Metabolic and Nutrition: Hyponatremia. 
Musculoskeletal: Rhabdomyolysis. 


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Nervous system disorders: Dysgeusia. 
Skin: Erythroderma. 
 
Drug Interactions 
Agents Increasing Serum Potassium 
Coadministration of Losartan with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor 
serum potassium in such patients. 
 
Lithium 
Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of 
lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use. 
 
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, 
coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists (including 
Losartan) may result in deterioration of renal function, including possible acute renal failure. These effects are usually 
reversible. Monitor renal function periodically in patients receiving Losartan and NSAID therapy. 
 
The antihypertensive effect of angiotensin II receptor antagonists, including Losartan, may be attenuated by NSAIDs, 
including selective COX-2 inhibitors. 
Dual Blockade of the Renin-Angiotensin System (RAS) 
Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased 
risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to 
monotherapy. 
 
The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial enrolled 1448 patients with type 2 diabetes, 
elevated urinary-albumin-to-creatinine ratio, and decreased estimated glomerular filtration rate (GFR 30 to 89.9 
mL/min), randomized them to lisinopril or placebo on a background of Losartan therapy and followed them for a median 
of 2.2 years. Patients receiving the combination of Losartan and lisinopril did not obtain any additional benefit compared 
to monotherapy for the combined endpoint of decline in GFR, end stage renal disease, or death, but experienced an 
increased incidence of hyperkalemia and acute kidney injury compared with the monotherapy group. 
In most patients no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined 
use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on Losartan potassium 
and other agents that affect the RAS. 
 
Do not co-administer aliskiren with Losartan potassium in patients with diabetes. Avoid use of aliskiren with Losartan 
potassium in patients with renal impairment (GFR <60 mL/min). 
 
6.1.2 DOSING AND ADMINISTRATION 
Treatment administration 
• 
For patients with baseline weight ≥ 70 kg and < 150 kg, start treatment with one capsule of 50 mg of 
losartan or matching placebo in the morning for 1 week, then increase to two 50 mg capsules in the morning 
(100 mg total) losartan or matching placebo starting in week 2. 
 
Dose adjustment: If patient is currently taking the higher dose (100 mg losartan or matching placebo), and he/she 
develops a treatment related CTCAE v5.0 -defined adverse event grade 3 or above, or low blood pressure defined as 


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either SBP < 90 mmHg or DBP < 60 mmHg, reduce dosage to a 50 mg dose (losartan or matching placebo, one capsule 
each morning) for one week. If the event resolves, an attempt to reach the higher dose may be made.  
If the event did not resolve at the lower 50 mg dose (losartan or matching placebo), the study medication will be 
stopped and the patient will no longer receive the study medication, but will continue to be followed in the study 
according to the protocol, in keeping with the “intention-to-treat” paradigm.  
 
Holding medication: If patient is currently taking the lower dose (50mg losartan or matching placebo), and he/she 
develops a treatment related CTCAE v5.0-defined adverse event grade 3 or above, or low blood pressure defined as 
either SBP < 90 mmHg or DBP < 60 mmHg, the medication will be stopped and the patient assessed by the site study 
investigator who is a licensed physician. See section 7.1 for additional stopping guidelines. If the low blood pressure was 
mild and short in duration, interventions recommended including 1) drinking more water 2) increasing salt intake and 
the low dose may be re-attempted giving the first dose in a controlled setting (pediatric research center) with 4 hours of 
post dose observation.  
 
If the low blood pressure was severe, prolonged, or in the view of the investigator the subject is intolerant of the 
medication, the study medication will be stopped and the patient will no longer receive the study medication, but will 
continue to be followed in the study according to the protocol, in keeping with the “intention-to-treat” paradigm. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
An investigator may not administer an investigational new drug to human subjects until the IND goes into effect (30 days 
after IND receipt by FDA) or sooner if notified.  And investigational drug under IND may only be used by an investigator 
in compliance with 21 CFR Part 50 and 21 CFR Part 56.  All drug and placebo will be distributed to the individual sites by 
the Drug Distribution Center (DDC) and received by the research pharmacist at each site.  Expired or unused drug at the 
end of the study will be disposed of by each site.   
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
FROM FDA PACKAGE INSERT: 
How Supplied/Storage and Handling 
Losartan Potassium USP 50 mg tablets are White to off-white, oval shaped, film-coated tablets with “A50” engraved on 
one side and break line on the other side. They are supplied as follows: 
  
NDC 42571-111-30 unit of use bottles of 30 
NDC 42571-111-90 unit of use bottles of 90 
NDC 42571-111-10 unit dose packages of 1000 
 
For this study, all losartan and placebo will be over-encapsulated to ensure the losartan and placebo capsules look 
identical and will be labeled as “losartan or placebo for investigational use only”. 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Keep container 
tightly closed. Protect from light. 
 
6.2.4 PREPARATION 
 
No preparation is required because capsules will be provided to sites in patient ready packaging.   


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6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Randomization: The randomization scheme will assign patients into two groups to receive either losartan potassium or 
placebo. The randomization design will be stratified by clinical center with assignments in permuted blocks of random 
length within each clinic. This scheme will ensure that the two groups will be balanced by calendar time of enrollment 
(to minimize secular effects) and by clinic (to minimize clinic-specific effects of differences in patient populations and 
management).  
The randomization plan will be prepared and administered centrally by the Data Coordinating Center (DCC) but will not 
require real time interaction with a DCC staff member. Requests for randomizations will be made by the clinics using a 
web-based application. An assignment will be issued only if the database shows that the patient is eligible, has signed 
the consent/assent statement, and has had all required baseline data keyed into the database. 
Treatment assignments are double masked throughout the study until all data collection for the STOP-NAFLD trial has 
been completed (i.e., after completion of the post-trial follow-up for all participants). Every effort will be made to 
maintain the masking throughout the study except in emergencies. The code of specific pharmacological treatment will 
not be broken without the knowledge of the clinical center’s principal investigator and the study leadership. 
Unmasking of study medication may occur under the following conditions: 
• Severe allergic reaction (Stevens-Johnson Syndrome): Study medication is stopped indefinitely. The patient, 
primary care provider (PCP), and the investigator may be unmasked. 
• Pregnancy during the study: Study medication will be stopped indefinitely, and the coded medication may be 
unmasked. The patient, PCP, and investigator will be notified of the associated risks of teratogenicity. 
• Development of hepatotoxicity: Hepatotoxicity will be defined as 1) the development of jaundice with a serum 
direct bilirubin of > 1.0 mg/dL, 2) an increase in the baseline ALT and AST value that is two-fold, or 3) ALT and 
AST value > 400 U/L during treatment.   Study medication will be discontinued; however, there will be no 
unmasking until study conclusion. 
• Development of hypotension: Drug will be stopped and participant evaluated.  Drug may be unmasked if the 
hypotension is severe.   
The Data and Safety Monitoring Board will review all instances of unmasking that occur. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Two important goals of this protocol are to optimize adherence to the pharmacological regimen and to maximize the 
retention of participants in the study. Assessment of adherence to the assigned study drug will provide clinic staff a 
means to identify participants having problems with adherence. Adherence will be assessed by: 
• Counts of capsules in the patient’s returned study drug bottles 


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• Conducting a brief, structured interview, in which the study coordinator will assist the patients in identifying 
problems in taking the study drug and in estimating adherence to the prescribed medicine since their previous 
visit. 
These assessments will guide the consideration of strategies to improve adherence. Resources will be provided to 
remove barriers to participation such as child care, transportation, and parking expenses. These resources can be 
provided as cash, transportation vouchers, or parking passes. An honorarium (up to $50 per visit) may be paid to 
participants in recognition of their time and effort when scheduled visits and procedures are completed successfully. 
Certificates of appreciation may be given at enrollment and at conclusion of the STOP-NAFLD trial as an incentive. 
6.5 
CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a properly 
authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are concomitant prescription 
medications, over-the-counter medications and supplements.  Certain medications known to interact with losartan 
potassium are excluded from use during the trial.  These include:  
• 
ACE inhibitors 
• 
Any anti-hypertensive drug 
• 
Potassium supplements 
• 
Any drug known to increase potassium  
• 
NSAIDs 
Participants will be questioned regarding any new medication at each visit and informed of the above exclusions.  
 
6.5.1 RESCUE MEDICINE 
N/A 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
If patient develops a treatment related CTCAE v5.0-defined adverse event (grade 3 or above) or low blood pressure 
defined as either SBP < 90 mmHg or DBP < 60 mmHg and he/she is on the starting dose (50 mg losartan or matching 
placebo), the medication will be held and the patient assessed by the site a study investigator who is a licensed 
physician.  If the low blood pressure was mild and short in duration, interventions recommended include 1) drinking 
more water 2) increasing salt intake; and the dose may be re-attempted giving the first dose in a controlled setting 
(pediatric research center) with 4 hours of post dose observation.  If the low blood pressure was severe, prolonged, or in 
the view of the investigator the subject is intolerant of the medication, the participant will be withdrawn from the study 
intervention but will continue to be followed.   See 6.1.2. 
 
Study medication will be STOPPED if participant is determined to be pregnant. 
Patients will be monitored for drug induced liver injury and will use the scale below to grade the adverse effects: 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ALT 
BSL nl: 3x ULN 
BSL elevated: 3x BSL  
BSL nl: >3-5x ULN 
BSL elevated: >3-5x BSL  
BSL nl: >5-20x ULN 
BSL elevated: >5 -20x 
BSL  
BSL nl: >20x ULN 
BSL elevated: >20x BSL  


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AST 
BSL nl: 3x ULN 
BSL elevated: 3x BSL 
BSL nl:>3-5x ULN 
BSL elevated: >3-5x BSL  
BSL nl:>5-20x ULN 
BSL elevated: >5-20x BSL  
BSL nl:>20x ULN 
BSL elevated: >20x BSL  
T 
Bilirubin  
1.5x ULN  
>1.5-3.0x ULN 
>3.0-10.0x ULN 
>10.0x ULN 
In addition, patients will have the study medication stopped if ANY of the following occur:  
If normal baseline AST: 
• 
AST value >5x ULN in two repeat tests; OR 
• 
AST value is >x8 ULN; OR 
• 
AST value >5x ULN AND total bilirubin >2x ULN* OR presence of symptoms suggesting liver injury (severe 
fatigue, nausea, vomiting or right upper quadrant pain), 
If elevated baseline AST or ALT: 
• 
ALT or AST value >3x ULN or 300 U/L in two repeat tests; OR 
• 
ALT or AST value >5x BSL or >500 U/L (whichever occurs first); OR 
• 
ALT or AST value >3x BSL or >300 U/L (whichever occurs first) AND total bilirubin >2x ULN* OR presence of 
symptoms suggesting liver injury (severe fatigue, nausea, vomiting or right upper quadrant pain) 
* For patients with suspected Gilbert’s Syndrome at baseline: doubling of direct bilirubin. Patients will be monitored for 
hyperkalemia and will use the CTCAE 5.0 based scale below to grade severity and determine course of action: 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Potassium 
>ULN - 5.5 mmol/L 
>5.5 - 6.0 mmol/L; 
intervention initiated  
 
>6.0 - 7.0 mmol/L; 
hospitalization 
indicated  
 
>7.0 mmol/L; life-
threatening 
consequences  
 
Study medication will be stopped if hyperkalemia reaches Grade 2. 
 
In addition, patients will be monitored for renal disease, and we will use the following CTCAE based scale to grade 
severity: 
 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Chronic Kidney 
Disease 
eGFR<LLN-60 
ml/min/1.73 m2 
eGFR 59-30 
ml/min/1.73 m2 
eGFR 29-15 
ml/min/1.73 m2 
eGFR <15 
ml/min/1.73 m2; 
dialysis or renal 
transplant indicated 
Creatinine Increased 
Creatinine 1.5x ULN  
Creatinine 1.5-3.0x 
baseline; >1.5 -3.0x 
ULN  
Creatinine >3.0x 
baseline; >3.0 -6.0x 
ULN 
Creatinine >6.0x ULN 
 
Study medication will be stopped if eGFR drops to 59 - 30 ml/min/1.73 m2, OR if creatinine becomes elevated > 1.5x 
ULN.  
Discontinuation from study medication (losartan or matching placebo) 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 


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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 data to be collected at the time of study intervention discontinuation will include the following: 
• 
Labs and anthropometrics 
• 
Study medication bottles and documentation of capsule counts 
 
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 
• 
Significant non-compliance with study intervention  
• 
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 
• 
If the participant meets an exclusion criterion (either newly developed or not previously recognized) that 
precludes further study participation 
• 
Participant unable to receive losartan potassium for > 4 weeks  
Discontinuation from study medication (losartan or matching placebo) does not mean discontinuation from the study, 
and remaining study procedures should be completed as indicated by the study protocol. The reason for participant 
discontinuation or withdrawal from the study will be recorded on the Case Report Form (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 visit and is unable to be 
contacted by the study site staff.  
 
The following actions must be taken if a participant does not return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit (within 4 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 investigator or designee will make every effort to regain 
contact with the participant (where possible, 3 telephone calls and, if necessary, a certified letter to the 
participant’s last known mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record or study file.  
• 
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 
EFFICACY ASSESSMENTS  
8.1.1 VISIT SCHEDULE OVERVIEW 


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The patient-related activities of the STOP-NAFLD trial can be divided into 4 phases: 
• 
Screening for eligibility for enrollment (60 days) 
• 
Randomization to treatment (1 visit) 
• 
Treatment phase (3 visits over 24 weeks) 
• 
Post-treatment washout phase (1 visit at 36 weeks) 
8.1.2 SCREENING AND BASELINE DATA COLLECTION 
Patients who appear to be eligible after chart review will be invited to undergo screening. Recording of screening data 
on NASH CRN forms may not start until the parent or legal guardian has signed the consent statement and the patient 
has signed the assent statement. Screening and baseline data collection procedures will include questionnaires, physical 
examination, measurement of fasting serum glucose and insulin, standard of care liver biopsy, lipid and metabolic tests, 
etiologic tests, urine analysis, and blood collection for DNA and serum and plasma banking.  Prior therapy for NAFLD will 
be reviewed as outlined in the inclusion and exclusion criteria. Patient charts will be reviewed for historical information 
and previous liver biopsy findings.  
All participants who sign the consent/assent documents will be registered in the trial database. Each participant who 
starts screening will be accounted for at the end of screening, as either a screening success (enrolling in the trial) or a 
screening failure. A screening failure is defined as a participant who signed the consent/assent form, but is found to be 
ineligible prior to randomization. Screening failures include patients who meet medical eligibility criteria but who refuse 
enrollment in the trial. Reasons for screening failure will be recorded in the trial database.  Screening data collection will 
be conducted over two clinic visits usually completed on separate calendar days. The goal of the first screening visit is to 
obtain consent and record data regarding the trial’s inclusion and exclusion criteria; the goal of the second screening 
visit is to complete collection of baseline data on patients who appear eligible. This separation of procedures between 
two visits is provided as a practical guideline. Screening procedures and data collection can be organized as appropriate 
at each clinical center.  The procedures completed during screening are described below. 
Screening visits 
Determination of eligibility will be based mostly on chart review of standard of care tests and procedures that were 
completed before the first screening visit. The parent or legal guardian and child will sign the consent and assent at the 
first screening visit (or before) to obtain any tests and procedures needed to finalize eligibility after chart review. 
Participants will undergo a medical history and detailed physical examination including anthropometric assessments 
(body weight [kg], body height [m], body mass index [BMI], waist circumference [cm], and hip circumference [cm]) to 
identify other illnesses and contraindications for participation, including hepatosplenomegaly, peripheral manifestations 
of liver disease, ascites, wasting or fetor, or stage 2 hypertension for their age and height based on the AAP Clinical 
Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents[104].  History of 
prior liver biopsies will be obtained and recorded. Laboratory test results that need to be recorded from chart review or 
obtained as part of the screening visits include: tests for hepatitis B (HBsAg) and hepatitis C, anti-nuclear antibody (ANA), 
anti-mitochondrial antibody (AMA), anti-smooth muscle antibody (ASMA), ceruloplasmin, A1AT concentration, iron 
overload (iron, TIBC, and ferritin). The ALT measurement must be completed within 30 days of randomization. The 
additional lab tests for screening must  be completed within 60 days of randomization: fasting serum glucose, insulin, 
HgbA1C, complete blood count (CBC) with white blood cell differential, hepatic panel (total and direct bilirubin, AST, 
alkaline phosphatase, albumin, total protein, GGT, PT, INR), metabolic panel (sodium, potassium, chloride, carbon 


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dioxide, calcium, BUN, creatinine, uric acid), eGFR (using Schwartz Bedside GFR Calculator for Children IDMS-traceable), 
C-reactive protein and lipid panel (total cholesterol, triglyceride, LDL, HDL).   
Females of childbearing potential must have a negative pregnancy test. Frequency and amount of alcohol intake will be 
obtained using the Alcohol Use Disorders Identification Test (AUDIT). Patients and parents will complete the health-
related quality of life questionnaire (PedsQL) and the BEV-Q questionnaire to document habitual beverage intake 
(grams, energy).  A blood sample will be drawn to obtain DNA for banking and serum/plasma for banking for future 
analysis of markers of exploratory outcomes including cytokines and NMR based lipids.   
Baseline liver biopsy  
Eligibility requires a liver biopsy within 730 days prior to enrollment). The baseline liver biopsy is not performed as a 
procedure in this study but as standard of care done for clinical care. Usually, this will have been done prior to 
consideration for this study.  If a child’s hepatologist believes that the child has NAFLD, has scheduled him or her for a 
clinical liver biopsy, and they meet all other inclusion and exclusion criteria, then the child may be registered prior to the 
liver biopsy. Regardless of whether the biopsy is done before or after registration, the liver histology must be 
determined to be NAFLD with a NAS of at least 3. The NASH CRN study physician should check if tissue blocks and/or 
additional slides can be obtained from the original biopsy. A NASH CRN certified pathologist will read and score the 
biopsy. For participants who have had a prior biopsy that was centrally reviewed by the NASH CRN pathologists, those 
scores will be used. 
Clinic staff should note that the date of the biopsy establishes a hard window for completion of screening procedures 
prior to randomization – randomization must take place within 730 days of the date of biopsy. Clinic staff will have to 
monitor completion of screening procedures in order to assure adherence to the allowable time window. 
The NASH CRN clinic data system will include software to check patient eligibility based on keyed data forms. The 
eligibility check task may be run at any time, and there is no limit on the number of times it may be run. The output from 
the task will list the eligibility checks that the patient has failed and a summary finding that the patient is eligible or 
ineligible for the trial. Clinic staff can use this task to identify the items that still need to be completed, keyed, or verified 
after data from the screening visit are keyed. The randomization visit should not take place until the eligibility check 
indicates that the patient is eligible except for the items that can be completed only at the randomization visit. 
8.1.3 RANDOMIZATION VISIT 
The randomization visit is the visit at which randomization takes place and the patient is issued the study medication 
randomly assigned to the patient. Randomization is the act of generating the random study medication assignment and 
is the procedure which defines a patient’s enrollment into the trial. Randomization can only occur after eligibility has 
been fully checked and all data collected at the screening visits have been keyed to the trial database. Since these 
processes take time, randomization cannot be done at a screening visit, and since study medication needs to be issued 
to the patient, the randomization visit must be completed in person with the patient. Therefore, a visit separate from 
the screening visit is necessary. Since this will be a visit on a different calendar day and medication will be started at this 
visit, good clinical practice requires that a few basic checks of the patient’s well-being be completed at the 
randomization visit. 


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The procedures completed at the randomization visit are: pregnancy test for females of child bearing potential; 
verification that the patient is feeling well; affirmation of consent; review of concomitant drugs and vital signs (systolic 
and diastolic blood pressure, heart rate, respiratory rate, body temperature). All patients will be given information on a 
healthy life style and diet appropriate for their weight and other factors. 
Generation of the random treatment assignment will occur at this visit.  The randomization process includes the same 
electronic check on eligibility that the staff may run prior to the randomization visit.  The medication assignment will not 
be generated unless the check finds that the patient is eligible, and the clinic staff indicates that they want to randomize 
the patient.  The random treatment assignment will consist of medication bottle numbers; these numbers will be unique 
and will be specific to the particular patient it was generated for.  They will correspond to numbered bottles of 
medications which have been sent to the clinical center’s research pharmacy (or clinical coordinator if not using a 
pharmacy) by the NASH CRN Drug Distribution Center.  The research pharmacy (or clinical coordinator) will issue the 
specific numbered bottles to the patient. Each patient’s random treatment assignment will be generated for that specific 
patient and will not be transferable to another patient.  Once the assignment has been generated, the patient should be 
issued the assigned study drug (in person) and instructed about starting the drug and monitoring for adverse effects and 
completion of the blood pressure log.  Patients and their parents will be taught to use an automated blood pressure 
monitor. Patients will be asked to take their blood pressure each morning for the first 14 days and bring the log to their 
next clinic visit. Patients and parents will be instructed to call the clinic if blood pressure drops below < 90 mmHg 
systolic or < 60 mmHg diastolic.  The logs will be reviewed at the first follow-up visit and checked for hypotension. The 
date of randomization is the 0 time for reckoning all follow-up visits (i.e., all follow-up visits are scheduled at specific 
times measured from the date of randomization).  The randomization computer program will generate a personalized 
appointment schedule for the patient; this schedule will indicate the ideal date for each follow-up visit, as well as the 
time window around the ideal date during which the follow-up visit may be done.  This will ensure that the data 
collected at the follow-up visit may be used in the trial. 
8.1.4 FOLLOW-UP VISITS 
Patients will be called by study staff during Week 2 after they have started on the higher dose (100 mg losartan or 
matching placebo). The blood pressure log will be reviewed on the telephone call and parents/patients will be asked 
about any adverse effects they (their child) may be experiencing. 
Patients will return to the clinical center for follow-up visits at 4, 12, 24 weeks after randomization. Patients will be seen 
for one visit at four weeks after randomization, then at 12 weeks after randomization, and 24 weeks after randomization 
(end of treatment visit).  A post-treatment washout phase visit will occur at week 36.  Each visit will have an interval of 
time surrounding the ideal date for the visit during which the visit may be done and the data included in the trial 
database.  The ideal date for a visit is the exact anniversary date from randomization.  Visit windows will be constructed 
to be contiguous, so that at any point in time, some visit window is open, subject to a check on the minimum separation 
of at least two weeks is required between consecutive visits.  The specific procedures to be completed at each of the 
follow-up visits are: 
• Week 4 visit:  Review of blood pressure log, medications, adverse effects, study drug adherence, pregnancy test, 
blood draw for metabolic panel (sodium, potassium, chloride, carbon dioxide, calcium, BUN, creatinine, 
eGFR), hepatic panel (total and direct bilirubin, AST, ALT, alkaline phosphatase, albumin, total protein); 
focused physical examination including height, weight, waist and hip measurements, vital signs 


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(temperature, heart rate, respiratory rate, blood pressure), and liver signs; and standardized nutrition and 
exercise prescription and counseling. Review study drug adherence with patient.  
• Week 12 visit:  Follow-up medical history including review of medications, adverse effects, and interim drinking 
history; focused physical examination including height, weight, waist and hip measurements, vital signs 
(temperature, heart rate, respiratory rate, blood pressure), and liver signs; blood draw for CBC, metabolic 
panel (sodium, potassium, chloride, carbon dioxide, calcium, BUN, creatinine, eGFR), uric acid, hepatic panel 
(total and direct bilirubin, AST, ALT, alkaline phosphatase, albumin, total protein), GGT, PT, INR, C-reactive 
protein; fasting glucose, insulin, HbA1c, lipid profile; plasma and serum for banking at a central repository;  
pregnancy test (for females of child-bearing potential); standardized nutrition and exercise prescription.  
Review study drug adherence with patient. 
• Week 24 visit:  Follow-up medical history including review of medications, adverse effects, and interim drinking 
history; a health-related quality of life questionnaire (PedsQL); BEV-Q questionnaire; detailed physical 
examination, including height, weight, waist and hip measurements, vital signs (temperature, heart rate, 
respiratory rate, blood pressure), organ systems and liver signs; blood draw for CBC, comprehensive 
metabolic panel (sodium, potassium, chloride, carbon dioxide, calcium, BUN, creatinine, eGFR), uric acid, 
hepatic panel (total and direct bilirubin, AST, ALT, alkaline phosphatase, albumin, total protein), GGT, PT, 
INR, C-reactive protein; fasting glucose, insulin, HbA1c, lipid profile; blood draw for plasma and serum 
banking at a central repository; pregnancy test (for females of child-bearing potential); standardized 
nutrition and exercise prescription and counseling. Review study drug adherence with patient. Collect all 
study drug bottles. 
• Week 36 visit:  Follow-up visit 12 weeks after discontinuation of study drug. Follow-up medical history including 
review of medications, adverse effects, and interim drinking history; a health-related quality of life 
questionnaire (PedsQL); BEV-Q questionnaire; focused physical examination including height, weight, waist 
and hip measurements, vital signs (temperature, heart rate, respiratory rate, blood pressure), and liver 
signs; blood draw for CBC, metabolic panel (sodium, potassium, chloride, carbon dioxide, calcium, BUN, 
creatinine, eGFR), C-reactive protein; uric acid, hepatic panel (total and direct bilirubin, AST, ALT, alkaline 
phosphatase, albumin, total protein), and for plasma and serum banking at a central repository. 
8.1.5 STANDARDIZED QUESTIONNAIRES  
Standardized questionnaires will be administered to patients enrolled in the STOP-NAFLD trial. Questionnaires will be 
administered at screening (prior to randomization) and during follow-up at specified intervals (see 1.3) for the data 
collection schedule). The purpose of the questionnaires is to obtain important information regarding alcohol intake, 
beverage intake, and health-related quality of life. 
Alcohol Use Disorders Identification Test (AUDIT) is a 10-item questionnaire with a simple scoring scale that will be 
administered during screening. A 3-item interim drinking history (AUDIT-C) measuring consumption since the last visit 
will be obtained during follow-up visits as part of the follow-up medical history.  The purpose of these questionnaires is 
to ascertain that there is no significant alcohol consumption prior to enrollment or during the study period.  
The Pediatric Quality of Life (PedsQL) questionnaire will be administered during screening, after 24 weeks of treatment, 
and at the week 36 visit. 


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Bev-Q: The Beverage questionnaire will be administered during screening, after 24 weeks of treatment and at the week 
36 visit.   
Specimen repositories 
Specimens will be collected and stored in the NIDDK central repositories for use as approved by the Steering Committee 
of the NASH CRN. Specimens include serum, plasma, and DNA. The blood collected during screening, and at the 12, 24, 
and 36 week follow-up visits will be separated into plasma and serum, and divided into 0.5 mL aliquots. Aliquots will be 
kept in a storage facility at -70 degrees C until they are shipped to the NIDDK Biosample Repository on dry ice.  If the 
patient provided additional consent, blood will be collected during screening and sent to a laboratory where DNA will be 
extracted, and the DNA sample will be shipped to the NIDDK Genetics Repository for banking.  
8.2 
SAFETY AND OTHER ASSESSMENTS 
Assessments for Safety 
• 
Physical examination (e.g., height, weight, waist and hip measurements, vital signs (temperature, heart rate, 
respiratory rate, blood pressure), and liver symptoms.   
• 
Laboratory results – All labs including creatinine (and calculated GFR) potassium levels and bicarbonate will be 
monitored at sites and in the central database and all abnormal values will be managed by the site investigator.  
If the potassium or creatinine is elevated (or GFR decreases by more than 30%), it will be repeated within 5 days 
See section 7.1 for discontinuation of the study medication.   
Biological specimen collection and laboratory evaluations – There will be consistent methods throughout the study 
to ensure comparison.  ALT will be measured at each site and the same lab used for the measurement throughout 
the study.  NMR lipids will be measured by Labcorp, a CLIA compliant entity.   
Management of Comorbid Conditions 
Elevated blood pressures, hyperlipidemia, and diabetes will be managed according to the guidance described in the 
Standard of Care document prepared by the Pediatric Standard of Care Committee of NASH CRN and in conjunction with 
the patient’s primary care physician or other specialist. If a participant develops hypertension during the patient’s 
enrollment in the trial, and the physician determines the need of an anti-hypertensive medication (e.g. because lack of 
response to life style changes), the use of diuretics, beta-blockers or calcium channel blocker will be recommended for 
the specialist to consider.  
Pregnancy will be managed according to the guidelines and study drug will be discontinued immediately upon discovery.  
In the event of major dermatological reactions such as generalized urticaria, bullous rashes, exfoliative dermatitis, or 
Stevens-Johnson Syndrome, study drug will be discontinued immediately and not restarted. For local skin reactions, 
study drug may be discontinued if the skin reactions are potentially drug related. If the rashes clear, the study drug may 
be restarted. 
If local skin reactions recur with restarting the study drug, study drug should be discontinued. In cases where the study 
medication has been discontinued, the study drug may be unmasked and the participant, investigator, and the primary 
care provider will be notified in order to prevent future exposures.   
Follow up of Ongoing Adverse Events 
Provisions for follow up of adverse events include phone calls by the coordinators to assess symptoms, in person follow 
up exams when needed to assess vital signs and physical findings and referral to local ongoing care by the pediatrician or 
hospital when needed.   
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 


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8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
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 (SAE)  
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the investigator or 
sponsor, 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 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be used to 
classify Adverse Events when possible. 
8.3.3.1 SEVERITY OF EVENT 
For adverse events (AEs) not included in the protocol defined grading system, 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 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who examines and 
evaluates the participant based on temporal relationship and his/her clinical judgment. The degree of certainty about 
causality will be graded using the categories below. In a clinical trial, the study product must always be suspect.  
 
• 
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 result, occurs in a plausible 
time relationship to study intervention administration and cannot be explained by concurrent disease or other 
drugs or chemicals. The response to withdrawal of the study intervention (de-challenge) should be clinically 
plausible. The event must be pharmacologically or phenomenologically definitive, with use of a satisfactory re-
challenge procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable time after 
administration of the study intervention, is unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and follows a clinically reasonable response on withdrawal (de-challenge). Re-challenge information 
is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event occurred within a 
reasonable time after administration of the trial medication). However, other factors may have contributed to 


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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, including an abnormal laboratory test result, whose temporal 
relationship to study intervention administration 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 other drugs or 
chemicals or underlying disease provides plausible explanations (e.g., the participant’s clinical condition, other 
concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or evidence exists 
that the event is definitely related to another etiology. There must be an alternative, definitive etiology 
documented by the clinician. 
 
8.3.3.3 EXPECTEDNESS  
Site PIs and investigators will be responsible for determining whether an adverse event (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 and in the package insert. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of study personnel 
during study visits and interviews of a study participant presenting for medical care, or upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the appropriate case 
report form (CRF). Information to be collected includes event description, time of onset, clinician’s assessment of 
severity, relationship to study product (assessed only by those with the training and authority to make a diagnosis), 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 deteriorates at any time during the study, it will be 
recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at each level of 
severity to be performed. AEs characterized as intermittent require documentation of onset and duration of each 
episode. 
 
Site coordinators will record all reportable events with start dates occurring any time after informed consent is obtained 
until the last day of study participation.  At each study visit, the investigator/coordinator 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 events will be recorded on study data forms whether or not they are thought to be associated with the study or 
with the study drug. Adverse events may be discovered during regularly scheduled visits or through unscheduled patient 
contacts between visits.   
 
Summary data on adverse events will be monitored by the DSMB quarterly and at its semiannual meetings or more 
frequently, as needed. These summaries will include analyses comparing rates of adverse events by treatment group, by 
clinic, or in other subgroups requested by the DSMB. Where applicable, signs and symptoms associated with the adverse 


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event will be graded as to severity by the clinical site staff as mild, moderate, or severe using Version 5.0 of the National 
Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE). 103 
 
After each DSMB meeting, the NIDDK will issue a written summary of the review of the study data, including adverse 
events, for transmission to the IRBs at each of the study centers. Analyses or listings of adverse events will not be 
provided to the IRBs; however, adverse events involving unanticipated problems involving risks to participants, or 
breaches of protocol which might entail risk to participants must be reported to local IRBs as soon as possible after they 
are discovered. Each participating center is responsible for ensuring that all local IRB requirements for reporting adverse 
events are met. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
Serious adverse events (SAE) must be reported upon discovery at the clinical center. This will involve completing a data 
form describing the severity and details of the event, which must be submitted to the Data Coordinating Center within 
one business day for review by the Safety Officer. 
 
 
If the SAE is unexpected AND there is a reasonable possibility that the study drug caused the SAE, then the clinical 
center must complete a data form for an IND Safety Report and submit it along with a narrative and a copy of the IRB 
report to the DCC.  The DCC will submit a preliminary report to the NIDDK for review within three business days of 
receiving the SAE data form. The pharmaceutical manufacturer will also be notified within 7 days of the serious adverse 
event, if applicable.  If NIDDK determines that the SAE requires an expedited IND Safety Report, the NIDDK program 
official or the NIDDK Regulatory Affairs Specialist will notify the FDA no more than 15 calendar days from the initial 
receipt of the SAE by the DCC (no later than 7 calendar days if the SAE is fatal or life threatening), if applicable. The 
clinical center investigator may also be responsible for completing an FDA MedWatch 3500 form and additional 
information for a follow-up SAE report as information becomes available. If the FDA determines that a change to the 
investigators brochure, IND or protocol is needed, the Data Coordinating Center will send a copy of the IND Safety 
Report to all clinical centers, with instructions to forward the report to their IRB.  
 
The DCC will maintain a list of all SAEs for reporting and review at Steering Committee meetings and DSMB meetings. 
The DSMB will review each SAE report. If requested by any member of the DSMB, a teleconference will be scheduled to 
discuss the SAE and recommend any actions to the NIDDK sponsor. The clinical center must submit to the NIDDK and to 
the Data Coordinating Center a follow-up memo within one month of the SAE (and periodic updates if needed) to report 
the details of the disposition of the SAE. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
N/A 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
N/A 
 
8.3.9 REPORTING OF PREGNANCY  
Participants will be monitored for pregnancy and required to take precautions to prevent pregnancy.  However, if a 
participant is found to be pregnant, the study medication will be stopped immediately and the coded medication may be 
unmasked. The parent and patient, primary care physician, and investigator will be notified of the associated risks of 
teratogenicity. 
 
 
8.4 
UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 


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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 Institutional Review Board (IRB)-approved research 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. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board (IRB) and to the 
Data Coordinating Center (DCC)/lead principal investigator (PI). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 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) must be reported to the IRB and to the DCC/study sponsor promptly 
but no later than 10 days from the date the investigator was aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within 10 days of the investigator 
becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s written reporting 
procedures), the supporting agency head (or designee), and the Office for Human Research Protections (OHRP) 
within 10 days of the IRB’s receipt of the report of the problem from the investigator. 
• 
Reports should be sent to: IRPT.OS@hhs.gov  
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
These would be reported to participants if they are unexpected, related or possibly related, and suggest greater risk of 
harm to participants. 
 
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
• 
Primary Efficacy Outcomes(s):  That losartan potassium at 100 mg orally daily for 24 weeks is better than placebo in 
improving ALT in children with NAFLD. 
• 
Secondary Efficacy Outcome(s): That losartan potassium at 100 mg orally daily for 24 weeks is better than placebo in 
improving: 
o Relative change in ALT at 24 weeks compared to baseline ALT 
o Proportion of patients achieving normalization of ALT at 24 weeks  
o Change in AST at 24 weeks compared to baseline AST 
o Change in GGT at 24 weeks compared to baseline GGT 


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o Change in ALT at 12 weeks compared to baseline ALT 
o Change in fasting markers of insulin resistance (HOMA-IR) at 24 weeks compared to baseline. 
o Change in anthropometric measurements (weight, BMI z-score, waist to hip ratio, waist circumference) at 24 
weeks compared to baseline 
o Change in serum lipid profiles at 24 weeks compared to baseline 
o Change in Health-related Quality of Life (HR-QoL) scores at 24 weeks compared to baseline 
o Change in frequency of adverse events compared to baseline 
9.2 
SAMPLE SIZE DETERMINATION 
Sample size considerations 
- 
2 equal size groups 
- 
Type 1 error (2-sided) = 0.05 
- 
Power = 90% 
- 
Loss to follow-up = 10%, assumed to be missing completely at random 
- 
Primary outcome = change (FU-BL) in ALT at 24 weeks 
- 
Assumptions based on CYNCH Placebo group 
o Mean (SD) change (FU-BL) in ALT at 24 weeks = -12 (55) U/L 
o Mean change (FU-BL) in ALT at 24 weeks = -12 U/L 
o SD change (FU-BL) in ALT at 24 weeks = 55 U/L (losartan and placebo) 
o Correlation of ALT at baseline and 24 weeks = 0.64 
- 
Method of analysis = ANCOVA (analysis of covariance) of ALT changes (FU-BL) regression 
- 
Detectable difference in change (FU-BL) in ALT at 24 weeks 
o 0.5 SD = 28 U/L (i.e., Losartan vs placebo = -40 vs. -12 U/L) 
- 
Sample size = 55 per group; 110 total  
Sample size and power estimation varying minimum clinically important difference (MCID) and correlation between 
baseline and follow-up 
 
Minimum clinically important 
difference (MCID) 
 
 
 
SDs 
ALT (U/L) 
Correlation between ALT 
at baseline and 24 weeks 
Power 
In protocol 
0.50 
28 
0.64 
0.90 
 
 
 
 
 
Varying MCID 
0.45 
25 
0.64 
0.83 
 
0.40 
22 
0.64 
0.74 
 
0.35 
19 
0.64 
0.62 
 
 
 
 
 
Varying correlation 
0.50 
28 
0.55 
0.85 
 
0.50 
28 
0.50 
0.82 
 
0.50 
28 
0.45 
0.80 
Assumptions: 
- 
Sample size is 55 per group (110 total) 
- 
2-sided Type I error = 5% 
- 
Increase in sample size due to missing data = 10% 
- 
Method of calculation = ANCOVA  


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9.3 
POPULATIONS FOR ANALYSES 
Analysis dataset will include:  
a.) Intention-to-Treat dataset for efficacy 
b.) Safety Analysis Dataset 
c.) Other Datasets for Sensitivity analyses (e.g. subgroups by dose, sex, age, baseline labs, adherence)  
 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
The primary analysis is an intention-to-treat analysis of the change in ALT from baseline over 24 weeks of treatment. The 
statistical model for change in ALT at 24 weeks will be an ANCOVA model with an indicator variable for treatment 
group adjusted for ALT at baseline. If the percentage of patients with missing data on the primary outcome is 
greater than 10%, multiple imputation modeling for missing data will be used; otherwise complete-case analysis will 
be used, excluding patients missing ALT over all 24 weeks of follow-up.   
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY OUTCOME(S) 
• 
Intention-to-Treat (ITT) Analysis Dataset  
The primary outcome is 24-week change in serum ALT, defined as the ALT obtained at 24 week visit minus ALT at the 
baseline visit. The change in serum ALT is measured on a continuous scale and is a single endpoint. The treatment effect 
will be estimated using an analysis of covariance (ANCOVA) model, modeling the change in ALT on an indicator variable 
for treatment group adjusting for the baseline value of ALT. The treatment group difference in adjusted mean change at 
24 weeks along with 95% confidence interval on the difference and p-value from the ANCOVA model will be presented. 
Sensitivity analyses include use of robust regression to down-weight the effect of influential outliers as well as to adjust 
for additional baseline variables. 
9.4.3 ANALYSIS OF THE SECONDARY OUTCOME(S) 
For each secondary outcome: 
 
• 
Analysis of secondary outcomes are not dependent on findings of primary endpoint  
• 
Intention-to-Treat (ITT) Analysis Dataset (i.e., all randomized participants)  
The analysis of secondary outcomes will use the ANCOVA model for continuous outcomes, logistic regression for binary 
outcomes, and Poisson regression for counts. Complete case analyses will be used if missing data < 10%, and multiple 
imputation will be used if missing data is 10% or greater. Sensitivity analyses include use of non-parametric regression 
for continuous data (lowess plots) and scale factor estimation to account for over-dispersion in generalized linear 
models for binary outcome data (dispersion-corrected logistic regression) and count outcome data (dispersion-corrected 
negative binomial regression). 
 
9.4.4 SAFETY ANALYSES 
Safety data will be presented by treatment group to the Data and Safety Monitoring Board during the course of the trial. 
Each adverse event will be displayed showing AE name per the CTCAE v5.0 when applicable, class, severity, patient ID, 
clinic, treatment group, time since randomization, resolution status and physician’s assessment of relatedness to 
treatment. Patient-specific summary tables including any adverse event (yes vs no), frequency of multiple adverse 


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events (i.e., 0, 1, 2, 3+) and highest severity of adverse event (none, mild, moderate, severe, life-threatening) will be 
displayed by treatment group along with p-values from Fisher’s exact tests. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Baseline data will be presented by treatment group and total. Data include stratification variables (clinic) demographics, 
liver enzymes, lipids, hematology, chemistries, metabolic factors, concomitant medications, comorbidities, liver 
histology findings. P-values will be presented as descriptive statistics noting that any treatment group differences are 
due to chance. 
 
9.4.6 PLANNED INTERIM ANALYSES  
There are no planned interim analyses. 
 
9.4.7 SUB-GROUP ANALYSES 
There are no formal planned sub-group analyses. Exploratory sub-group analyses will include treatment effects of 
primary and selected secondary outcomes by stratum variable (clinic), demographics (age, race, sex, and puberty 
status), severity of NAFLD, insulin resistance and study drug adherence. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
For monitoring of adverse effects, individual data may be presented to the Data and Safety Monitoring Board. In that 
case, study patients will be identified by study IDs. Names and other unique individual identifiers such as Social Security 
Number are not collected by the study and therefore will not be presented to the DSMB. Individual data including ID will 
not be presented in a manuscript.  
 
9.4.9 EXPLORATORY ANALYSES 
Similar to the statistical methods used to compare continuous outcomes between the treatment groups for both the 
primary and secondary analyses, ANCOVA analysis (linear regression of 24-week change among treatment groups 
adjusted for baseline value of outcome) will be used for exploratory analyses.  
Exploratory outcomes: 
 
• 
Change in peripheral pro-inflammatory cytokine levels (including IL-6, TNF, TGF-beta) from baseline to 24 weeks  
• 
Change in NMR MetaboProfile Analysis (LP4) from baseline to 24 weeks. 
  
 
In addition, the exploratory outcomes above will be compared by treatment group within subgroups of patients defined 
by response to treatment at the end of the trial. Response to treatment is defined as ≥ 28 U/L decrease in ALT at 24 
weeks from baseline. Analysis 1 will compare treatment groups with respect to each of the exploratory outcomes above 
using ANCOVA analyses. Analysis 2 will determine whether the treatment group differences for each of the exploratory 
outcomes will differ depending on whether a patient is a responder or not. This requires 2 ANCOVA models (one for 
each exploratory outcome) with an indicator variable for treatment group (losartan vs. placebo), an indicator variable 
for treatment response (yes vs. no), and an interaction term that is the product of these two indicator variables. If the 
interaction term is statistically significant (p<0.01), we will conclude that the response to losartan varied by responder 
status and we will present the treatment group comparisons and ANCOVAs within subgroups of responders and non-
responders.   
Losartan is known to improve insulin sensitivity through inhibition of PAI-1 production and restoration of hepatocyte 
growth factor activity.  We hypothesize that the MetaboAnalysis panel (“deep lipids panel”) performed by Labcorp will 
show improvement in the risk prediction panel for diabetes and will show improvement in the lipoprotein particle 
profile (specifically smaller VLDL particle sizes and fewer atherogenic small LDL particles after treatment with losartan.  


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Cytokines, including IL-6 and TNF-alpha are markers of the inflammatory state in NAFLD.  Modulation of the angiotensin 
system by ARB’s such as losartan are likely to decrease the chronic inflammation of NAFLD.  We hypothesize that IL-6 
and TNF-alpha will decrease after treatment with losartan.   
 
These exploratory endpoints are research measurements and will be conducted using batched samples after the final 24 
weeks visit of the last patient.  The MetaboAnalysis panel frozen plasma samples will be shipped to Labcorp.  The IL-6 
and TNF-alpha can be measured in frozen serum and will be performed at a core research lab. 
 
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 parent or legal 
guardian and participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The draft consent materials are submitted with this protocol. 
Template parent consent and pediatric assent documents will be prepared for the trial for screening to determine 
eligibility with an affirmation of consent for randomization in the trial. Individual sites may add material but may not 
delete material thought to be necessary for informed consent. Clinics may reformat and reword information to conform 
to their local requirements. The patient’s guardian must sign the consent and the patient must sign the assent to be 
eligible for the trial. The consent documents will describe the purpose of the trial, the procedures to be followed, and 
the risks and benefits of participation. Copies of the signed consent/assent forms will be given to the patient and 
patient’s guardian, and this fact will be documented in the patient’s record. 
 
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 Institutional Review Board (IRB)-approved and the 
parent or legal guardian and the participant will be asked to read and review the consent and assent documents. The 
investigator will explain the research study to the parent/legal guardian and 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 surrogates or think about it prior to agreeing to 
participate. The parent or legal guardian will sign the informed consent document and the participant will sign the 
assent 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.  Copies of the 
informed consent and assent documents will be given to the participants for their records. The informed consent 
process will be conducted and documented in the source document (including the date), and the form signed, before 
the participant undergoes any study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they decline to participate in 
this study. 


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10.1.2  
STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause.  Written 
notification, documenting the reason for study suspension or termination, will be provided by the suspending or 
terminating party to study participants, investigator, funding agency, the Investigational New Drug (IND) sponsor and 
regulatory authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly 
inform study participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the 
termination or suspension.  Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary outcome has been met 
• 
Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy the 
sponsor, IRB and/or Food and Drug Administration (FDA). 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their interventions. This confidentiality is extended to cover testing of biological samples and genetic 
tests in addition to the clinical information relating to participants. Therefore, the study protocol, documentation, data, 
and all other information generated will be held in strict confidence. No information concerning the study or the data 
will be released to any unauthorized third party without prior written approval of the sponsor.  
All laboratory specimens, study forms, reports, and other records that are part of the study data collection materials will 
be identified by coded number to maintain patient confidentiality. All records will be kept in locked file cabinets. All 
electronic records of study data will be identified by coded number. Clinical information will not be released without 
written permission of the patient, except as necessary for monitoring by the IRB. Consent procedures and forms, and the 
communication, transmission and storage of patient data will comply with individual site IRB and NIH requirements for 
compliance with The Health Insurance Portability and Accountability Act (HIPAA). 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review Board 
(IRB), regulatory agencies or pharmaceutical company supplying study product may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the participants in this study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use during the study. 
At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by the 
reviewing IRB, Institutional policies, or sponsor requirements. 
 


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Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be transmitted 
to and stored at the NASH CRN DCC. This will not include the participant’s contact or identifying information. Rather, 
individual participants and their research data will be identified by a unique study identification number. The study data 
entry and study management systems used by clinical sites and by NASH CRN DCC research staff will be secured and 
password protected. At the end of the study, all study databases will be de-identified and archived at NASH CRN DCC. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored at the NASH CRN Data Coordinating Center. After the study is 
completed, the de-identified, archived data will be transmitted to and stored at NIDDK Central Repository, for use by 
other researchers including those outside of the study. Permission to transmit data to the NIDDK Central Repository will 
be included in the informed consent.  
 
With the participant’s approval and approval by local Institutional Review Boards (IRBs), de-identified biological samples 
will be stored at the NIDDK Central Biorepository with the same goal as the sharing of data with the NIDDK. These 
samples could be used to research the causes of NAFLD, its complications and other conditions for which individuals 
with NAFLD are at increased risk, and to improve treatment. The NIDDK Repository will also be provided with a code-link 
that will allow linking the biological specimens with the phenotypic data from each participant, maintaining the 
anonymity of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have biological specimens 
stored for future research. However, withdrawal of consent with regard to biosample storage will not be possible after 
the study is completed.  
 
When the study is completed, access to study data and/or samples will be provided through the NIDDK Central 
Repository.   
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
Principal Investigator 
Medical Monitors 
Miriam B. Vos, MD, MSPH 
Joel Lavine, MD, PhD 
Mariana Lazo, MD and  
Jeanne Clark, MD, MPH 
Emory University 
Columbia University 
Johns Hopkins University 
1760 Haygood Dr, Decatur, GA 
New York, New York 
2024 E Monument St Rm 2-600, 
Baltimore, MD 21205 
404-803-7733 
 
410-614-4096 
mvos@emory.edu 
jl3553@columbia.edu  
mlazo@jhu.edu and  
jmclark@jhmi.edu  
NASH CRN Executive Committee (EC)- Consists of NASH-CRN co-chairpersons, SC representatives, principal investigator 
of the Data Coordinating Center, safety officer, NIDDK program official, and NIDDK project scientist. The NASH CRN EC 
discusses directions and strategic issues related to the scientific aims of the NASH CRN; organizes and sets agenda for 
Steering Committee meetings and provides oversight of the study.  
 
NASH CRN Steering Committee (SC) – Consists of principal investigators of each of the clinical centers, the principal 
investigator of the Data Coordinating Center, and the NIDDK project officer each of whom has one vote in any decision 
requiring formal vote. Ex officio members include NIDDK scientific staff.  The NASH CRN SC is the major decision making 
body for NASH-CRN which provides oversight in planning and conduct of study.  The SC votes on all important decisions 
and approves the final database and protocol and any amendments or modifications of the protocol.  
 
10.1.6 SAFETY OVERSIGHT: DATA AND SAFETY MONITORING BOARD 


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Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of individuals with 
the appropriate expertise, including gastroenterology, hepatology, cardiology and statistics. Members of the DSMB are 
independent from the study conduct and free of conflict of interest, or measures should be in place to minimize 
perceived conflict of interest.   
An independent Data and Safety Monitoring Board (DSMB), appointed by the NIDDK, will review the protocol for the 
STOP-NAFLD trial and monitor the safety data as the trial progresses to ensure patient safety and to review efficacy. The 
DSMB is a multidisciplinary group with a written charge provided by the NIDDK. The DSMB reports to the NIDDK, which 
will communicate DSMB recommendations to the investigators, as appropriate. The DSMB will hold a meeting to 
approve the protocol. The DSMB will review performance and safety data. The DSMB may request more frequent 
meetings if necessary to fulfill its charge. It may also request additional safety reports on a more frequent basis. For 
example, all serious adverse events are reported to the DSMB for their consideration and recommendations as they 
occur.  
Interim data on safety measures requested by the DSMB are reviewed at each of the scheduled semi-annual full 
meetings. Two additional written safety reports will be reviewed by the DSMB between scheduled full meetings. Serious 
adverse events will be reviewed by the DSMB as they occur with the option of a teleconference discussion if any DSMB 
member so requests. 
The DSMB will review quarterly reports by masked treatment groups of incident hepatotoxicities, as well as counts of 
patients who required more frequent liver function testing due to rises in ALT levels of more than 2 times baseline ALT 
or beyond 300 U/L. The DSMB will also examine the trends in ALT or AST levels for each patient who experiences a rise 
in ALT. 
The DSMB also reviews the overall progress of the trial in terms of recruitment and data quality and makes a formal 
recommendation to the NIDDK at the end of each scheduled meeting as to whether the trial should continue 
unmodified, continue with protocol modifications, or be stopped. 
 
10.1.7 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are protected, that the 
reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol/amendment(s), with International Conference on Harmonisation Good Clinical Practice (ICH 
GCP), and with applicable regulatory requirement(s).  
• 
Monitoring for this study will be performed by the DCC of the NASH CRN.    
• 
To ensure data quality and reduce data entry error, double data entry of all data collection forms is required.  
The DCC will incorporate into the data entry programs a series of edit checks, including range checks, logic 
checks (e.g., skip patterns), and consistency checks, both within a data form and across forms.  These integral 
checks are designed to detect deficiencies in the data before they are entered into the study database, so that 
the deficiencies may be easily and accurately corrected.  In addition, the DCC will perform frequent 
computerized edit checks on entered data.  The DCC will also perform ongoing comparisons of copies of entered 
data forms with the databases to ensure that data entered into the data system reflect those recorded on the 
forms.  Such audits will help to pinpoint problems that cannot be detected by computer editing and may be used 
to guide increased scrutiny when needed.  Any data queries identified will be flagged for action by the clinical 


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site until resolved.  
• 
The data system will maintain a clear and complete audit trail of all changes to the study databases.  All changes 
to data forms will be documented appropriately on the paper form and entered into NASH CRN data system.  All 
forms entered and/or edited in the data system will be identified by the PIN of the operator, the network 
address (the “IP” address) of the computer being used, and the date and time of the operation.  Records will not 
be deleted but rather marked as having been superseded.  The DCC will implement various procedures to ensure 
the quality of its internal operations.  These will include the development and maintenance of documentation 
regarding procedures for receiving, processing, and analyzing data, and duplicated programming for selected 
procedures to check for errors in software database and analysis systems. 
• 
Performance monitoring: The web-based data system will allow for real-time reporting of most recruitment and 
data management activities.  However, additional performance reports will be generated and circulated monthly 
and typically reviewed at each Steering Committee (SC) meeting.  These reports include several key indicators of 
study performance, including counts of patients screened and randomized, of completed visits and of missing 
key data, of missed visits, and statistics summarizing performance with respect to timeliness of data entry and 
response to data queries. 
The SC and the DSMB will conduct a formal review of the study by conference call or in-person meeting twice a 
year and will address quality assurance as part of their agenda.  These committees will have responsibility for 
recommending corrective actions based on the performance data.  It is anticipated that the primary 
responsibility for formulating and implementing these actions will reside in the SC.  Potential actions might 
include specific recommendations for training, redistribution of study resources, or possibly termination of 
support for a center. 
• 
Independent audits outside the DCC will not be conducted. 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological specimen collection, 
documentation and completion.   
 
Quality control (QC) 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 site(s) for 
clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the NASH CRN monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and reported in 
compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and 
applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the 
purpose of monitoring and auditing by the NASH CRN, and inspection by local and regulatory authorities.   
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site investigator. The 
investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data.   
 


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Hard copies of the study visit worksheets will be provided for use as source document worksheets for recording data for 
each participant enrolled in the study.  Data recorded in the electronic case report form (eCRF) derived from source 
documents should be consistent with the data recorded on the source documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions data and clinical 
laboratory data) will be entered into NASH CRN database, a 21 CFR Part 11-compliant data capture system provided by 
the NASH CRN. The data system includes password protection and internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from 
the source documents (case report forms).   
 
10.1.9.2 STUDY RECORDS RETENTION  
The NIDDK records retention policy is to maintain clinical trial records for 3 years after the granting period ends or the 
trial ends, whichever is later. 
 
10.1.10 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on Harmonisation 
Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The noncompliance may be either on 
the part of the participant, the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations within 5 
working days of identification of the protocol deviation, or within 10 working days of the scheduled protocol-required 
activity.  All deviations must be addressed in study source documents, reported to NIDDK Program Official and the Data 
Coordinating Center. Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) per their 
policies. The site investigator is responsible for knowing and adhering to the reviewing IRB requirements. Further details 
about the handling of protocol deviations will be included in the SOP. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the following publication and data sharing policies and regulations and 
the policies of the NASH CRN: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the published results 
of NIH funded research. It requires scientists to submit final peer-reviewed journal manuscripts that arise from NIH 
funds to the digital archive PubMed Central upon acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial 
Information and the Clinical Trials Registration and Results Information Submission rule. As such, this trial will be 
registered at ClinicalTrials.gov, and results information from this trial will be submitted to ClinicalTrials.gov. In addition, 
every attempt will be made to publish results in peer-reviewed journals.  Data from this study may be requested from 
the NIDDK Central Repository (https://www.niddkrepository.org/search/study/) two years after the completion of the 
primary outcome.  
 
In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-funded research that 
generates large-scale human or non-human genomic data, as well as the use of these data for subsequent research. Large-


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scale data include genome-wide association studies (GWAS), single nucleotide polymorphisms (SNP) arrays, and genome 
sequence, transcriptomic, epigenomic, and gene expression data. 
  
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is 
critical.  Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, 
or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest 
will be required to have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial.  The NASH CRN leadership in conjunction with the NIDDK has established policies and procedures 
for all study group members to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
n/a 
10.3 ABBREVIATIONS 
 
A1AT 
alpha-1-antitrypsin 
AE 
Adverse Event 
ALT 
alanine aminotransferase 
AMA 
antimitochondrial antibody 
ANA 
antinuclear antibody 
ANCOVA 
Analysis of Covariance 
Anti-HCV 
hepatitis C antibody 
ASMA 
anti-smooth muscle antibody 
AST 
aspartate aminotransferase 
AUDIT 
Alcohol Use Disorders Identification Test 
BMI 
body mass index (kg/m2) 
BUN 
blood urea nitrogen 
CC 
Clinical Center 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Comprehensive Metabolic Panel 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CRN 
Clinical Research Network 
CRP 
C reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Event 
DCC 
Data Coordinating Center 
DDC 
Drug Distribution Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Executive Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 


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GFR 
glomerular filtration rate 
GGT 
gamma glutamyltransferase 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HbA1c 
hemoglobin A1c 
HBc 
hepatitis B core antigen 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma 
HCV 
Hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act  
HOMA-IR 
Homeostatic Model Assessment of Insulin Resistance 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IL-6 
Interleukin-6 
IND 
Investigational New Drug Application 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCV 
mean corpuscular volume 
MSDS 
Material Safety Data Sheet 
NAFL 
nonalcoholic fatty liver 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
nonalcoholic fatty liver disease activity score 
NASH 
nonalcoholic steatohepatitis 
NCT 
National Clinical Trial 
NIDDK 
National Institute of Diabetes and Digestive and Kidney Diseases  
NIH  
National Institutes of Health 
NMR Lipo 
Nuclear magnetic resonance lipid profile 
NSAID 
Nonsteroidal anti-inflammatory drugs 
OHRP 
Office for Human Research Protections 
PAI-1 
Plasminogen activator inhibitor-1 
PI 
Principal Investigator 
PPARγ 
peroxisome proliferator-activated receptor-gamma 
PT 
prothrombin time 
QA 
Quality Assurance 
QC 
Quality Control 
ROC 
reactive oxidative species 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
Standard of Care 
SOP 
Standard Operating Procedures 
TIBC 
Total iron binding capacity 
TNFα 
Tumor necrosis factor alpha 


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UP 
Unanticipated Problem 
US 
United States 
WBC 
White blood cell count 


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10.4 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 
1.3 
18 Feb 19 
Section 1.1, Synopsis: Changed 
HbA1c time window to 60 days. 
Changed to allow 60-day time 
window for all laboratory 
measurements except ALT. 
1.3 
18 Feb 19 
Section 1.3, Data Collection 
Schedule: Removed Focused Physical 
Examination from the data collection 
at the randomization visit.  
A brief physical is required to 
determine if the patient is 
feeling well on the day of 
randomization, but the Focused 
Physical Examination form is 
not completed. 
1.3 
18 Feb 19 
Section 8.1.2, Screening Visits: 
Protocol text changed to allow 60-
day time window for all laboratory 
measurements except ALT. 
ALT measurement must be 
completed within 30 days of 
randomization; additional lab 
tests for screening must be 
completed within 60 days of 
randomization. 
1.3 
18 Feb 19 
Section 12.3, Blood Collection 
Schedule: CBC + WBC and uric acid 
added to blood collection at f36 visit, 
to align with the Data Collection 
Schedule and visit procedures 
specified in the protocol. 
The total blood volume 
collected at f36 corrected from 
35mL to 42mL. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12 APPENDIX  
12.1 PARTICIPATING CENTERS 
Clinical Centers 
Northwestern University, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH  
Columbia University, New York, NY  
Emory University, Atlanta, GA  
Indiana University, Indianapolis, IN  
Saint Louis University, St. Louis, MO  
Texas Children’s Hospital, Houston, TX 
University of California, San Diego, CA  
University of California, San Francisco, CA  
University of Washington, Seattle Children's Hospital,  Seattle, WA  
Data Coordinating Center: 
Johns Hopkins University, Baltimore, MD 
National Institutes of Health: 
National Institute of Diabetes and Digestive and Kidney Diseases  
NIDDK Central Repositories: 
Biosample repository: Precision for Medicine, Frederick, MD 
Genetics repository: RUCDR Infinite Biologics, Piscataway, NJ 
Data repository: Information Management Services (IMS), Calverton, MD 
 
 


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12.2 BLOOD COLLECTION SCHEDULE (amounts in mL) 
 
 
Screening
visits 
 
Follow-up visits- 
Weeks from Randomization 
mL 
Labs 
 
RZ 
f04 
f12 
f24 
     f36 
Total mL 
Complete blood count + WBC 
5 
 
 
5 
5 
5 
20 
Basic metabolic panel + eGFR 
2 
. 
2 
2 
2 
 2 
10 
Uric acid 
2 
 
 
2 
2 
2 
8 
Hepatic panel (Liver function test) 
2 
. 
2 
2 
2 
2 
10 
Gamma glutamyltransferase -GGT 
2 
. 
 
2 
2 
 
6 
Prothrombin time (PT), INR  
5 
. 
 
5 
5 
 
15 
C-Reactive Protein (CRP) 
1 
 
 
1 
1 
1 
4 
Fasting lipid profile 
2 
. 
. 
2 
2 
 
6 
Fasting serum glucose 
2 
. 
. 
2 
2 
 
6 
Fasting serum insulin HbA1c 
2 
. 
. 
2 
2 
 
6 
Fasting HbA1c 
5 
. 
. 
5 
5 
 
15 
Etiologic tests (as needed) 
20 
. 
. 
. 
. 
 
20 
Banking: 
 
 
 
 
Fasting  plasma 
10 
. 
. 
10 
10 
10 
40 
Fasting serum 
20 
 
 
20 
20 
20 
80 
DNA 
10 
. 
. 
. 
. 
. 
10 
Total (not including optional DNA) 
80 
 
4 
60 
60 
42 
246 
Total (Including optional DNA) 
90 
 
4 
60 
60 
42 
256 
All STOP-NAFLD study visits are fasting visits and need to be scheduled for early morning. Fasting is defined as nothing 
by mouth except water in the 12 hours prior to blood draw. 
* Etiologic tests as needed: Hepatitis B surface antigen, hepatitis C antibody, alpha-1-antitrypsin level, ceruloplasmin. 
Autoantibodies: (ANA, AMA ASMA), serum iron, ferritin and total iron binding capacity (TIBC) 
 

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National Institutes of Health (NIH) 
 
Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) 
 
INFORMED CONSENT DOCUMENT 
(Parent Permission) 
 
Study Title:  Losartan for the Treatment of Pediatric NAFLD (STOP-NAFLD): A  
Phase 2, Randomized, Placebo-Controlled Clinical Trial 
 
Principal Investigator: 
PI Version Date: 18 February 19 
IRB No.: 
 
 
 
What you should know about this study 
• Your child is being asked to join a research study. 
• This consent form explains the research study and your child’s part in the 
study. 
• Please read it carefully and take as much time as you need. 
• Your child is a volunteer. He or she can choose not to take part. If your child 
agrees to join, he or she may quit at any time. There will be no penalty if your 
child decides to quit the study. 
• During the study, we will tell you if we learn any new information that might 
affect whether you wish to allow your child to continue to be in the study. 
 
Purpose of research project 
Nonalcoholic fatty liver disease (NAFLD) is a common liver disease in children, is 
potentially serious, and is without an approved treatment. NAFLD can lead to severe 
liver disease in some children. The term NAFLD covers a range of liver disease 
progression. NAFLD is usually discovered by blood tests, or other tests such as liver 
ultrasound or CT scan. A liver biopsy (small amount of liver tissue removed by needle) 
is usually done to confirm liver disease. The biopsy results may show different amounts 
of fat, inflammation (swelling), and scarring in the liver. Your child has been asked to be 
in this research study because one of the liver tests noted above has shown your child 
has NAFLD. This is a nationwide study funded by the National Institutes of Health (NIH). 
 
Why you are being asked to participate 
The purpose of this study is to find out whether treatment with losartan improves 
NAFLD compared to treatment with a placebo (an inactive study drug).  The placebo 
capsule looks just like the losartan capsule, but has no active ingredients. 


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Your child must be at least 8 years old and have had a liver biopsy in the past that 
showed NAFLD to join this study. Your child will not be allowed to join this study if he/ 
she has poorly controlled diabetes or cirrhosis. Your child cannot have drunk 
significant amounts of alcohol. We will ask your child questions to check that he/she is 
not drinking significant amounts of alcohol during the study. 
 
If your child is capable of becoming pregnant and is sexually active, she must use two 
effective forms of birth control during the study. Examples of birth control are: no sexual 
intercourse, hormonal contraceptives (oral, implant, transdermal patch, or injection) at a 
stable dose for at least 1 month prior to screening, and barrier (condom with spermicide, 
diaphragm with spermicide). We will do a urine pregnancy test to make certain that your 
daughter is not pregnant before she begins this study; a pregnancy test will also be 
administered at each study visit. If your daughter is nursing an infant, she may not enroll 
in the study. 
 
If your child is eligible and your child agrees to join the study, he/she will be one of 
about 110 children nationwide enrolled in this study. Children will be randomly put into 
one of two groups by using a chance mechanism, similar to flipping a coin: (1) those 
taking losartan or (2) those taking placebo only. Neither you, your child, nor the study 
staff, will know which drug he/she is taking. The type of study drug your child is taking 
will be available to the study doctor if it is needed in an emergency. The masking of 
study drug is done so that the study gives fair and unbiased results. Your child will 
swallow one capsule each morning for one week and then increase to two capsules 
once per day, for 24 weeks during the study. 
 
We intend to learn more about treating fatty liver in children. There will be an NIH 
database to store medical information collected during this study, and blood will be 
collected for serum and plasma analysis and storage (banking) in a NIDDK-
sponsored biorepository. 
 
Procedures 
If you agree to have your child in this study, the following will happen: 
Visit #1 - Screening ~ 3hours 
You and your child will be asked to sign permission forms allowing us to look at your 
child’s medical records. Your child needs to come to this visit fasting. This means that 
your child can drink only water for 12 hours before the visit. We will draw about five 
tablespoons (80 mL) of your child’s blood for tests. We will interview you and/or your 
child and give him/her a physical exam. Your child’s blood pressure, heart rate, 
temperature, and respiratory rate will be measured. We will measure your child’s height, 
weight, waist, and hips. You and your child will complete surveys about alcohol use, 
beverage intake and quality of life. 


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The study doctor will conduct a detailed physical exam and review your child’s 
medical history. The study doctor will listen to your child’s heart and lungs, and check 
his/her eyes, limbs, and abdomen, skin, eyes, ears, throat, chest, extremities, and 
nervous system. We will ask about your child’s health and any medicines your child is 
taking or has taken in the past. 
 
The Study Coordinator will provide educational material regarding diet and 
exercise. Your child may not be pregnant during this study, if she is able to become 
pregnant, we will perform a urine pregnancy test. 
 
Visit #2 - Randomization (Treatment Assignment) ~45 minutes 
 
The randomization visit occurs after the screening evaluations are complete. We will 
review that eligibility criteria continue to be met.  A brief physical exam will be done and 
any changes in medication use will be documented. Your child’s blood pressure, heart 
rate, temperature, and respiratory rate will be measured. Height, weight, hip, and waist 
measurements will be made. The study doctor will listen to your child’s heart and lungs, 
and check his/her eyes, limbs, and abdomen. You will be asked about your child’s 
health. Girls who have started having periods will have a urine pregnancy test. 
 
If your child is still eligible for the study, we will use a computer to randomly choose 
the study drug your child will be given. This is random, like a flip of a coin.  Neither your 
child nor the study team will know whether your child is receiving losartan or placebo. 
Once the assignment has been generated, the study staff will provide the assigned 
study drug (in person) and teach you and your child about starting the drug. Your child 
will swallow one capsule each morning for one week and then increase to two capsules 
once per day, for weeks 2-24 during the study. The study staff will teach you and your 
child how to use an automated blood pressure monitor. You will be asked to take your 
child’s blood pressure each morning for the first 14 days and record it on a blood 
pressure log. The study staff will discuss possible side effects and teach you how to 
complete the blood pressure log. Patients and/or parents should call the clinic if your 
child’s blood pressure drops below < 90 mmHg systolic or < 60 mmHg diastolic and for 
symptoms of hypotension (dizziness, fainting, and lightheadedness). The log will be 
reviewed with you over the telephone during the second week and checked for 
hypotension. Study drug will be given with written instructions to reach the prescribed 
dose. Your child will return in approximately 4 weeks for the next clinical follow-up visit.  
 
Telephone Visit – Week 2  
We will arrange a telephone visit after your child has started the higher dose (100 
mg) to review your child’s blood pressure log, the dosing instructions, and any adverse 
effects he or she may be experiencing. 
 
Visit #3 – Week 4 Follow-Up Visit ~1 hour 


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We will interview you and/or your child. Your child’s blood pressure, heart rate, 
temperature, and respiratory rate will be measured. We will measure your child’s height, 
weight, waist, and hips. You and your child will answer questions about alcohol use. 
We will ask about your child’s health and any changes in medicines your child is taking 
and how well they followed their study drug dosing schedule. You will be given 
information to maintain diet and exercise. We will collect all study drug bottles for capsule 
counts. Females who are of child bearing potential will have a urine pregnancy test. 
Approximately 1 teaspoon (4 mL) of blood will be drawn for lab tests to monitor your 
child’s response to and tolerance of the study drug. 
 
The study doctor will review your child’s medical history. The study doctor will listen to 
your child’s heart and lungs, and check his/her eyes, limbs, and abdomen. The study 
doctor will discuss any side effects with you and your child. The study doctor may change 
study drug dosing as needed. Your study doctor or study coordinator will review dosing 
instructions. You will return in approximately 8 weeks for your next follow-up visit. 
 
Visit # 4- Week 12 Follow-Up Visit ~1 hour 
Your child needs to come to this visit fasting and bring his/her study medication 
bottle(s). This means that your child can drink only water for the 12 hours before to the 
visit. We will interview you and/or your child. Your child’s blood pressure, heart rate, 
temperature, and respiratory rate will be measured. We will measure your child’s height, 
weight, waist, and hips. We will ask about your child’s health and any changes in 
medicines your child is taking and how well they followed their study drug dosing 
schedule. You will be given information to maintain diet and exercise. We will collect all 
study drug bottles for capsule counts. Females who are of child bearing potential will 
have a urine pregnancy test. Approximately 4 tablespoons of blood (60 mL) will be drawn 
for lab tests, to monitor your child’s response to the study drug and for serum and plasma 
sample storage. 
 
The study doctor will review your child’s medical history. The study doctor will listen to 
your child’s heart and lungs, and check his/her eyes, limbs, and abdomen. The study 
doctor will discuss any side effects with you and your child. The study doctor may change 
study drug dosing as needed.  Your study doctor or study coordinator will review dosing 
instructions. You will return in approximately 12 weeks for your next follow-up visit. 
Visit # 5- Week 24 End of treatment visit ~1 hour 
Your child needs to come to this visit fasting and bring his/her study medication 
bottle(s). This means that your child can drink only water for the 12 hours before to the 
visit. We will interview you and/or your child. Your child’s blood pressure, heart rate, 
temperature, and respiratory rate will be measured. We will measure your child’s height, 
weight, waist, and hips. You and your child will complete surveys about alcohol use, 
beverage intake and quality of life. We will ask about your child’s health and any 
changes in medicines your child is taking and how well they followed their study drug 
dosing schedule. You will be given information to maintain diet and exercise. We will 
collect all study drug bottles for capsule counts. Females who are of child bearing 


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potential will have a urine pregnancy test. We will draw about four tablespoons (60 mL) 
of your child’s blood for lab tests, to monitor your child’s response to the study drug and 
for serum and plasma sample storage. 
 
The study doctor will conduct a detailed physical exam and review your child’s 
medical history. The study doctor will listen to your child’s heart and lungs, and check 
his/her eyes, limbs, abdomen, skin, eyes, ears, throat, chest, extremities, and nervous 
system. The study doctor will discuss any side effects with you and your child. The study 
doctor may change study drug dosing as needed. You will return in approximately 12 
weeks for your final study visit to assess any duration of treatment response, and to 
evaluate for any adverse effects of treatment. 
Visit # 6- Week 36 Follow-Up Visit 
(Completion of the study) 
Your child needs to come to this visit fasting and bring any remaining study 
medication bottle(s) to the visit. This means that your child can drink only water for the 
12 hours before to the visit. You and your child will complete surveys about alcohol use, 
beverage intake and quality of life. The study doctor will conduct a focused physical 
exam and review your child’s medical history. The study doctor will listen to your child’s 
heart and lungs, and check his/her eyes, limbs, abdomen, skin, eyes, ears, throat, chest, 
extremities, and nervous system. The study doctor will discuss any side effects with you 
and your child. We will draw about two tablespoons (42 mL) of your child’s blood for lab 
tests, to monitor your child’s response to the withdrawal of study drug and for serum and 
plasma sample storage. 
 
Risks/discomforts 
 
Are there risks if my child gets pregnant? There are risks to an unborn baby if your 
daughter becomes pregnant during the STOP-NAFLD Trial. The use of losartan in 
pregnancy is contraindicated. Use of losartan during the second and third trimesters of 
pregnancy can cause injury and death to the developing fetus. Potential adverse effects to 
the baby include skull and lung hypoplasia (incomplete development), anuria (kidneys do 
not make urine), hypotension (low blood pressure), kidney failure, and death. If your 
daughter decides to take part in this study, and she has periods, she must be as sure as 
possible that she is not pregnant. It is important that you contact the study doctor right 
away if you think your daughter may be pregnant, if she has missed a period or if it is 
late, or if she has had a change such as heavier bleeding than usual or bleeding 
between periods. If your daughter becomes pregnant during the study she will stop 
taking the study drug. 
 
Blood Draws: Blood drawing is mildly painful and can cause bruising and very rarely, 
dizziness or fainting, blood clots, bleeding or an infection at the site. If numbing cream is 
used for blood draws, it may cause pain, skin irritation, or the skin temporarily turning red, 
white or developing a rash. This usually doesn’t last very long. During the entire study 
period, your child will have approximately 17 tablespoons of blood drawn (246 mL). 


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Losartan: This drug is an "angiotensin 2 receptor antagonist", used primarily to treat 
high blood pressure in both children and in adults. It keeps blood vessels from narrowing, 
which lowers blood pressure and improves blood flow. It is also used to lower the risk of 
stroke in certain adults with heart disease. Losartan is used also to slow long-term kidney 
damage in people with type 2 diabetes who also have high blood pressure. The most 
common side effects are dizziness and lowered blood pressure. Other side effects are 
listed below:  
• Low blood pressure – Losartan is a medicine that is commonly used to treat 
children with high blood pressure so it can lower the blood pressure in children 
with NAFLD.  It may make the blood pressure too low and could cause dizziness, 
fainting and lightheadedness.  This is more likely to happen if your child is not 
drinking enough water and becomes dehydrated.  You will be instructed to 
measure your child’s blood pressure each morning for 14 days after starting 
losartan to monitor for low blood pressure.  During the study, it will be important 
for your child to drink water regularly and avoid becoming dehydrated.   
• Cold or flu symptoms such as cough, stuffy nose, sore throat or fever.  Tell the 
study staff if your child experiences these.  
• High potassium levels – Medications such as losartan can rarely cause the 
potassium level in the blood to become elevated.  Do not give your child a 
potassium supplement or potassium based salt substitutes while on the study 
medication.  Your child’s potassium levels will be checked regularly during the 
study.  
• High acid levels – Losartan can rarely elevate acid levels in the blood. This will be 
checked at each appointment.   
• Kidney injury - Losartan can rarely cause injury to the kidneys, especially if taken 
with other medications that can injure the kidneys.  Your child’s kidney function 
will be monitored closely through the blood work during the study.  If your child is 
prescribed new medications while in the study, tell the study coordinator or 
investigator right away.   
• Muscle pain - In rare cases, losartan can cause a condition that results in the 
breakdown of skeletal muscle tissue. Call the study doctor or the study staff right 
away if you have unexplained muscle pain, tenderness, or weakness; especially if 
you also have fever, unusual tiredness, and dark colored urine. 
 
If you want more information about these risks you should ask the study doctor 
before you sign this consent. 
 
If your child has any illness or discomfort as a result of using the study drug call 
your study doctor immediately.  If necessary, your child might need to stop taking the 
study drug. 
 
Other risks: 
• Your child’s condition may not improve, it may stay the same, or it may get worse 


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while in this study. 
• There may be side effects or discomforts from the use of the study drug that we 
don’t know about yet. 
 
Benefits 
Your child may receive no benefit from being in this study. He/she may receive 
benefit from the counseling on diet and exercise offered in this study. Your child’s liver 
disease may improve because of treatment with the study drug. He/she may benefit from 
health information obtained during the physical exams, laboratory tests, and other study 
procedures. Your child’s participation may help future patients by providing important 
information about the treatment of NAFLD. 
 
Payment 
You/your child will be compensated $50 for time and travel for each of the clinic 
visits completed. You/your child will receive up to $300 if he/she completes all aspects of 
the study. 
 
Data Sharing 
Representatives of the National Institutes of Health, Data Coordinating Center, or 
other experts may review your consent document, your child’s records at visits to the clinic 
as part of the ongoing monitoring of the progress of the study. In addition, representatives 
from the United States Food and Drug Administration (FDA), Office for Human Research 
Protections (OHRP) or the <<insert your Institution>> Institutional Review Board may review 
your child’s records, including your child’s medical records. 
 
Protecting data confidentiality 
Your child’s health and medical information will be labeled with only an identifying 
number and a random three letter code that cannot be linked to your child’s name or other 
personal identifiers except at the clinical center where your child completes visits. Your 
child’s health and medical information will be sent to the Data Coordinating Center currently 
located at The Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, 
and at the end of the study to the NIDDK Central Data Repository. Your child’s name, 
address, social security number, date of birth and other personal identifiers will not be sent 
to the data Repository, and hence the Repository will not be able to give out your child’s 
name or other information that identifies your child to the researchers who use your child’s 
data. 
 
A Data and Safety Monitoring Board will have access to the research records including 
your health information. 
All research projects carry some risk that information about a participant may 
become known to people outside of a study. Every reasonable effort will be made to keep 
your child’s records confidential. Your child’s participation in this study will be kept 
confidential, and your child’s name, address, and other personal identifying information 
will not be made known to anyone other than study staff at this clinic. When results from 


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this study are published in medical literature, your child will not be identified by name. 
 
Per NIH Notice NOT-OD-17-109 (Notice of Changes to NIH Policy for Issuing 
Certificates of Confidentiality https://grants.nih.gov/grants/guide/notice-files/NOT-OD-17-
109.html) this research is deemed to be issued a Certificate through this Policy and is 
therefore required to protect the privacy of individuals who are subjects of such research in 
accordance with subsection 301(d) of the Public Health Service Act. 
 
A certificate of confidentiality from the U.S. Department of Health and Human 
Services has been provided for this study so that research staff can avoid disclosing your 
child’s records in Federal or State courts if requested by outside organizations or 
individuals without your written consent (involuntary disclosure). You, your child’s legal 
representative, or government agencies (FDA, NIH, DHHS) may still request your child’s 
study information from the research staff and it will be provided (voluntary disclosure). This 
Certificate does not mean that the government approves or disapproves of this study. This 
Certificate adds special protection for research information that identifies your child. It 
allows us, in some circumstances, to refuse to give out study information about your child 
without your consent when it is sought in a legal action.  Still, we may disclose identifying 
information about your child if, for example, you need medical help. 
 
We may also give out information about your child if the government audits us. The 
research team will also give information to local or state authorities: 
• 
If they suspect abuse or neglect of a child or dependent adult; 
• 
If certain communicable diseases are present; and 
• 
If the team learns that you or your child plan to harm someone. In this case, the 
team also may warn the person who is at risk. 
 
Protecting subject privacy during data collection 
Your child’s records will not be released without your consent to the extent the law 
allows. As a way to establish and maintain a trusting relationship with your child, it is 
necessary that we keep confidential any discussion that we have with him/her about 
certain sensitive subjects (e.g., alcohol or drug use, sexual activities) unless your child 
permits otherwise, or unless there is a strong compelling medical reason for doing 
differently. 
 
Alternatives to procedures or treatments 
You have the option not to allow your child to participate in this study. There are no 
approved treatments for NAFLD in children. You may discuss other alternatives with your 
child’s gastroenterologist. 
 
Biological specimens 
The blood (plasma, serum), and data collected from your child during this study are 
important to science. You will not own the plasma and serum samples, or data after it is 
given to the study.  You will not receive any financial benefit from any product or idea 


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created by the investigators using the data or samples collected from your child. 
 
Your child’s specimens – the serum and plasma samples collected as part of this 
study – will be sent to the NIDDK Biosample Repository. At the end of the study, the data 
collected on your child will be sent to the NIDDK Data Repository. The Repositories are a 
research resource supported by the NIH. The Repositories store and distribute samples 
and study data from people with many kinds of disorders, from unaffected family 
members, and from other healthy people. The purpose is to make samples and data 
available for use in health research. Your child’s samples and data will be used by the 
researchers carrying out the STOP-NAFLD Trial, but they also may be used by other 
researchers, both during the study and after it ends. Your child’s samples and data may 
be stored indefinitely. 
 
Your child’s samples and data will be labeled with a code number before they are 
sent to the Repositories. Your child’s name, address, social security number, date of birth, 
and other personal identifiers will not be sent to the Repositories, and hence the 
Repositories will not be able to give out your child’s name or other information that 
identifies your child to the researchers who use your child’s samples and data. 
 
If you do not agree to have your child’s samples and data sent to the 
Repositories, your child may not join the STOP-NAFLD Trial. If you agree to have your 
child’s samples and data sent to the Repositories, you can change your mind up until 
the end of the trial. When study researchers receive written instructions from you, they 
will destroy your child’s samples and all information that identifies them. You may 
withdraw unused samples during the study. After this study ends, you will not be able to 
withdraw your child’s sample because the Repository will not know which one is your 
child’s.  The sample will stay in the Repository indefinitely. 
 
Because researchers will not have access to your child’s identity, you will not get 
the results of any studies that might be performed on your child’s samples. Sometimes 
research results in findings or inventions that have value if they are made or sold. These 
findings or inventions may be patented or licensed, which could give a company the sole 
right to make and sell products or offer testing based on the discovery. Some of the profits 
may be paid back to the researchers and the organizations doing this study, but you or 
your child will not receive any financial benefits. 
 
Cost of participation in the study 
There are no costs to you regarding this study 
 
What happens if you leave the study early? 
Participation in research is entirely voluntary.  Your child may refuse to participate 
or decide to stop participating at any time without jeopardy to the medical care they 
receive. 
 


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We will tell you about new information that may affect your child’s health, welfare, or 
willingness to stay in this study. Your decision will not result in any penalty or loss of benefits 
to which your child is entitled. If you have questions about your child’s rights, or to report 
research related problems, please contact: << insert contact info>> 
 
Conflict of Interest 
The study staff does not have any conflict of interest in conducting the study. 
 
Payment of treatment costs for injury or illness from study participation 
If your child is injured as a direct result of participation in this research, the 
<<Insert your Institution>> will provide any medical care needed to treat those injuries. 
The <<Insert your Institution>>> will not provide any other form of compensation to you or 
your child if he/she is injured. You may call the <<insert your Institution>> Human 
Research Protections Program office to inquire about your child’s rights as a research 
subject or to report research-related problems at (xxx) xxx-xxxx. 
 
Clinical Trial Registration 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site at 
any time. 
 
Authorization for Disclosure of Protected Health Information for Research 
 
We are asking you to authorize the disclosure and use of your child’s private health 
information for this research study.  By signing this authorization, you agree that the 
following health care providers may release your child’s private health information to us for 
use in this research study: 
 
<<List Providers)>> to use or disclose (release) your health information that identifies you 
for the research study described in this document. 
 
The health information that we may use or disclose (release) for this research includes: 
 
• Information from health records such as diagnoses, progress notes, medications, lab 
or radiology findings, etc. 
• Demographic information (name, date of birth, age, gender, race, etc.) 
 
The people who may receive or use your child’s private health information include the 
researchers and their staff. 
 
The Health Care Providers listed above are required by the Federal Privacy Rule to protect 
your child’s private health information.  By signing this Authorization, you permit them to 
release your child’s information to the researchers for use in this research study.  The 


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researchers will try to make sure that everyone who needs to see your child’s private 
information for this research keeps it confidential, but we cannot guarantee this. The people 
who may receive or use your child’s private health information include the researchers and 
their staff.  
 
Some other people may see your child’s private health information outside of the research 
team. They may include the sponsor of the study (NIH: National Institutes of Health), study 
safety monitors, government regulators, and legal compliance staff. All these people must 
also keep your child’s information confidential.  
 
You do not have to sign this Authorization, but if you don’t, your child will not join the study.  
It is your choice.  
 
Please note that you may change your mind and revoke (take back) this Authorization at 
any time. Even if you revoke this Authorization, researchers, their staff and their 
collaborators on this research project, the Institutional Review Board, NIH: NATIONAL 
INSTITUTES OF HEALTH and their representatives, regulatory agencies such as the U.S. 
Department of Health and Human Services, data coordinating center, Data and Safety 
Monitoring Board, may still use or disclose health information they already have obtained 
about you as necessary to maintain the integrity or reliability of the current research (for 
example, to account for a subject's withdrawal from the research study, to conduct 
investigations of scientific misconduct, or to report adverse events). If you revoke this 
Authorization, you will no longer be allowed to participate in the research described in this 
Authorization. 
 
To revoke this Authorization, you must write to: <<insert PI name and contact info>> 
 
This authorization does not have an expiration date. If all information that does or can 
identify you is removed from your health information, the remaining information will no 
longer be subject to this authorization and may be used or disclosed for other research 
purposes. 
 
Ending Consent 
You may end your permission at any time.  Information obtained and used before you end 
your permission will continue to be used for research.  If you wish to end your permission 
allowing your child to participate, let us know. 
 
Who do I call if I have questions or problems? 
• Call the principal investigator, <<insert name>>, at <<telephone number>> if you 
have questions, complaints, or get sick or injured as a result of being in this 
study. 
 
• Call or contact the <<institution>> IRB Office if you have questions about your 
rights as a study participant. Contact the IRB if you feel you have not been 


IRB Office Use Only: 
Approval Date: 
Approved Consent IRB Version No.: 
PI Name: 
IRB No. 
Submit Consent Documents in Microsoft Word ONLY 
Leave blank for IRB Office Use. 
 
 
Page 12 of 12 
 
P:\Shared\Doc\NASH\STOP-NAFLD(Losartan)\Consents\Parent.Consent.STOP-NAFLD_18Feb19.docx 
18 Feb 19 
treated fairly or if you have other concerns. The IRB contact information is: 
 
Address: 
 
 
Telephone: 
Toll Free: 
1-xxx-xxx-xxxx 
Fax: xxx-xxx-xxxx 
E-mail: 
 
What does your signature (or thumbprint/mark) on this consent form mean? 
Your signature below means that you have read the above information about this study 
and have had a chance to ask questions to help you be informed about what your child 
will do in this study.  Your signature also means that you have been told that you can 
change your mind later if you want to. You will be given a copy of this consent form to 
keep. By signing this consent form you are not giving up any of your legal rights or 
those of your child.  You agree to let your child participate. 
 
 
 
 
 
 
Print name of Parent/Legal Guardian 
Signature of Parent/Legal Guardian 
Date 
 
 
 
Print name of child participant ________________________________________ 
 
 
 
 
 
 
Print name of Person Obtaining 
Signature of Person Obtaining Consent 
Date 
Consent 
 
 
 
 
 
Print name of Witness 
Signature of Witness 
Date 
 
 
Give one copy to the participant and keep one copy in study records 

ICF_003.pdf: 
(Once approved, IRB logo goes here)
Approval date:
Approved Authorization IRB version No.:
IRB Study No: 
STOP-NAFLD.Med.Rec.Rel_HIPAA_Parent.docx 
 
1 
(T.3Oct2016)  21May18 
 
 
 
INSTRUCTIONS FOR DRAFTING  
A HIPAA COMPLIANT MEDICAL RECORD RELEASE FORM FOR RESEARCH 
 
The purpose of this form is to have the participant identify those health 
providers from whom you need the participant’s medical records for your 
research.  You will send this form to those providers that the parent/legal 
guardian names to execute the authorization.  It is important that the 
parameters around the request be clearly spelled out – what records do you 
need, and for what time period? 
This form may be used in conjunction with a consent form with a HIPAA 
Authorization and/or a consent form without a HIPAA Authorization.  If you are 
obtaining informed consent inside a U.S. covered entity, you should use the 
combined consent/authorization form.  If you are obtaining informed consent 
outside of a covered entity, you may use the consent form without the HIPAA 
authorization. 
x
Please complete all the sections indicated. 
x
Delete this page. 
 
 


(Once approved, IRB logo goes here)
Approval date:
Approved Authorization IRB version No.:
IRB Study No: 
STOP-NAFLD.Med.Rec.Rel_HIPAA_Parent.docx 
 
2 
(T.3Oct2016)  21May18 
 
Authorization for Release  
of Protected Health Information (PHI) for Research  
 
Medical Record Release Form 
(from Pediatrician to Principal Investigator, and from Principal Investigator to Pediatrician) 
 
Principal Investigator:  
 
IRB Study No.:   
 
Study Title: Losartan for the Treatment of Pediatric NAFLD (STOP-NAFLD): A  
Phase 2, Randomized, Placebo-Controlled Clinical Trial  
 
Sponsored by: National Institutes of Health (NIH) and the  Nonalcoholic Steatohepatitis Clinical Research 
Network (NASH CRN)  
 
 
Participant Name: 
 
__________________________________________________________ 
  
Date of Birth:   
_______________________________ 
 
 
 
 
 
 
We are asking you to authorize the disclosure and use of your child’s private health information 
(PHI) for this research study.   
 
The people who may receive or use your child’s PHI include the researchers and their staff.  The 
Health Care Providers listed below are required by the Federal Privacy Rule to protect your child’s 
PHI.  By signing this Authorization, you permit them to release your child’s information to the 
researchers for use in this research study.  The researchers will try to make sure that everyone who 
needs to see your child’s private information for this research keeps it confidential, but we cannot 
guarantee this. Although the researchers may not be covered by the Federal Privacy Rule, they will 
make an effort to protect your child’s information using the same standards.      
 
Some other people may see your child’s PHI outside of the research team.  They may include the 
sponsor of the study, study safety monitors, government regulators, and legal compliance staff.   All 
these people must also keep your child’s information confidential. 
 
You do not have to sign this Authorization, but otherwise your child may not join the study.  It is 
your choice. 


(Once approved, IRB logo goes here)
Approval date:
Approved Authorization IRB version No.:
IRB Study No: 
STOP-NAFLD.Med.Rec.Rel_HIPAA_Parent.docx 
 
3 
(T.3Oct2016)  21May18 
 
 
Your Authorization does not have an expiration date; it will continue as long as the research 
continues.  You may change your mind and take back this Authorization at any time.  If you take it 
back, the researchers may still use the PHI they have collected about your child to that point.  To 
take back the Authorization, you must contact the researcher.   
 
 
I hereby give my authorization for: 
 
______________________________________________________________________________ 
 
 
 
Name of doctor(s) and/or health care provider(s) 
 
 
 
______________________________________________________________________________ 
 
 
 
Address of doctor(s) and/or health care provider(s) 
 
 
To provide information from my child’s medical records between: 
 
DATE_______ and DATE________ 
 
 
My child’s health information may be sent to:     
 
                                          
PLEASE INCLUDE STUDY CONTACT INFORMATION HERE 
 
 
 
 
Parent/Legal Guardian                   Parent/Legal Guardian Signature                                    Date 
Printed Name                                                   
 
 
 
 
 
 
NOTE:  A COPY OF THE SIGNED AUTHORIZATION MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR; A COPY MUST BE GIVEN TO THE 
PARTICIPANT’S PARENT; AND IF APPROPRIATE A COPY OF THE SIGNED AUTHORIZATION MUST BE PLACED IN THE PARTICIPANT’S 
MEDICAL RECORD.