Clinical trial NCT02684591
Conditions: Nonalcoholic Fatty Liver Disease HIV
Sponsor: University of California, San Diego
Start date: 2016-01-01; Completion date: 2018-02-01
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A subset of patients with NAFLD that have not been extensively studied are those infected with human immunodeficiency virus (HIV). Currently, there is no FDA approved treatment for NAFLD or NASH. Additionally, there have been no significant clinical trials for HIV patients with NAFLD and there are no approved treatment options. We plan to conduct a randomized, double-blinded, placebo-controlled clinical trial to examine the efficacy of 600 mg of Aramchol daily (including 200 mg tablet and 400 mg tablet) versus identical placebo given over 12 weeks to improve HIV-associated hepatic steatosis as measured by a validated and accurate magnetic resonance imaging (MRI)-based technique.

Detailed description:
We plan to conduct a randomized, double-blinded, placebo-controlled clinical trial to examine the efficacy of Aramchol at 600 mg/day orally versus identical placebo given over 12 weeks to improve HIV-associated hepatic steatosis as measured by a validated and accurate magnetic resonance imaging (MRI)-based technique. In this study, we propose to randomize up to 50 patients with HIV-associated NAFLD to either Aramchol or placebo for 12 weeks. We plan to enroll a total of 55 patients, expecting some drop outs prior to randomization. After an initial evaluation for insulin sensitivity, liver fat measurement by MRI, and total body fat content by DEXA, patients will be randomized to receive either Aramchol 600 mg/day or placebo orally for 12 weeks. Patients will be monitored at regular intervals for symptoms of liver disease, side effects of medication, and serum biochemical and metabolic indices. Patients will also be assessed for continued HIV viral load suppression and continued tolerance of antiretroviral therapy. At the end of 12 weeks, patients will have a repeat medical evaluation, liver fat measurement, and total body fat content measurement. Pre and post treatment liver fat by MRI, ALT/AST, HbA1c, CRP, insulin sensitivity, and DEXA for whole body fat will be compared. The primary end point of successful therapy will be improvement in liver fat by MRI. Secondary end points will be improvement in total body fat, insulin sensitivity and liver biochemistry.

Arms: arm 1: Total 600 mg Aramchol (200 mg/tablet and 400 mg/tablet) per day once a day orally for 12 weeks.

Intervention: Aramchol arm 2: Placebo in the form of a tablet; Two bottles will be given to patient and they will take two pills, once a day orally for 12 weeks.
Interventions: intervention 1: Aramchol intervention 2: Placebo
Intervention descriptions: intervention 1: Aramchol, a conjugate of Cholic acid and Arachidic acid, is a first in class member of a novel family of synthetic Fatty-Acid / Bile-Acid Conjugates (FABACs). FABACs are composed of endogenic compounds, orally administrated with potentially good safety and tolerability parameters intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
 
 
UCSD Human Research Protections Program 
New Biomedical Application 
RESEARCH PLAN 
Instructions for completing the Research Plan are available on the HRPP website. 
The headings on this set of instructions correspond to the headings of the Research Plan. 
General Instructions: Enter a response for all topic headings. 
Enter “Not Applicable” rather than leaving an item blank if the item does not apply to this project. 
Version date: 05/11/2011 
1. PROJECT TITLE 
Aramchol for HIV-associated nonalcoholic fatty liver disease and lipodystrophy 
2. 
PRINCIPAL INVESTIGATOR  
Rohit Loomba, M.D., MHSc 
3. 
FACILITIES 
UCSD Medical Center-Hillcrest 
Clinical and Translational Research Institute-La Jolla 
4. 
ESTIMATED DURATION OF THE STUDY 
The study is anticipated to start by March 1, 2015 and end January 1, 2018 for duration of 3 years. The recruitment phase 
will begin as soon as IRB approval is received. 
5. 
LAY LANGUAGE SUMMARY OR SYNOPSIS (no more than one paragraph) 
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases ranging from simple steatosis to nonalcoholic 
steatohepatitis (NASH), the progressive form of liver disease that can lead to cirrhosis and liver-related mortality in persons 
who drink little or no alcohol. NAFLD is defined as the presence of hepatic steatosis with no evidence of hepatocellular 
injury in the form of ballooning of the hepatocytes. NASH is defined as the presence of hepatic steatosis and inflammation 
with hepatocyte injury (ballooning) with or without fibrosis. NASH is benign in many affected individuals but can cause 
progressive liver injury and, indeed, may be the major cause of cryptogenic cirrhosis1. A subset of patients with NAFLD 
that have not been extensively studied are those infected with human immunodeficiency virus (HIV). Among patients with 
HIV infection, liver disease is one of the leading causes of death.16 Progression of liver disease in HIV is linked to metabolic 
derangements associated with hepatic steatosis. Till date there are no therapies for the treatment of HIV-associated NAFLD 
and this area remains understudied with paucity of clinical trials. Currently, there is no FDA approved treatment for HIV-
associated NAFLD. Weight loss and exercise are the recommended but often difficult maintain these lifestyle changes in 
the long term and therefore therapeutic agents have been investigated. In this study, we propose to treat 50 patients with 
HIV-associated NAFLD with either aramchol or placebo for 12 weeks. After an initial evaluation, MRI liver fat distribution 
and full body DEXA scan, patients will receive 600 mg of Aramchol ( a 200 mg/tablet and a 400 mg tablet) per day or 
placebo. Patients will be monitored at regular intervals for symptoms of liver disease, side effects of aramchol, and serum 
biochemical and metabolic indices. Patients will also be assessed for continued HIV viral load suppression and continued 
tolerance of antiretroviral therapy.  At the end of 12weeks, patients will have a repeat medical evaluation, liver MRI and 
full body DEXA scan. Pre and post treatment MRI-derived liver fat content and DEXA-full body fat measurement will be 
compared. The primary end point of successful therapy will be improvement in hepatic steatosis measured by MRI in 
patients with HIV-associated NAFLD. Secondary end points will be improvement in total body fat content assessed by 
DEXA in patients with HIV-associated NAFLD. 
 
6. 
SPECIFIC AIMS 
Primary objectives:  
1. To examine the efficacy of Aramchol , comparing 600 mg daily (including 200 mg tablet and 400 mg tablet) versus 
identical placebo in improving hepatic steatosis assessed by magnetic resonance imaging in patients with HIV-
associated NAFLD 
Secondary objectives: 
1. To examine the efficacy of aramchol , comparing 600 mg daily (including 200 mg tablet and 400 mg tablet) versus 
identical placebo in improving total body fat content assessed by DEXA in patients with HIV-associated NAFLD  
2. To examine the efficacy of Aramchol , comparing 600 mg daily (including 200 mg tablet and 400 mg tablet) versus 
identical placebo in improving serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in 
patients with HIV-associated NAFLD 
Exploratory objectives: 
1. To examine the efficacy of aramchol in improving imaging-based biomarkers associated with changes in NAFLD  


 
 
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7. 
BACKGROUND AND SIGNIFICANCE 
 
Nonalcoholic fatty liver disease is the most common cause of chronic liver disease in the United States and it 
affects almost 30% of adults in Western countries.1-3 With climbing obesity rates and more sedentary patient populations, 
the prevalence of NAFLD is increasing worldwide and is becoming the predominant cause of chronic liver disease in 
parts of the world.4 NAFLD represents a spectrum of diseases ranging from simple steatosis to nonalcoholic 
steatohepatitis (NASH), the progressive form of fatty liver disease that can lead to cirrhosis and liver-related mortality in 
persons who drink little or no alcohol. NASH represents the more severe end of this spectrum and is characterized by 
steatosis, ballooning degeneration and lobular inflammation with or without fibrosis.5 Long-term risks of NASH include 
cirrhosis, hepatocellular carcinoma and end stage liver disease requiring liver transplantation.6, 7  
The majority of patients with NAFLD are asymptomatic. Clinical history, laboratory and radiological 
investigations are useful in excluding other causes of liver disease but do not permit an accurate diagnosis of NAFLD.8 
The diagnosis is usually suspected in a patient with elevated serum alanine aminotransferase (ALT) who drinks no or 
minimal amounts of alcohol, who has evidence of increased fat in the liver by ultrasound, CT scan or MRI, and who tests 
negative for the common causes of chronic liver disease.  Liver biopsy is the gold standard for the accurate diagnosis of 
NAFLD, but inherent risks of biopsy such as pain, bleeding, and bacteremia make interval biopsies impractical in the 
management of this disease. 
Recently, innovative imaging tools have demonstrated potential to change how we study and monitor liver 
disease.9, 10 An advanced magnetic resonance imaging based biomarker, the proton-density fat fraction (MRI-PDFF), has 
been validated as a precise and accurate method of quantifying liver fat in NAFLD.11-15 This provides a unique 
opportunity to research the progression and treatment of NAFLD without invasive procedures.  
A subset of patients with NAFLD that have not been extensively studied are those infected with human 
immunodeficiency virus (HIV). Among patients with HIV infection, liver disease is one of the leading causes of death.16 
Progression of liver disease in HIV is linked to metabolic derangements associated with hepatic steatosis. Till date there 
are no therapies for the treatment of HIV-associated NAFLD and this area remains understudied with paucity of clinical 
trials. 
Medical Therapy for NAFLD in HIV patients: 
Currently, there is no FDA approved treatment for NAFLD or NASH. Additionally, there have been no significant 
clinical trials for HIV patients with NAFLD and there are no approved treatment options. Current treatments for NAFLD 
are limited to weight loss and exercise, but this is often difficult to adhere to for many patients. Therapeutic agents are being 
investigated but the trials thus far including ursodeoxycholic acid, metformin, clofibrate, betaine, N-acetylcystine, 
atorvastatin, and orlistat have demonstrated very limited benefit. Pioglitazone has been shown to be somewhat beneficial 
reducing liver fat but weight gain due to increased adiposity is harmful in the long run. Additionally, none of these trials 
were for HIV-infected patients. Further therapies for NAFLD and NASH are still under investigation. 
Aramchol: 
Aramchol, also known as arachidyl amido cholanoic acid, is a fatty acid bile acid conjugate (FABAC) that was 
created by conjugating 2 natural components, cholic acid and arachidic acid, through a stable amide bond. Aramchol inhibits 
stearoyl coenzyme A desaturase 1 (SCD1), a key enzyme in fatty acid synthesis. SCD1 is an endoplasmic reticulum enzyme 
that catalyzes the rate-limiting step in the biosynthesis of monounsaturated fatty acids from saturated fatty acids.  Inhibiting 
SCD1 decreases synthesis and increases beta-oxidation of fatty acids, causing decreased storage of fatty acids. SCD1 has 
been demonstrated to be tightly associated with control of lipid homeostasis and body weight regulation. Within in vitro 
models, Aramchol has demonstrated significant (70% to 83%) inhibition of the SCD1 activity.17 Additionally, Aramchol 
increases cholesterol efflux by stimulating the adenosine triphosphate-binding cassette transporter A1. This has 
demonstrated an anti-atherogenic effect in animal models with increased fecal sterol output and decreased plasma 
cholesterol levels in mice.18  
Aramchol and the liver: 
The three proposed mechanisms of Aramchol’s effects on liver fat are 1) reducing de novo fatty acid synthesis, 2) 
reducing SCD1 activity, and 3) increasing beta-oxidation of fatty acids.19 In a 2003 study by Gilat,20 Aramchol significantly 
reduced hepatic fat content in animals (rats, hamsters, and mice) with a high-fat diet model. These animals gained total 
weight although they had less fat deposition in their liver, measured histologically, which suggests a redistribution of fat 
deposition in the body. The authors hypothesized that redistribution of liver fat to adipose tissue was the most likely 
explanation, but the mechanism was unknown.  


 
 
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However, additional animal studies demonstrated that FABACs have specific metabolic effects as they increase 
cholesterol efflux from fibroblasts and may not affect the import of dietary fat.21 In addition, preliminary data indicate that 
aramchol may increase fatty acid catabolism in the liver by acting as a peroxisome proliferator-activated receptor agonist.22, 
23 These studies have proposed possible mechanisms of FABACs but further study of fatty acid and triglyceride synthesis 
vs. degradation in the liver are needed to identify the in vivo mechanisms of aramchol. 
 
Effect of Aramchol on NAFLD and total body fat: 
A recent study by Safadi24 demonstrated that aramchol significantly reduced liver fat content, measured by 
magnetic resonance sprectroscopy (MRS), in 60 Israeli NAFLD patients after 12 weeks of 300mg aramchol per day. Their 
trial gave patients either 100mg or 300mg of aramchol or placebo (3 groups; n = 20/group) once daily for 12 weeks. Their 
primary finding was that liver fat content decreased by 12.57% (+/- 22.14% standard deviation) in the high dose aramchol 
group. There were no serious or drug-related adverse events in the study and the authors proposed that aramchol might be 
used for the treatment of fatty liver disease. In the preceding Phase I study of aramchol, dosing up to 900mg was studied 
and found to have a good safety profile.  An international, multicenter trial is currently being conducted using a two doses 
of Aramchol , a 200 mg/tablet and a 400 mg tablet per day given the excellent safety profile and expectation of increased 
liver fat reduction at higher doses.  Aramchol has not yet been studied in HIV-associated NAFLD. 
 
Side effects of Aramchol: 
Patient trials with Aramchol are limited to the Safadi study,24 but the clinical trial demonstrated no significant adverse 
events in the 12-week treatment period for 58 patients that underwent the trial. The few adverse events were mild 
(abdominal pain, back pain, constipation) and did not cause anyone to drop out of the trial. There were no severe adverse 
effects. Aramchol does not induce or inhibit the CYP450 enzyme family and is not expected to have significant drug 
interaction. The previous studies on Aramchol were done in animal models. 
 
Aims and Significance: 
We plan to investigate the role of aramchol in patients with HIV-associated NAFLD residing in the United States and assess 
liver fat changes during therapy with MRI of the liver. Here we hypothesize that aramchol would lead to a greater 
improvement in liver fat content compared with placebo and may lead to greater improvement in total body fat content 
assessed by DEXA scan as compared to placebo. In this pilot study, we propose to randomize approximately 50 patients 
(1:1 ratio) to 600 mg of Aramchol (a 200 mg/tablet and a 400 mg tablet) per day or placebo over 12-weeks in order to 
evaluate changes in baseline laboratory data, total body fat content assessed by DEXA, and liver fat by MRI during therapy. 
8. 
PROGRESS REPORT 
Not applicable. 
 
9. 
RESEARCH DESIGN AND METHODS 
We plan to conduct a randomized, double-blind, placebo-controlled clinical trial to examine the efficacy of aramchol 600 
mg daily (including 200 mg tablet and 400 mg tablet) versus identical placebo given over 12 weeks to improve HIV- 
associated hepatic steatosis as measured by a validated and accurate magnetic resonance imaging (MRI)-based technique. 
Galmed will not receive any subject or study data. 
 
Initial Evaluation 
Patients will be initially screened in the UCSD NAFLD research center clinic with history, physical examination, review 
of outside medical records (including HIV status) and routine blood tests. Alcohol history will be assessed in the medical 
interview, and the lifetime alcohol consumption will be estimated by standardized questionnaires. All patients will be asked 
to stop any medications being used for their liver disease, including herbal medications and vitamins.  Only those meeting 
all inclusion criteria and avoiding all exclusion criteria will be invited to participate in the study. After the initial visit, those 
who meet all eligibility criteria and have no exclusion criteria will undergo more thorough evaluation with liver MRI, 
cardiac MRI, Ultrasound transient elastography with CAP and DEXA scan for total body fat. Patients with MRI-PDFF > 
5% will be invited to participate in the study. Total screening time will be approximately 3 hours (2 hours screen visit, 10 
minutes ARFI, 6-10 minutes DEXA scan, 30 minutes MR scan, 5 minutes Ultrasound transient elastography with CAP), 
20 minutes Cardiac MRI scan. 
 


 
 
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Following an information session during which the primary consent document, a genetic sampling consent document and 
the UCSD HIPAA forms are reviewed, discussed and signed the following tests and procedures will be done shortly before 
starting therapy at the UCSD Medical Center, Hillcrest.  If they have already been completed elsewhere as part of the 
patient’s original diagnostic evaluation at the referring clinic they do not need to be repeated. 
The following evaluation will be done shortly before starting therapy. 
1. History and physical examination. 
2. Blood tests. These include complete blood count (CBC with differential and platelet count), prothrombin time, INR, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct and total serum bilirubin, alkaline phosphatase, 
albumin, total protein, fasting plasma glucose, hemoglobin A1c, C-reactive protein (CRP), creatinine phosphokinase (CPK), 
lactic acid, sodium, chloride, potassium, bicarbonate, blood urea nitrogen, creatinine, uric acid, calcium, phosphorus, 
ferritin, antinuclear antibody, antimitochondrial, antibodies if indicated, thyroid stimulating hormone (TSH), HBsAg, anti 
HBs, anti HAV, anti HCV, ceruloplasmin, alpha-1-antitrypsin if indicated, hemochromatosis gene test (HFE test) if 
indicated, alfa feto protein, fasting insulin, , Elisa HIV test if indicated, CD4 T-count, HIV PCR, CK-18 level. 1.  A 
pregnancy test will be performed for women of childbearing age who are not using oral, barrier or surgical methods of 
contraception.  Women who have had hysterectomies are also excluded from pregnancy testing.  If the pregnancy test is 
positive they will not be enrolled in the study. The participants will be required to provide urine and stool samples as well.  
3. Routine urinalysis. 
4. Detailed metabolic characterization 
     a. Oral glucose tolerance test (OGTT): after an overnight fast, subjects will be given 75 grams oral glucose solution. 
Plasma glucose, insulin levels, and free fatty acids will be obtained from blood samples drawn at 0 and 120 minutes after 
the oral glucose load 26.  
     b.Lipid profiles. Levels of fasting triglyceride, total cholesterol, LDL cholesterol, HDL cholesterol, free fatty acid will 
be obtained after an overnight fast. 
5. Estimation of body fat and fat distribution 
    a.Body Mass Index (BMI): For each patient, weight (kg) and height (m) will be recorded with empty bowel and bladder. 
BMI is calculated by the formula: BMI = weight (kg)/ height (m)2. 
    b. A trained investigator will measure waist/hip ratio at the same time as other measures are taken.  
    c. DEXA scan for whole body fat 
    d. Magnetic resonance imaging (MRI) of the liver:  MRI is done to evaluate liver size and estimate liver fat content. 
    e. MR Elastography (MRE) of the liver: MRE will be done to evaluate changes in liver stiffness before and after therapy 
if additional funding is available. 
    f. Cardiac MRI scan: will be done to assess improvement in cardiovascular risk by lowering of pericardial fat with 
aramchol relative to placebo. 
    j. Ultrasound transient elastography with CAP of the liver: Ultrasound transient elastography with CAP is a noninvasive 
test used to asses liver stiffness.  
6. ARFI ultrasound measurements are made automatically by the ARFI software that is loaded on the Siemens S2000 
ultrasound machine by Siemens. An ARFI ultrasound imaging examination of the abdomen will be performed.  ARFI 
ultrasound imaging examinations will be performed without contrast agents by well-trained staff and lasts about 10 minutes 
long. ARFI measurements are made automatically by the ARFI software that is loaded on the Siemens S2000 ultrasound 
machine we will use.  
 
Treatment Phase: 
After the initial evaluation, patients who continue to fulfill all inclusion criteria will be randomized to receive 600 mg daily 
of Aramchol (including 200 mg tablet and 400 mg tablet) versus identical placebo orally for a total of 12 weeks. 
Medication diaries and a count of residual tablets will monitor patient compliance at scheduled visits. Patients will be 
interviewed and examined by an investigator and have blood draw at weeks 0, 4, 8, and 12 of treatment.  In addition, an ARFI 
ultrasound imaging examination of the abdomen will be performed. At each visit particular attention will be paid to symptoms 
associated with the possible side effects of Aramchol and patients will complete a standardized symptom scale. 
 
Labs to be checked during the treatment phase include: 
1. Urinalysis will be done with extended blood tests. 
2. Routine blood tests (Fasting specimens): CD4 counts, HIV PCR, Complete metabolic panel (CMP) and prothrombin/INR. 
In addition, research blood will be taken for cytokine levels and changes in lipid biomarkers. 


 
 
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3. Extended blood tests (Fasting specimens):  Insulin, plasma glucose, lipid profile (cholesterol, triglyceride, LDL and HDL), 
free fatty acids (FFA), and creatinephosphokinase (CPK), lactic acid, and glycosylated hemoglobin (HbA1c).  In addition, 
research blood will be taken for cytokine levels and changes in lipid biomarkers.  
4. Stool and urine sample will be collected for analysis of changes related to the study drug.   
5. If the subject consents to genetic blood sampling the specimen will be drawn at this time.   
 
Post-Treatment Phase: 
At the end of the study, patients will undergo the same evaluation as listed under the initial evaluation as above, following 
which treatment will be stopped. Repeat MRI of the liver, ultrasound transient elastography with CAP of the liver and full 
body DEXA scan will also be performed at study conclusion. It is not possible to predict the outcome of this study, but if 
aramchol appears to have a significant effect on liver fat by MRI and/or total body fat by, we will probably develop a follow-
up protocol to assess long-term therapy with aramchol in a large multicenter study to examine the efficacy in improving liver 
histology.  Total post treatment visit time will be approximately 3hours (30 minutes MR scan, 20 minutes cardiac MRI scan, 
5 minutes ultrasound transient elastography with CAP, and 10 minutes DEXA scan).  
 
From screening to finish, total amount of time required of a patient will be approximately 6-7 hours (2 hours screen visit, 10 
minutes ARFI, 10 minutes DEXA scan, 5 minutes ultrasound transient elastography with CAP, 30 minutes week 4 and 12 
visits, 30 minutes MR scan, 2 hours post-treatment visit).   
 
Stored specimen: 
The specimens (serum, plasma, urine, saliva, whole blood (DNA), PBMCs, and stool) collected as part of this study will 
be kept at CTF building A. The purpose of this collection is to analyze inflammatory markers associated with treatment 
response in patients with HIV-associated NAFLD and to elucidate the mechanism of action of aramchol in the treatment of 
HIV-associated NAFLD. These samples and data may be stored indefinitely. At the end of the study, the data collected will 
be maintained at NARF building GI offices in a locked computer file with access available to the principal and study 
investigators only. 
 
All samples and data will be labeled with a code number. The name, address, social security number, date of birth and other 
personal identifiers will not be available on the sample, and we will not give out any information that identifies the patient 
to the researchers who use these samples and data. Samples may be given to other researchers for collaborative research 
only if said researchers have proof of IRB approval for use of stored samples. 
Table I. Study design 
Week  
0 
4 
8 
12 
Routine blood tests 
Serum/plasma banking 
X 
X 
X 
X 
X 
X 
X 
X 
Extended blood tests 
Stool/urine/DNA/saliva banking 
X 
X 
 
X 
X 
X 
X 
Physical exam and vital sign 
X 
 
X 
X 
DEXA 
X 
 
 
X 
OGTT 
X 
 
 
X 
MRI-PDFF 
MRE 
X 
X 
 
 
X 
X 
Aramchol VS placebo 
600 mg of 
Aramchol( a 200 
mg/tablet and a 
400 mg tablet) 
per day 
600 mg of 
Aramchol( a 200 
mg/tablet and a 
400 mg tablet) 
per day 
600 mg of 
Aramchol( a 200 
mg/tablet and a 
400 mg tablet) 
per day 
Stop 
 
Annual follow up visits: 


 
 
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Patients will be offered annual follow up visits if they choose to attend. At the annual follow up visit, subjects will undergo 
a detailed history and physical examination. Standardized questionnaires Skinner Lifetime Drinking History in addition to 
the Alcohol Use Disorders Identification Tests (AUDIT) will be used. A urine pregnancy test will be performed for all 
women of childbearing age.  Women who have had hysterectomies are excluded from pregnancy testing.  If the pregnancy 
test is positive, the patient will not be enrolled in the study. The patient will undergo full body DEXA scan, magnetic 
resonance elastography, and a magnetic resonance imaging for liver stiffness calculation and hepatic fat fraction, 
respectively. 
 
Assessment of Response and Statistical Analyses: 
The primary outcome of this study will be improvement in hepatic steatosis by liver MRI. Statistical analyses will 
compare liver fat improvement between the treatments versus placebo-arms. It is not possible to predict what the 
spontaneous or therapeutic response rate will be. Thus, we predict that the spontaneous improvement rate would be zero 
to less than 1%.  The sample size is chosen to avoid exposure of a large number of patients to 12 weeks of therapy and 
extensive evaluation if the study medication has no effect, but also to avoid missing a reasonably significant beneficial 
effect. We will require a sample size of 22 patients in each arm to have a power 90% (or higher) with a β of 0.05. We 
expect that Aramchol therapy group would have at least 6% reduction in liver fat compared to baseline as compared to 
1% or less improvement in the placebo group. These estimates are also based upon our recent trial using MRI-PDFF as an 
accurate and reproducible marker of hepatic steatosis.12 We expect to enroll up to 55 patients in this study and randomize 
at least 50 of them to either treatment or placebo arm for a full 12weeks with follow up evaluations. Clinical trials of 
experimental medications have had variable dropout rates.  Our pilot studies of metformin had less than 9% dropouts, and 
all remaining patients underwent follow up evaluation and liver biopsy. In the randomized-controlled trial of colesevelam 
versus placebo, we had a 10% drop rate. Therefore, we expect less than a 10% drop out. Dropouts would be considered 
non-responders based upon intention to treat analysis. A modified intention to treat analysis will be done in which we will 
exclude the patients who dropped out before getting the week 12 exit evaluation. 
Secondary outcomes will be assessed comparing pre-treatment to 12-weeks outcomes on therapy using parametric or non-
parametric tests as indicated.  The major secondary outcomes to be evaluated are: 
1. Total body fat via DEXA scan 
2. Serum ALT and AST values. 
3. Lipid profiles. 
We will compare the changes in the mean difference in the MRI-PDFF determined fat fraction between the treatment arm 
and the placebo arm at the co-localized region of interest. A two-tailed t-test would be utilized to compare the differences 
between the two groups. A two-tailed p-value of less than 0.05 is considered statistically significant. We will also conduct 
segment-to-segment changes in liver fat before and after treatment. We may perform internal validation by comparing MRI-
PDFF with magnetic resonance spectroscopy between the two treatment arms in selected cases. 
10. 
HUMAN SUBJECTS 
In this study, we propose to randomize up to 50 patients with HIV-associated NAFLD to either aramchol or placebo for 
12weeks. We plan to enroll a total of 56 patients, Spanish and English speaking participants will be included. We are 
expecting some drop outs prior to randomization and a dropout of a small number of patients because of intolerance to 
aramchol.  
 
Inclusion criteria: 
1. 
Age at entry at least 18 years. 
2. 
And at least one of the following risk factors for more severe liver disease. 
a. 
Hypertiglyceridemia  based upon ATP-III guidelines  
b. 
Increased LDL cholesterol or increased total cholesterol based on ATP-III guidelines 
c. 
Decreased HDL cholesterol based upon ATP-III guidelines  
d. 
Serum alanine (ALT) aminotransferase that are above the upper limits of normal. 19 or more in women and 30 
or more in men. 
e. 
Overweight as defined as BMI: 25 < 30 kg/m2   
f. Obesity as defined BMI ≥ 30 kg/m2   


 
 
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g. Hyperuricemia based upon A TP-III guidelines   
h. Prediabetes or Diabetes by American Diabetes Association Criteria 
3. Lipodystrophy will be confirmed on both clinical and radiologic assessment and defined as:  
a. 
Clinical history and/or exam by the study physician with signs of either facial, temporal,  upper or lower 
extremity lipoatrophy   
b. 
Documented abdominal fat accumulation with presence of hepatic steatosis on MRI  (defined below)   
 
4. 
Evidence of hepatic steatosis or liver fat (≥5%) by MRI. 
5. 
History of HIV documented by a previously positive HIV elisa or PCR 
6. 
Stable HIV infection as defined by the following parameters: Stable antiretroviral (ART) regimen for at least 12 
weeks prior to study inclusion 
a. 
CD4 count of less than 200 
b. 
Detectable viral load  
c. 
Changes to ART regimen in the preceding 12 weeks  
d. 
Lack of alternative ART regimens should the patient virologic breakthrough 
e. 
History of opportunistic infection in the preceding 12 months  
7. 
Written informed consent. 
 
Exclusion criteria: 
8. 
Evidence of another form of liver disease. 
a. 
History of hepatitis B as defined as presence of hepatitis B surface antigen (HBsAg). 
b. 
History of hepatitis C as defined by presence of hepatitis C virus (HCV) RNA in serum. 
c. 
History of autoimmune hepatitis as defined by anti-nuclear antibody (ANA) of 1:160 or greater and liver histology 
consistent with autoimmune hepatitis or previous response to immunosuppressive therapy. 
d. 
History of autoimmune cholestatic liver disorders as defined by elevation of alkaline phosphatase and anti-
mitochondrial antibody of greater than 1:80 or liver histology consistent with primary biliary cirrhosis or elevation 
of alkaline phosphatase and liver histology consistent with sclerosing cholangitis. 
e. 
History of wilson disease as defined by ceruloplasmin below the limits of normal and liver histology consistent 
with Wilson disease. 
f. 
History of alpha-1-antitrypsin deficiency as defined by alpha-1-antitrypsin level less than normal and liver 
histology consistent with alpha-1-antitrypsin deficiency. 
g. 
History of hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy and homozygosity 
for C282Y or compound heterozygosity for C282Y/H63D. 
h. 
Drug-induced liver disease as defined on the basis of typical exposure and history. 
i. 
Bile duct obstruction as shown by imaging studies. 
9. 
History of excess alcohol ingestion, averaging more than 30 gm/day (3 drinks per day) in the previous 10 years, or 
history of alcohol intake averaging greater than 10 gm/day (1 drink per day or 7 drinks per week) in the previous one 
year. 
10. Contraindications to MRI: 
a. 
The subject has any contraindication to MR imaging, such as patients with pacemakers, metallic cardiac valves, 
magnetic material such as surgical clips, implanted electronic infusion pumps or other conditions that would 
preclude proximity to a strong magnetic field. 
b. 
The subject has a history of extreme claustrophobia 
c. 
The subject cannot fit inside the MR scanner cavity 
11. Decompensated liver disease, Child-Pugh score greater than or equal to 7 points 


 
 
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12. History of gastrointestinal bypass surgery or ingestion of drugs known to produce hepatic steatosis including 
corticosteroids, high-dose estrogens, methotrexate, tetracycline or amiodarone in the previous 6 months. 
13. Recent use (within the last 90 days) of medications to treat hepatic steatosis such as pioglotazone (or medications in 
the same class) or vitamin E. 
14. Use of cyclosporine, alfentanyl and fentanyl on a chronic basis  
15. Use of simvastatin and lovastatin at a dose of 40 mg once daily or higher. 
16. Use of the following medications for more than 3 consecutive days: rifampicin, carbamazepine, phenytoin, 
enzalutamide and St John’s wort  
17. Use of clarithromycin, verapamil, diltiazem, itraconazole, difluconazole, ciprofloxacin, and grapefruit juice on a 
chronic basis (> 3 days consecutive days)  
18. Use of Aramchol or agents in the same class. 
19. HbA1c > 9 or uncontrolled diabetes. 
20. Significant systemic or major illnesses other than liver disease, including congestive heart failure, coronary artery 
disease, cerebrovascular disease, pulmonary disease with hypoxia, renal failure (defined as GFR < 45 or CKD IIIB), 
organ transplantation, serious psychiatric disease, malignancy that, in the opinion of the investigator would preclude 
treatment with Aramchol and adequate follow up.  
21. Active substance abuse, such  inhaled or injection drugs within the previous three months. 
22. Pregnancy or inability to practice adequate contraception in women of childbearing potential.  
23. Nursing mothers 
24. History  of hepatocellular carcinoma: alpha-fetoprotein levels greater than 200 ng/ml and/or liver mass on imaging 
study that is suggestive of liver cancer. 
25. HIV specific exclusions:  
a. 
CD4 count of less than 200 in the previous 6 months 
b. 
Detectable viral load in the previous 6 months 
c. 
changes to ART regimen in the preceding 12 weeks 
d. 
History of opportunistic infection in the preceding 6 months 
e. 
AIDS wasting syndrome 
26. Symptoms of uncontrolled gastrointestinal disorders involving motility, gastric acid or gastric emptying or 
malabsorption.  
a. 
Disorders including but not limited to peptic ulcer disease, gastroesophageal reflux, severe dyspepsia, 
gastroparesis, chronic diarrhea, chronic constipation, gall bladder disease,  pancreatitis, severe lactose 
intolerance and celiac disease.   
b. 
Patients who have used anticholinergic or other drugs known to affect gastrointestinal  motility within 7 days 
prior to dosing and throughout the study will also be excluded   
27. Patients with hypersensitivity to Aramchol or to any of the excipients in the tablets or with hypersensitivity to cholic 
acid or bile acid sequestrants  
28. Any other condition, which, in the opinion of the investigators would impede competence or compliance or possibility 
hinder completion of the study. 
29. Women who are pregnant or may become pregnant 
11. 
RECRUITMENT 
Enrollment of patients may be initiated once IRB approval is acquired and will continue until June 2015.  
 
English speaking and Spanish speaking patients will be recruited from the following populations: 
•   Primary care and internal medicine clinics 
•   Tertiary referral clinics at the Hillcrest Campus and Perlman Clinics: 
     -  GI/Liver clinic 
     -  Liver transplant clinic 


 
 
Biomedical IRB Application Instructions 
Page 9 
     -  Owen clinic 
     -  Bariatric surgery clinic 
     -  Lipid disorders clinic 
 
Physicians taking care of the patients would provide information regarding the study (flyer and stamped consent form 
will be used to provide information regarding the study) and then either refer the patient to our clinic or ask the patient 
to directly contact the PI or research team. 
 
Patient would be given information regarding possible studies in HIV-associated NAFLD in liver clinic by their 
providers. We would ask the patient to call or email the PI or research team to further discuss the study, if they are 
interested. 
 
In addition, potential subjects will also be recruited by newspaper advertisements and fliers posted on the UCSD campus 
bulletin in order to have enough participants to study the desired aims. Volunteers who appear to be a good match for the 
study will receive study announcement material that excludes any direct study contact information (email/phone). Contact 
information of interested participants only will be released to the research study team. Patients who are interested in the 
study can call our office to speak to the study team to find out more information about the study.   
 
12. 
INFORMED CONSENT 
Adult consents have been uploaded to the UCSD HRPP web site for approval.  Subjects will be provided consent either by 
the participating investigator while at their clinic visit or will be given contact information for the research team and told 
to contact them if they are interested in participating.  All signed consents will be maintained in marked binders, secured in 
locked filing cabinets within private administrative offices at UCSD Medical Center, Hillcrest. Offices are accessible to 
study staff only.    
Sub Investigator Dr. Irine Vodkin  is fluent in Spanish.  She will be the one  to explain the study to participants that prefer 
Spanish or are Spanish speaking only. 
 
There is a separate optional component of the study where subjects will be asked to donate a blood sample for genetic 
research.  Subjects will be offered the opportunity to review, discuss and sign the consent at their scheduled visit.  All 
questions will be answered at this time and throughout the study.  Declining to give a genetic sample does not prohibit the 
participant from participating in the study. 
 
13. 
ALTERNATIVES TO STUDY PARTICIPATION 
Currently there are no FDA approved therapies for HIV-associated NAFLD. The alternative to study participation is not to 
participate in this study. 
 
14. 
POTENTIAL RISKS 
The risks and discomforts of frequent phlebotomy: To document changes in levels of biochemical markers of liver disease 
and to monitor the metabolic effects and toxicities of aramchol, frequent blood sampling will be required. Patients will have 
4 venipunctures during the treatment period of the study.  Each venipuncture will remove 15 to 50 ml of blood. However, 
no more than 1.5 ml/kg will be drawn from any one person during a four-week period.  Blood collection by venipuncture 
is associated with mild discomfort, and the possibility of localized bruising, phlebitis, or extravasation. The risk of infection 
or fainting is extremely small. 
 
The risks and discomforts of HIV testing:  Patients will sign a standard consent for HIV testing for this study. 
Risks and discomforts of Oral Glucose Tolerance Test (OGTT): There will be two OGTT’s during this protocol, one at the 
beginning and one after 12 weeks of treatment with Aramchol. The purpose of this test is to assess insulin sensitivity, insulin 
secretion as well as free fatty acid metabolism.  The patients will have an intravenous catheter placed in the arm and be 
given 75mg of glucose as an oral solution. Subjects occasionally complain of nausea and rarely may vomit and there is a 
small risk of rebound hypoglycemia. Repeat blood draw will be done at 2 hours. Total amount of blood that will be drawn 
for glucose and insulin measurements during this test will be 100 to 120 ml. No more than 6 ml/kg of blood will be drawn 
from any one person during a four-week period 
 
The risks and discomforts of other tests: 


 
 
Biomedical IRB Application Instructions 
Page 10 
a. MRI of abdomen and liver. Patients will undergo two MRI examinations of the liver during this study. Each session will 
be completed within 30 minutes. While serial MRI scanning is thought to be safe, the procedure may cause anxiety in some 
patients since current equipment used at the Clinical Center uses a closed tube. Patients will be offered sedatives such as 
Valium if they express worry about being in a closed space. 
b. MRE is a type of MR imaging where the images indicate tissue stiffness.  MRE imaging involves placing a vibrating 
paddle over the abdomen while images are being obtained. This is an FDA-approved procedure when used clinically, but 
is considered to be investigational in this study. These vibrations have been reported to be well tolerated by patients. (14)  
However, the vibrating paddle could be uncomfortable to some subjects, and so subjects will be instructed to tell the MR 
technologist if the vibrations become uncomfortable, and the MRE part of the examination will be discontinued. 
c. Cardiac MRI (without contrast). Patients will undergo two Cardiac MRI examinations during this study. Each session 
will be completed within 20 minutes. While serial MRI scanning is thought to be safe, the procedure may cause anxiety in 
some patients since current equipment used at the Clinical Center uses a closed tube. Patients will be offered sedatives such 
as Valium if they express worry about being in a closed space. 
d. The ARFI ultrasound imaging method to be used for this study is investigational, and is considered to be of minimal (i.e., 
non-significant) risk. This investigational imaging method has the same safety precautions built into it as the ones that are 
used clinically, and so the method we will use is considered by the FDA to be of minimal risk and of similar safety as the 
sequences that are approved by the FDA for clinical use. As per 63 FR 216:60364-60367, ultrasound is considered a 
(Category 4) minimal risk procedure because it involves the “collection of data through non-invasive procedures (not 
involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or 
microwaves ...”, for which “examples include … ultrasound …”. 
The conventional ultrasound imaging that will be performed in this study is the same as is used clinically. When it is used 
clinically it is FDA approved; however, for the purposes of this research study it will be considered to be investigational 
and not FDA approved since we are using it for research. Possible effects of ultrasound imaging on nursing mothers have 
not been examined. Therefore, nursing mothers will be excluded. 
e. Reproductive risks: 
Although ultrasound and magnetic resonance imaging are routinely performed in pregnancy in clinical practice. We will 
take a conservative approach as potential effects of ultrasound and MRI imaging on human embryonic or fetal development 
may not have been examined. Therefore, women of childbearing potential, including those who have had a tubal ligation, 
will be required to take a urine pregnancy test and have negative results before enrolling into study. 
f. Unforeseeable risks: 
Although serious injury to organs or death have never been attributed to ultrasound imaging or MRI, it is possible that 
currently unforeseen side effects, including serious injury to organs or death may occur. Also, because this is an 
investigational study, there may be some other unknown risks that are currently unforeseeable. The subject will be informed 
of any significant new findings. 
g. Dual energy x-ray absorptiometry (DEXA) body composition assessment will be obtained using the Hologic Discovery 
W densitometer with APEX software (Hologic, Inc., Bedford, MA).  The DEXA systems assess body composition by 
measuring the differential absorption of x-ray at two frequencies to separate tissue into fat, lean, and bone mineral.  A whole 
body composition DEXA scan last approximately 6 minutes and the radiation dose is 9 mrem (0.09 mSv) for two DEXA 
scan, one at screening and one at the post treatment phase.  
h. Ultrasound transient elastography with CAP is a noninvasive procedure to measure liver density. There are no known 
direct risks from the Ultrasound transient elastography with CAP medical device which uses ultrasound waves. However, 
you may feel minor discomfort or minor soreness over the area where the ultrasound probe contacts the abdomen. There is 
a small risk of allergic reaction to the gel used during the procedure. Ultrasound gel is water-based. There is no radiation 
exposure and the CAP measure is simply an additional calculation. 
 
Side effects due to Aramchol: Patient trials with Aramchol are limited to the Safadi study24, but the clinical trial 
demonstrated no significant adverse events in the 12-week treatment period for 58 patients that underwent the trial. The 
few adverse events were mild (abdominal pain, back pain, constipation) and did not cause anyone to drop out of the trial. 
There were no severe adverse effects. The previous studies were done in animal models. Due to the paucity of clinical 
trials to evaluate side effects of Aramchol, we will encourage patients to notify staff of any adverse reactions and we will 
monitor patients via physical exams and laboratory testing at regular intervals to ensure patient safety.  
Dosage modification and discontinuation of Aramchol: patients will be monitored for side effects and the toxicity will be 
ranked as Grades 1 to 4.  We will use the common toxicity criteria (CTC), version 4.0, for scoring adverse events during 


 
 
Biomedical IRB Application Instructions 
Page 11 
therapy.  Specific scoring of toxicity for the major safety parameters to be followed in this study is shown in Table II.   
The criteria for grading leukocytes, platelets, prothrombin time, partial thromboplastin time, bilirubin, ALT, and AST are 
modified slightly from the CTC version 4.0 because these factors are likely to be abnormal before therapy in patients with 
chronic liver disease.   An adverse event is defined as any adverse change from the patient’s baseline (pre-treatment) 
condition. These include current illness during the course of the study, regardless of the illness being considered unrelated 
to treatment. Patients will also be monitored closely for antiretroviral therapy tolerance and continued virologic 
suppression of HIV.  
 
Dose modification of Aramchol: If any grade 2 adverse events (anemia, elevated serum CPK, hypoglycemia, 
decrease in serum bicarbonate, elevation in liver transaminases, elevation in bilirubin, anorexia, nausea, diarrhea) 
occur and persist on repeat testing for one week, Aramchol will be reduced 600 mg daily (including 200 mg tablet 
and 400 mg tablet) versus identical placebo to 300 mg daily and the patient will be closely monitored. If the 
adverse event resolves and in retrospect is not believed to be due to Aramchol, the drug will be restarted at the 
dose of 600 mg daily (including 200 mg tablet and 400 mg tablet) versus identical placebo. If the adverse event 
recurs or persists for 2 weeks despite this dose reduction, Aramchol will be stopped.  
 
Discontinuation of Aramchol: In this study, discontinuation of Aramchol will be based upon the scoring of 
adverse events as shown in the table below. Factors that will lead to discontinuation of Aramchol include 
pregnancy, any one of the grade 3 or 4 adverse events or any adverse event, which, in the opinion of the 
investigator, places the patient at increased risk. Factors specific to the HIV population which will lead to 
discontinuation of aramchol will include: development of HIV viremia, decrease in CD4 T-cell count below 200, 
any evidence of increased antiretroviral toxicity (lactic acidosis, as well as grade 3 or 4 myalgia, CPK elevation 
or LFT abnormalities), and any aramchol related side effects that interfere with adherence to antiretroviral 
therapy.  Aramchol will not be restarted unless another cause for the abnormality or symptom is found.  
Table II. Scoring of toxicity for dose modification 
Adverse 
events 
1 
2 
3 
4 
5 
Allergic 
reaction 
Transient 
flushing or 
rash, 
drug fever <38 
degrees C 
(<100.4 
degrees F); 
intervention 
not indicated 
Intervention or 
infusion 
interruption 
indicated; 
responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDS, 
narcotics); 
prophylactic 
medications 
indicated for 
<=24 hrs 
Prolonged 
(e.g., not 
rapidly 
responsive to 
symptomatic 
medication 
and/or brief 
interruption of 
infusion); 
recurrence of 
symptoms 
following 
initial 
improvement; 
hospitalization 
indicated for 
clinical 
sequelae (e.g., 
renal 
impairment, 
pulmonary 
infiltrates) 
Life 
threatening 
consequences; 
urgent 
intervention 
indicate 
Death 
Anaphylaxis 
 
 
Symptomatic 
bronchospasm, 
with or without 
urticaria; 
parenteral 
intervention 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 


 
 
Biomedical IRB Application Instructions 
Page 12 
indicated; 
allergy-related 
edema/angioed
ema; 
hypoten 
Anorexia 
Loss of 
appetite 
without 
alteration in 
eating habits 
 Oral intake 
altered without 
significant 
weight loss or 
malnutrition; 
oral nutritional 
supplements 
indicated 
Associated 
with significant 
weight loss or 
malnutrition 
(e.g., 
inadequate oral 
caloric 
and/or fluid 
intake); tube 
feeding or TPN 
indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Nausea 
Loss of 
appetite 
without 
alteration in 
eating habits 
Oral intake 
decreased 
without 
significant 
weight loss, 
dehydration or 
malnutrition 
Inadequate oral 
caloric or fluid 
intake; tube 
feeding, TPN, 
or 
hospitalization 
indicated 
- 
- 
Diarrhea 
Increase of <4 
stools per day 
over baseline; 
mild increase 
in ostomy 
output 
compared to 
baseline 
Increase of 4 - 
6 stools per 
day over 
baseline; 
moderate 
increase in 
ostomy output 
compared to 
baseline 
Increase of 
>=7 stools per 
day 
over baseline; 
incontinence; 
hospitalization 
indicated; 
severe increase 
in ostomy 
output 
compared to 
baseline; 
limiting self 
care ADL 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Fatigue 
Fatigue 
relieved by rest 
Fatigue not 
relieved by 
rest; 
limiting 
instrumental 
ADL 
Fatigue not 
relieved by 
rest, limiting 
self care ADL 
- 
- 
Myalgia 
Mild pain 
Moderate pain; 
limiting 
instrumental 
ADL 
Severe pain; 
limiting self-
care ADL 
 
 
Anemia 
Hemoglobin 
(Hgb) <LLN - 
10.0 g/dL; 
<LLN - 6.2 
mmol/L; 
Hgb <10.0 - 
8.0 g/dL; <6.2 
- 
4.9 mmol/L;  
<100 - 80g/ 
Hgb <8.0 - 6.5 
g/dL; <4.9 - 
4.0 
mmol/L; <80 - 
65 g/L; 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 


 
 
Biomedical IRB Application Instructions 
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<LLN - 100 
g/L 
transfusion 
indicated 
Leukocytes 
(cell/mm3) 
3300 to 9600 
2500 to 3300 
2000 to 2500 
1000-2000 
<1000 
Platelet count 
per mm3 
154,000 to 
345,000 
70,000 to 
150,000 
50,000 to 
70,000 
10,000 to 
50,000 
<10,000 
Prothrombin 
time  
11.8 to 14.7 
14.8 to 16 
 
16.1 to 18 
>18 
- 
Activated 
partial 
thromboplasti
n time 
prolonged 
23.4 to 34.5 
35.6 to 42 
42 to 50 
>50 
- 
Alkaline 
phosphatase 
(U/L) 
37-116 
117-250 
401 - 400  
401-600 
>600 
ALT  
(U/L) 
Baseline-<1.5 
times baseline 
>200 and > 1.5 
X baseline 
300-400 and > 
2 x baseline 
401-800 and > 
3x baseline 
>800 
AST  
(U/L) 
Baseline-<1.5 
times baseline 
>200 and > 1.5 
X baseline 
300-400 and > 
2 x baseline 
401-800 and > 
3x baseline 
>800 
Total 
Bilirubin 
(mg/dL) 
0.1 to 1 
1.1 to 1.5 and 
direct bilirubin 
>0.5 
1.5 to 5 and 
direct bilirubin 
> 1 
5.1 to 10 
>10 
Albumin 
 (g/dL) 
<LLN - 3 g/dL; 
<LLN - 30 g/L 
<3 - 2 g/dL; 
<30 - 20 g/L 
<2 g/dL; <20 
g/L 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
CPK 
increased 
(U/L) 
  2.5 x above 
baseline  
CPK2.5 x - 5 x 
x above 
baseline 
>5 x  - 10 x 
above baseline  
>10 x baseline 
- 
Glucose  
(mg/dL) 
<LLN - 55 
mg/dL; <LLN 
- 3.0 mmol/L 
<55 - 40 
mg/dL; <3.0 - 
2.2 mmol/L 
<40 - 30 
mg/dL; <2.2 - 
1.7 mmol/L 
<30 mg/dL; 
<1.7 mmol/L; 
life threatening 
consequences; 
seizures 
Death 
Creatinine 
(mg/dL) 
Creatinine 
level increase 
of >0.3 mg/dL; 
creatinine 1.5 - 
2.0 x above 
baseline 
Creatinine 2 - 3 
x above 
baseline 
Creatinine >3 x 
baseline or 
>4.0 mg/dL; 
hospitalization 
indicated 
Life-
threatening 
consequences; 
dialysis 
indicate 
Death 
 
Table II. Scoring of toxicity for dose modification. Scoring of toxicity from the CTC Version 4.0, with modifications for 
leukocytes, platelets, prothrombin time, partial thromboplastin time, ALT, AST and bilirubin. Normal ranges for values at 
UCSD center are used.   
 
Potential Loss of Confidentiality: All means will be employed to ensure that there is not a loss of confidentiality. Although 
study material will be kept private and inside a locked cabinet there is a slight possibility that a breach of confidentiality 
may occur. A special code de-identifying the research subject from the data and specimens collected will be assigned to all 
research subjects and their study material. Only the P.I. and their research team will be able to link the research subject to 


 
 
Biomedical IRB Application Instructions 
Page 14 
the assigned code. It still may be possible, but highly unlikely, that the information in the research records could become 
known outside of the research setting. 
 
15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES 
Data and Safety Monitoring: 
The principal investigator and research coordinator of this protocol will monitor data and safety regularly at weekly 
meetings. These meetings are separate from regular clinical rounds and consist of review of all study patients including 
flow sheets of major safety and efficacy measurements.  The rationale for not using an outside data and safety monitoring 
committee is that this is a small, single center study using a FDA approved medication that has been associated with few 
severe side effects.  All measurements and tests are well established in clinical medicine.  Yearly reports are made to the 
UCSD IRB regarding safety and efficacy. 
 
Adverse Event Reporting 
All serious adverse events will be reported to the UCSD IRB and Galmed within 7 days.  Unexpected and related fatal or 
life-threatening events will be reported within 48 hours and reports will be sent to the FDA, MEDWATCH program 
(telephone 1-800-FDA-1088; or via the Internet at www.fda.gov/medwatch/index.html) and Galmed Pharmaceutical.  
 
Informed Consents 
All consents will be stored in well-marked binders in locked file cabinets located in private offices at UCSD Medical center. 
Databases with identifying information will be secure as they will be password protected and encrypted.  Staff will be 
trained in HIPAA guidelines and confidentiality issues. 
 
Patient Privacy: To help us protect the privacy of the research subjects, we have obtained a Certificate of Confidentiality 
from the National Institutes of Health, which will allow us to resist any demands for health information, with a few 
exceptions as explained below. The Certificate protects us from being forced to disclose information that may identify 
research subjects, even if by a court subpoena. We are also protected from demands for information made by federal, state, 
local civil, criminal, administrative, legislative, or other sources. However, the Certificate cannot be used to resist a demand 
from the U.S. Government that is used for auditing or evaluation of federally funded projects or for information that must 
be disclosed in order to meet the requirements of the U.S. Food and Drug Administration. All data and study forms will be 
in secured locations (locked room or cabinet) and access is limited to study personnel.  Subject names are not used; instead 
a name code is assigned upon enrollment.  Release of data to persons or organizations outside study personnel will require 
written consent of the subject. 
 
MRI Findings: Liver MRI (Fat fraction) sequence and Cardiac MRI (without contrast) do not provide detailed information 
regarding other organs within the abdomen cavity and is mainly dedicated to the liver or cardiovascular region. However, 
if there are any unexpected findings on the liver MRI and/or Cardiac MRI, we would utilize following protocol to safeguard 
patient interest. A trained radiologist will read all MRI images. All abnormal findings will be communicated to the PI by 
the radiologist. Dr. Loomba (PI) is a gastroenterologist and a transplant hepatologist at UCSD and routinely provides 
consultation to other services regarding abnormal imaging findings and is therefore, well versed with the management of 
these findings. He would clinically correlate the significance of any unexpected MRI findings. These findings will be 
discussed with the patient by the study investigator and a follow-up plan will be established and documented. If the patient 
desires, this information will be released to the referring physician or any provider or entity that the patient would like us 
to send the information. PI would be available to discuss the findings with the patient or their health care providers and 
assist in providing adequate follow-up. These abnormal findings would be systematically recorded and reported at yearly 
renewals and in the final manuscript. 
16. PRIVACY 
AND 
CONFIDENTIALITY 
CONSIDERATIONS 
INCLUDING 
DATA 
ACCESS 
AND 
MANAGEMENT 
All study data will be kept confidential. No publication or written reports will link subject data with a name or any individual 
protected health information. Protected health information will not be re-used or disclosed for other purposes. Computer 
data file entry and access will require a password. 
Research subjects will have control over access to themselves (privacy) and how study data will be managed and used 
(confidentiality). 


 
 
Biomedical IRB Application Instructions 
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Privacy will be provided for all contact with research subjects during recruitment, informed consent, ultrasound and MRI 
scanning, and any other contact with subjects that may occur by ensuring privacy at our facility (210 Dickinson Street) 
where we have adequate dedicated space – a separated waiting room and a private examination room, each with doors that 
close. Subjects will also have access to, and will use a private bathroom / changing room to change into and out of a gown. 
Confidentiality will be assured by allowing review in this study of medical records and imaging studies only by study 
investigators who are directly involved in reviewing or capturing this information. Captured information will be stored in 
a de-identified form. Data will be accessed at workstations at require secure login and password access, in the CTF building. 
Research records with personal health information will be kept in locking file cabinets in rooms that are locked after hours 
and which are only accessible to authorized personnel during working hours. The 408 Dickinson building where the MRIs 
are performed is itself locked after hours. Security of medical records is maintained as per University of California Medical 
Center policy, UCSD IRB security policies, and study personnel, all who have been CITI IRB trained. Security policy in 
the 408 Dickinson building is further maintained by Mark Wood MSc, dedicated on-site information technology and 
security officer, who will control computer access to medical records. De-identification of data will be done and data labels 
and study ID would be used. The data key to de-identified data will be the enrollment log for this study, which will be 
stored in a secure, locked filing cabinet in the CTF building. Identifiers will be kept in a separate file, which will be password 
protected until this study is concluded, at which time they will be destroyed.  
17. POTENTIAL BENEFITS 
Potential benefits include possible improvement in liver profile, insulin resistance, and metabolic profile for the patient. 
The research subject’s liver disease may improve because of treatment with the study drug. However, the research subject 
may receive no benefit. The research subject may help future patients by providing important information about the 
treatment of HIV-associated NAFLD. The research subject may benefit from health information obtained during the 
physical exams, laboratory tests, and other study procedures. At the research subject’s direction, we will provide the results 
of any procedures done to screen him/her for this study to their liver care provider. 
 
18. RISK/BENEFIT RATIO 
The PI believes that the there is a favorable risk/benefit ratio as risks associated with treatment with Aramchol, data 
collection and confidentiality does not outweigh potential benefits to the discovery of potential treatments for HIV-
associated NAFLD. There are currently no approved treatments for NAFLD/NASH. Data collection and blood draws are 
procedures being performed as outlined in the study protocol and all efforts will be made to minimize any risk to the 
research subject.  Staff will have HIPAA certification training. 
 
19. EXPENSE TO PARTICIPANT 
There is no expense to the research subjects. 
 
20. COMPENSATION FOR PARTICIPATION 
Participants will be paid $25 each at the first visit and at weeks 4 and 8. $50 at the completion of the study at week 12. 
 
21. PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES 
Dr. Rohit Loomba is an adult gastroenterologist and transplant hepatologist at UCSD Medical Center. He is a licensed 
physician in the state of California with full privileges at UCSD Medical Center. He has full privileges at UCSD medical 
center to conduct liver biopsies and also manage patients with chronic liver disease. Dr. Loomba has completed training 
relevant to clinical research including HIPAA certification, and Ethics training. He holds a Master’s Degree in Health 
Sciences in Clinical Research from Duke University School of Medicine. Copies of licenses and certification are maintained 
at the Department of Medicine.  
 
Dr. Claude Sirlin, an American Board of Radiology certified radiologist, has two licenses:  a CA medical license, and a 
fluoroscopy operator license. Dr. Sirlin has completed training relevant to clinical research including Human Subjects 
certification, HIPAA certification, and Ethics training. 
 
Dr. Saima Aslam is an adult infectious disease specialist at UCSD Medical Center and the director of the solid organ 
transplant infectious diseases service. She is a licensed physician in the state of California with full privileges at UCSD 


 
 
Biomedical IRB Application Instructions 
Page 16 
Medical Center. Dr. Aslam has completed training relevant to clinical research including HIPAA certification, and Ethics 
training. Copies of licenses and certification are maintained at the Department of Medicine. 
 
Dr. Edward Cachay is an adult infectious disease specialist at UCSD Medical Center and the director of the solid organ 
transplant infectious diseases service. He is a licensed physician in the state of California with full privileges at UCSD 
Medical Center. Dr. Cachay has completed training relevant to clinical research including HIPAA certification, and Ethics 
training. Copies of licenses and certification are maintained at the Department of Medicine. 
 
Irine Vodkin is a UCSD fellow in gastroenterology and is board certified in California.  Dr. Vodkin has privileges at UCSD 
medical Center.  She has completed training relevant to clinical research through the Clinical Research Enhancement 
Supplemental Training program. Copies of licensure and certification are maintained in the UCSD Department of Medicine. 
 
Daniel Lee is an adult infectious disease specialist at UCSD Medical Center, he director of the Owen lipid/lipodystrophy 
clinic. He is a licensed physician in the state of California with full privileges at UCSD Medical Center. Dr. Lee has 
completed training relevant to clinical research including HIPAA certification, and Ethics training. Copies of licenses and 
certification are maintained at the Department of Medicine. 
Ahilan Arulanandan is a UCSD resident in gastroenterology and is board certified in California.  Dr. Arulanandan has 
privileges at UCSD medical Center.  He has completed training relevant to clinical research through the Clinical Research 
Enhancement Supplemental Training program. Copies of licensure and certification are maintained in the UCSD 
Department of Medicine. 
 
Lisa Richards, NP is a Hepatology nurse practitioner at the UCSD Medical Center. She has special expertise as the nurse 
practitioner for the UCSD NAFLD clinic. Her licenses and degrees are held at the gastroenterology unit UCSD Medical 
Center.  
 
Emily Rizo, NP is a Hepatology nurse practitioner at the UCSD Medical Center. She has special expertise as the nurse 
practitioner for the UCSD NAFLD clinic. Her licenses and degrees are held at the gastroenterology unit UCSD Medical 
Center.  
 
Shirin Bassirian will serve as a study coordinator acting under the supervision of the PI, will assist in the execution of the 
proposed research, including arranging logistics; perform recruitment activities, enroll and consent patients, disburse 
monetary compensation to patients, serve as first-contact liaison and perform administrative tasks as needed. She has 
completed training relevant to clinical research including Human Subjects certification, HIPAA certification, and ethics 
training.  Copies of licensure and certification are maintained in the UCSD Department of Medicine. 
 
Phirum Nguyen and Carolyn Hernandez, will serve as the backup study coordinators acting under the supervision of the PI, 
will assist in the execution of the proposed research, including arranging logistics; perform recruitment activities, enroll 
and consent patients, disburse monetary compensation to patients, serve as first-contact liaison and perform administrative 
tasks as needed. She has completed training relevant to clinical research including Human Subjects certification, HIPAA 
certification, and ethics training.  Copies of licensure and certification are maintained in the UCSD Department of Medicine. 
 
22. BIBLIOGRAPHY 
1. 
Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the 
United States: impact of ethnicity. Hepatology 2004;40:1387-95. 
2. 
Zelber-Sagi S, Nitzan-Kaluski D, Halpern Z, et al. Prevalence of primary non-alcoholic fatty liver disease in a 
population-based study and its association with biochemical and anthropometric measures. Liver Int 
2006;26:856-63. 
3. 
Lazo M, Clark JM. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis 
2008;28:339-50. 
4. 
Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013;10:686-90. 
5. 
Loomba R, Abraham M, Unalp A, et al. Association between diabetes, family history of diabetes, and risk of 
nonalcoholic steatohepatitis and fibrosis. Hepatology 2012;56:943-51. 


 
 
Biomedical IRB Application Instructions 
Page 17 
6. 
Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. 
Gastroenterology 2002;123:745-50. 
7. 
Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for 
nonalcoholic fatty liver disease. Hepatology 2005;41:1313-21. 
8. 
el-Hassan AY, Ibrahim EM, al-Mulhim FA, et al. Fatty infiltration of the liver: analysis of prevalence, 
radiological and clinical features and influence on patient management. Br J Radiol 1992;65:774-8. 
9. 
Venkatesh SK, Yin M, Ehman RL. Magnetic resonance elastography of liver: clinical applications. J Comput 
Assist Tomogr 2013;37:887-96. 
10. 
Kim D, Kim WR, Talwalkar JA, et al. Advanced fibrosis in nonalcoholic fatty liver disease: noninvasive 
assessment with MR elastography. Radiology 2013;268:411-9. 
11. 
Tang A, Tan J, Sun M, et al. Nonalcoholic fatty liver disease: MR imaging of liver proton density fat fraction to 
assess hepatic steatosis. Radiology 2013;267:422-31. 
12. 
Noureddin M, Lam J, Peterson MR, et al. Utility of magnetic resonance imaging versus histology for quantifying 
changes in liver fat in nonalcoholic fatty liver disease trials. Hepatology 2013;58:1930-40. 
13. 
Johnson BL, Schroeder ME, Wolfson T, et al. Effect of flip angle on the accuracy and repeatability of hepatic 
proton density fat fraction estimation by complex data-based, T1-independent, T2*-corrected, spectrum-modeled 
MRI. J Magn Reson Imaging 2014;39:440-7. 
14. 
Hines CD, Frydrychowicz A, Hamilton G, et al. T(1) independent, T(2) (*) corrected chemical shift based fat-
water separation with multi-peak fat spectral modeling is an accurate and precise measure of hepatic steatosis. J 
Magn Reson Imaging 2011;33:873-81. 
15. 
Meisamy S, Hines CD, Hamilton G, et al. Quantification of hepatic steatosis with T1-independent, T2-corrected 
MR imaging with spectral modeling of fat: blinded comparison with MR spectroscopy. Radiology 2011;258:767-
75. 
16. 
Weber R, Sabin CA, Friis-Møller N, et al. Liver-related deaths in persons infected with the human 
immunodeficiency virus: the D:A:D study. Arch Intern Med 2006;166:1632-41. 
17. 
Dobrzyn A, Ntambi JM. Stearoyl-CoA desaturase as a new drug target for obesity treatment. Obes Rev 
2005;6:169-74. 
18. 
Leikin-Frenkel A, Gonen A, Shaish A, et al. Fatty acid bile acid conjugate inhibits hepatic stearoyl coenzyme A 
desaturase and is non-atherogenic. Arch Med Res 2010;41:397-404. 
19. 
Gilat T, Somjen GJ, Mazur Y, et al. Fatty acid bile acid conjugates (FABACs)--new molecules for the prevention 
of cholesterol crystallisation in bile. Gut 2001;48:75-9. 
20. 
Konikoff FM, Leikin-Frenkel A, Goldiner I, et al. Biliary and systemic effects of fatty acid bile acid conjugates. 
Eur J Gastroenterol Hepatol 2003;15:649-55. 
21. 
Goldiner I, van der Velde AE, Vandenberghe KE, et al. ABCA1-dependent but apoA-I-independent cholesterol 
efflux mediated by fatty acid-bile acid conjugates (FABACs). Biochem J 2006;396:529-36. 
22. 
Leikin-Frenkel A, Parini P, Konikoff FM, et al. Hypocholesterolemic effects of fatty acid bile acid conjugates 
(FABACs) in mice. Arch Biochem Biophys 2008;471:63-71. 
23. 
Gonen A, Shaish A, Leikin-Frenkel A, et al. Fatty acid bile acid conjugates inhibit atherosclerosis in the C57BL/6 
mouse model. Pathobiology 2002;70:215-8. 
24. 
Safadi R, Konikoff FM, Mahamid M, et al. The Fatty Acid-Bile Acid Conjugate Aramchol Reduces Liver Fat 
Content in Patients With Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 2014. 
25. 
Reeder SB, Cruite I, Hamilton G, et al. Quantitative assessment of liver fat with magnetic resonance imaging and 
spectroscopy. J Magn Reson Imaging 2011;34:729-49. 
26. 
World Health Organization: Diabetes Mellitus: Report of a WHO study Group, Geneva, World Health 
Organization, 1985. 
 
23. FUNDING SUPPORT FOR THIS STUDY 
This is an investigator-initiated study not solicited by the sponsor company Galmed Pharmaceutical. Funding is provided 
by Galmed Pharmaceutical under investigator initiated studies program. 
 
24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 
Not applicable. 


 
 
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25. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 
Application has been submitted to the FDA. IND# 128222 
 
26. IMPACT ON STAFF 
Lisa Richards, NP is seasoned clinician, licensed and certified to perform physical exams and appropriate medical 
procedures and case manage quality of care. The certified study coordinator and other key personnel at the UCSD Medical 
center have been trained or will be trained for their role in the study on-site. 
 
Emily Rizo, NP is clinician, licensed and certified to perform physical exams and appropriate medical procedures and case 
manage quality of care.  
 
 
27. CONFLICT OF INTEREST 
A conflict of interest has been disclosed.  Dr. Loomba follows the IRC recommended management strategy in order to 
manage the conflict of interest. Recompensed activities with Galmed Pharmaceutical during the course of study will be 
discontinued. 
 
28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES 
Not applicable. 
29. OTHER APPROVALS/REGULATED MATERIALS 
Not applicable. 
30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY ASSESSMENT 
Subject must be able to consent to the study. Based upon past experience, we expect that the population of patients we 
will be including in this protocol will be competent to give informed consent. If the investigator feels that the decision-
making capacity to consent to be a part of this study is insufficient, then a post-consent quiz will be administered after the 
consent form has been explained to the subject. The post consent quiz will be submitted to HRPP for review. If the 
subject is unable to answer any of the questions in the post-consent quiz, any information not clearly understood from the 
consent form will be repeated or explained in greater detail. If there is any concern by an investigator that a potential 
research participant has a condition or circumstance that is associated with a possible decrease in decision-making 
capacity, that subject will not be included in the study. 
 
 
 
Version date: May 11, 2011