Clinical trial NCT04480827
Conditions: Hepatic Impairment
Keywords: Pharmacokinetics
Sponsor: Galmed Research and Development, Ltd.
Start date: 2020-02-13; Completion date: 2022-03-24
Enrollment: 57 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 1, multicenter, open-label, 2-part, single- and multiple-dose study designed to assess the effect of hepatic insufficiency on the PK of aramchol

Detailed description:
Each of the 2 parts of the study consisted of a screening period, a check in day, a treatment period, and an end of study (EOS) visit.

In Part 1 (single-dose): 39 subjects were enrolled: 8 subjects each in the mild (Cohort A), moderate (Cohort B), and severe (Cohort C) hepatic impairment cohorts and 15 healthy control subjects with normal hepatic function (Cohort D). Enrollment of 8 subjects with mild hepatic impairment (Cohort A) proceeded only if there is evidence of reduced clearance of aramchol in Cohort B. Assignment to cohorts A to C, was according to Child Pugh classification system.

Serial blood samples for PK analysis of aramchol concentrations in plasma were collected before dosing (0 hour) and up to 168 hours for healthy subjects and 240 hours for hepatically impaired subjects after administration of aramchol.

In Part 2 (multiple-dose), a cohort of 4 subjects comprising of mild, 7 moderate , as well as a cohort of 7 healthy volunteers was administered with aramchol as multiple doses to obtain the PK profile of aramchol at steady state. Aramchol was given twice daily for 12 days. Trough blood samples for analysis of aramchol plasma concentrations was collected before the AM dose on several days and at intervals to 12 hours after the AM dose on Day 12.

Arms: arm 1: 8 mild hepatic impaired subjects arm 2: 8 moderate hepatic impaired subjects arm 3: 8 severe hepatic impaired subjects arm 4: 15 matched healthy volunteers arm 5: 4 mild hepatic impaired subjects arm 6: 7 moderate hepatic impaired subjects arm 7: 7 matched healthy volunteers
Interventions: intervention 1: Aramchol free acid tablet 600mg, single dose intervention 2: Aramchol free acid tablet 300mg, bid
Intervention descriptions: intervention 1: Aramchol free acid tablet 600mg, single dose intervention 2: Aramchol acid tablet 300mg, bid for 12 days

Protocol documents:
Prot_SAP_000.pdf: 




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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
I agree to conduct the study as outlined in the protocol titled “A Phase 1, Open-Label Study 
to Evaluate the Safety, Tolerability, and Pharmacokinetics of Aramchol in Subjects With 
Hepatic Impairment” in accordance with the guidelines and all applicable government 
regulations, including US Title 21 of the Code of Federal Regulations Part 54. I have read 
and understand all sections of the protocol. 
 
Principal Investigator 
 
 
Date 


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TABLE OF CONTENTS 
SIGNATURE PAGE ............................................................................................................... 2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ..................................................... 3 
TABLE OF CONTENTS ........................................................................................................ 4 
PROTOCOL SYNOPSIS ....................................................................................................... 7 
1. 
INTRODUCTION ............................................................................................. 15 
1.1 
BACKGROUND ..............................................................................................15 
1.2 
RATIONALE FOR STUDY ............................................................................15 
1.3 
RATIONALE FOR DOSE SELECTION.........................................................16 
2. 
STUDY OBJECTIVES ...................................................................................... 16 
2.1 
PRIMARY OBJECTIVE ..................................................................................16 
2.2 
SECONDARY OBJECTIVE ............................................................................16 
3. 
STUDY DESIGN ................................................................................................ 17 
3.1 
SCHEDULE OF EVENTS - SINGLE DOSE ARAMCHOL (PART 1) ..........20 
3.2 
SCHEDULE OF EVENTS - MULTIPLE DOSE ARAMCHOL (PART 2) .....22 
4. 
STUDY POPULATION..................................................................................... 24 
4.1 
INCLUSION CRITERIA .................................................................................24 
4.2 
EXCLUSION CRITERIA ................................................................................25 
4.3 
OTHER SCREENING CONSIDERATIONS ..................................................28 
4.4 
WITHDRAWAL OF SUBJECTS FROM THE STUDY .................................28 
4.4.1 
Reasons for Withdrawal................................................................................28 
4.4.2 
Handling of Withdrawals ..............................................................................29 
4.4.3 
Replacements ................................................................................................30 
5. 
STUDY TREATMENTS ................................................................................... 30 
5.1 
TREATMENTS ADMINISTERED .................................................................30 
5.2 
INVESTIGATIONAL PRODUCTS ................................................................30 
5.2.1 
Study Drug Packaging and Storage ..............................................................31 
5.2.2 
Study Drug Accountability ...........................................................................31 
5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS .........31 
5.4 
BLINDING .......................................................................................................32 
5.5 
TREATMENT COMPLIANCE .......................................................................32 
5.5.1 
Prior and Concomitant Medications .............................................................32 
5.5.1.1 
Prior Medications ..................................................................................... 33 
5.5.1.2 
Concomitant Medications ........................................................................ 33 
6. 
STUDY PROCEDURES ................................................................................... 33 
6.1 
PHARMACOKINETIC ASSESSMENTS AND ENDPOINTS ......................33 
6.1.1 
Pharmacokinetic Sample Collection .............................................................35 
6.1.2 
Pharmacokinetic Sample Analysis................................................................35 


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6.2 
SAFETY ASSESSMENTS AND ENDPOINTS ..............................................35 
6.2.1 
Adverse Events .............................................................................................35 
6.2.1.1 
Adverse Event Definitions ....................................................................... 36 
6.2.1.2 
Eliciting and Documenting Adverse Events ............................................ 37 
6.2.1.3 
Reporting Adverse Events ....................................................................... 37 
6.2.1.4 
Assessment of Severity ............................................................................ 38 
6.2.1.5 
Assessment of Causality .......................................................................... 39 
6.2.1.6 
Follow-up of Adverse Events .................................................................. 39 
6.2.2 
Clinical Laboratory Testing ..........................................................................39 
6.2.3 
Vital Sign Measurements ..............................................................................41 
6.2.4 
Electrocardiograms .......................................................................................41 
6.2.5 
Physical Examinations ..................................................................................42 
7. 
STATISTICAL ANALYSIS PLANS ................................................................ 42 
7.1 
SAMPLE SIZE CALCULATIONS..................................................................42 
7.2 
ANALYSIS SETS ............................................................................................42 
7.3 
STATISTICAL ANALYSIS .............................................................................43 
7.3.1 
Pharmacokinetic Analyses ............................................................................43 
7.3.2 
Safety Analyses ............................................................................................44 
7.4 
HANDLING OF MISSING DATA ..................................................................44 
7.5 
INTERIM ANALYSES ....................................................................................45 
8. 
REFERENCE LIST........................................................................................... 46 
9. 
APPENDICES .................................................................................................... 47 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS ..................................................47 
9.2 
APPENDIX 2: STUDY GOVERNANCE .......................................................48 
9.2.1 
Data Quality Assurance ................................................................................48 
9.2.2 
Investigator Obligations ...............................................................................48 
9.2.2.1 
Confidentiality ......................................................................................... 48 
9.2.2.2 
Institutional Review ................................................................................. 49 
9.2.2.3 
Subject Consent ....................................................................................... 49 
9.2.2.4 
Study Reporting Requirements ................................................................ 49 
9.2.2.5 
Financial Disclosure and Obligations ...................................................... 50 
9.2.2.6 
Investigator Documentation ..................................................................... 50 
9.2.2.7 
Study Conduct ......................................................................................... 51 
9.2.2.8 
Case Report Forms and Source Documents ............................................ 51 
9.2.2.9 
Adherence to Protocol ............................................................................. 51 
9.2.2.10 
Reporting Adverse Events ....................................................................... 52 
9.2.2.11 
Investigator’s Final Report ...................................................................... 52 
9.2.2.12 
Records Retention .................................................................................... 52 


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9.2.2.13 
Publications .............................................................................................. 52 
9.2.3 
Study Management .......................................................................................53 
9.2.3.1 
Monitoring ............................................................................................... 53 
9.2.3.2 
Management of Protocol Amendments and Deviations .......................... 53 
9.2.3.3 
Study Termination .................................................................................... 54 
9.2.3.4 
Final Report ............................................................................................. 54 
 
 
LIST OF TABLES 
Table 5–1 
Child-Pugh Classification System .................................................................. 32 
 
 


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PROTOCOL SYNOPSIS 
PROTOCOL NO.: Aramchol-019 
TITLE: A Phase 1, Open-Label Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of Aramchol in Subjects With Hepatic Impairment 
STUDY PHASE: 1 
STUDY SITES: 3 clinical sites in the United States 
OBJECTIVES: 
The primary objective of this study is to compare the pharmacokinetic (PK) profile of 
aramchol administered orally in subjects with hepatic impairment with that of healthy 
subjects. 
The secondary objective of this study is to assess the safety and tolerability of aramchol 
administered orally in subjects with hepatic impairment. 
STUDY DESIGN: 
This is a Phase 1, multicenter, open-label, 2-part, single- and multiple-dose study designed to 
assess the effect of hepatic insufficiency on the PK of aramchol. 
Each part of the study will consist of a screening period, a check-in day, a treatment period, 
and an end-of-study (EOS) visit. 
In Part 1 (single-dose), up to 48 subjects are planned: 8 subjects each in the mild (Cohort A), 
moderate (Cohort B), and severe (Cohort C) hepatic impairment cohorts and 8 to 24 healthy 
control subjects with normal hepatic function (Cohort D). Enrollment of 8 subjects with mild 
hepatic impairment (Cohort A) will proceed only if there is evidence of reduced clearance of 
aramchol in Cohort B. At screening, subjects will be assigned to a study cohort according to 
the Child-Pugh classification system as follows: 
Cohort 
Hepatic Condition 
Child-Pugh Grade 
Number of Subjects 
A(a) 
Mild impairment 
Class A (Score of 5 to 6) 
8 
B 
Moderate impairment 
Class B (Score of 7 to 9) 
8 
C 
Severe impairment 
Class C (Score of 10 to 15) 
8  
D 
Healthy (control) 
— 
8 to 24 
(a) Enrollment of subjects into Cohort A will only proceed if there is evidence of reduced clearance of aramchol 
in Cohort B. 
Healthy control subjects (Cohort D) will be matched with hepatically impaired subjects 
(Cohorts A, B, and C) according to gender, age (±10 years), and body mass index (±20%). 
Safety data and PK profiles of aramchol from at least 4 subjects with moderate hepatic 
impairment (Cohort B) will be obtained and reviewed while enrollment to this cohort 
continues. These 4 subjects in Cohort B must demonstrate satisfactory safety (no serious 
adverse events [AEs] or severe AEs related to aramchol) and PK results for up to 4 days after 
dosing before enrollment of subjects with severe hepatic impairment (Cohort C) is initiated. 
Two subjects with severe hepatic impairment must demonstrate satisfactory safety and 
tolerability (no serious AEs or severe AEs related to aramchol) for up to 4 days after dosing 
before the remaining subjects with severe hepatic impairment may be dosed. 


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Enrollment of subjects into Cohort A (mild hepatic impairment) will proceed only if there is 
evidence of reduced clearance of aramchol in the first 4 subjects in Cohort B (moderate 
hepatic impairment), defined as a reduction in apparent total oral clearance (CL/F) of greater 
than 30% compared with values in historical healthy control subjects.  
In Part 2, a cohort of at least 8 subjects comprising of mild and moderate or moderate and 
severe hepatic impairment subjects will be administered aramchol as multiple doses to obtain 
the PK profile of aramchol at steady state. A decision on the severity of hepatic impairment 
of subjects to participate in Part 2 (multiple-dose) will be made by the sponsor based on the 
available safety and PK results from Part 1 (single-dose). 
Healthy control subjects will be matched with the hepatically impaired subjects according to 
gender, age (±10 years), and body mass index (±20%). 
Single Dose (Part 1): 
On Day 1, subjects will receive a single oral dose of 600 mg aramchol administered with 
water in the morning, after an overnight fast of at least 10 hours, and approximately 
30 minutes after consuming a standardized breakfast. Subjects will remain fasted except for 
water for 2 hours after dosing. During the study, subjects may consume water on an ad 
libitum basis. Hepatically impaired subjects will receive a diet standardized for hepatic 
impairment and healthy control subjects will receive a similar diet. 
Serial blood samples for PK analysis of aramchol concentrations in plasma will be collected 
before dosing (0 hour) and up to 168 hours for healthy subjects and 240 hours for hepatically 
impaired subjects after administration of aramchol. 
Subjects will be confined to the clinical site from Day –1 until discharge on Day 8 for healthy 
control subjects and on Day 11 for hepatically impaired subjects. The duration of the study, 
excluding screening, is approximately 23 days. 
Multiple Dose (Part 2): 
Multiple dosing will involve twice daily (approximately 12 hours apart) oral administration 
of aramchol for 11 days with a single AM dose on Day 12 to achieve steady state. The dosage 
will not exceed 300 mg twice daily but may be adjusted to give lower exposure depending on 
review of available data on any reduction in clearance associated with hepatic impairment 
seen with single doses in Part 1. Subjects will consume a standardized meal 30 minutes prior 
to the AM and PM doses of aramchol. Subjects will remain fasted except for water for 
2 hours after dosing. During the study, subjects may consume water on an ad libitum basis. 
Hepatically impaired subjects will receive a diet standardized for hepatic impairment and 
healthy control subjects will receive a similar diet. 
Blood samples for analysis of aramchol concentrations in plasma will be collected before the 
AM dose on Days 1, 4, 8, 9, 10, 11, and 12 and at intervals to 12 hours after the AM dose on 
Day 12. Samples of plasma will also be stored for analysis of metabolites pending results of a 
mass balance study. 


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Subjects will be confined to the clinical site from Day –1 until discharge on Day 13. The 
duration of the study, excluding screening, is approximately 28 days. 
STUDY POPULATION: 
Inclusion Criteria: 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. The subject is male or female 18 to 79 years of age, inclusive. 
2. The subject has a body mass index of 19 to 40 kg/m2, inclusive, at screening. 
3. Females of childbearing potential must practice a highly effective method of 
contraception throughout the study period and for 1 month after treatment 
discontinuation. Highly effective methods are defined as those that can achieve a failure 
rate of less than 1% per year when used consistently and correctly. Such methods, in 
accordance with the recommendations of the Clinical Trial Facilitation Group Working 
Group on Contraception include: hormonal contraception associated with inhibition of 
ovulation, intrauterine device, intrauterine hormonal-releasing system, bilateral tubal 
occlusion, vasectomized partner, and sexual abstinence. All female subjects must have a 
negative pregnancy test at screening and before the first dose of study drug. 
4. Male subjects with female partners of childbearing potential must be vasectomized, be 
willing to use an acceptable method of birth control, or practice abstinence during the 
study. 
5. The subject has a resting pulse rate of ≥40 and <100 beats per minute with no clinically 
significant deviation as judged by the investigator. 
6. The subject has a QT interval corrected for heart rate using Fridericia’s formula of 
<500 msec. 
7. The subject agrees to comply with all protocol requirements. 
8. The subject is able to provide written informed consent. 
Additional Inclusion Criteria for Healthy Subjects Only (Cohort D): 
9. The subject has normal hepatic function. 
10. The subject has a resting blood pressure of 90 to 150 mm Hg (systolic) and 50 to 
100 mm Hg (diastolic). 
11. The subject is judged by the investigator to be in good general health, as determined by 
medical history, clinical laboratory assessments, vital sign measurements, 12-lead 
electrocardiogram (ECG) results, and physical examination findings. 
Additional Inclusion Criteria for Subjects With Hepatic Impairment Only (Cohorts A, B, 
and C): 
12. The subject has cirrhosis with evidence of impaired liver function. The etiology of the 
cirrhosis may be alcoholic, autoimmune, nonalcoholic steatohepatitis, or chronic viral 
hepatitis type B or C. 
13. The subject has chronic (more than 6 months) and stable hepatic impairment (ie, no acute 
episodes of illness within 30 days before screening due to deterioration of hepatic 


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function) as assessed by a Child-Pugh classification score of mild (5 to 6 points), 
moderate (7 to 9 points), or severe (10 to 15 points). 
14. The subject has a resting blood pressure of 90 to 155 mm Hg (systolic) and 50 to 
100 mm Hg (diastolic). 
15. The subject is judged by the investigator to be in good general health, as determined by 
medical history, clinical laboratory assessments, vital sign measurements, 12-lead ECG 
results, and physical examination findings, except for findings that, as judged by the 
investigator, are consistent with the subject’s hepatic impairment or other stable 
concomitant medical conditions. 
Exclusion Criteria: 
Subjects meeting any of the following criteria will be excluded from the study: 
1. The subject has a history or clinical manifestations of a significant neurological, renal, 
cardiovascular, gastrointestinal, pulmonary, hematologic, immunologic, or psychiatric 
disease that would preclude study participation, as judged by the investigator. 
2. The subject has a positive test result for human immunodeficiency virus type 1 or 
2 antibodies at screening. 
3. The subject has a history of drug abuse within 3 months before screening. 
4. The subject has a history of alcoholism within 3 months before screening, or excessive 
alcohol consumption (regular alcohol intake >15 units per week) (1 unit is equal to 
approximately ½ pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure 
[25 mL] of spirits). 
5. The subject smokes >10 cigarettes daily and is unwilling to reduce to ≤5 daily from the 
time of screening through the last PK sample. 
6. The subject is unable or unwilling to abstain from alcohol, caffeine, xanthine-containing 
beverages or food (eg, coffee, tea, chocolate, and caffeinated sodas, colas), grapefruit, 
grapefruit juice, Seville oranges, or products containing any of these, from 48 hours prior 
to study drug dosing until discharge. 
7. The subject is involved in strenuous activity or contact sports within 24 hours of the first 
dose of study drug or during the study. 
8. The subject has donated blood or blood products >450 mL within 3 months before the 
first dose of study drug. 
9. The subject has a presence or history of relevant drug and/or food allergies (ie, allergy to 
aramchol, cholic acid, or any excipients, or any significant food allergy. 
10. The subject has received study drug in another investigational study within 30 days of 
dosing. 
11. In the opinion of the investigator, the subject is not suitable for entry into the study. 
Additional Exclusion Criteria for Healthy Subjects Only (Cohort D): 
12. The subject has clinically significant findings at screening including history, physical 
examination, ECG, or laboratory values. 
13. The subject has used an herbal remedy (including St John’s wort) known to interfere with 
liver enzymes during the 28 days before dosing with the study drug. 


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14. The subject has a past history of surgery or a medical condition that might affect 
absorption of medicines (hernia repair is acceptable). 
15. The subject has a positive test result for hepatitis B surface antigen or antibodies to 
hepatitis C virus. 
16. The subject has used any prescription (excluding hormonal birth control and hormone 
replacement therapy) or over-the-counter medications (except paracetamol [up to 2 grams 
per day]), including herbal or nutritional supplements, within 14 days before the first 
dose of study drug and throughout the study. 
17. The subject has a positive test result for drugs of abuse or alcohol at screening or before 
the first dose of study drug. 
Additional Exclusion Criteria for Subjects With Hepatic Impairment Only (Cohorts A, B, 
and C): 
18. The subject has a current >Grade 1 (mild) encephalopathy. Subjects with a history of 
Grade 3 or 4 encephalopathy that have responded to treatment with medicines such as 
lactulose, rifaximin, or neomycin may be included with the subject receiving the point 
score for Grade 3 or 4 encephalopathy. 
19. The subject has clinically demonstrated massive tense ascites. Subjects with a history of 
moderate or severe ascites that have responded to diuretics may be included with the 
subject receiving the higher score. 
20. The subject has esophageal varices that have caused hemorrhage within a period of 
8 weeks prior to dosing or are considered of high risk for hemorrhage. 
21. The subject has the following types of liver disease: primary biliary cirrhosis, sclerosing 
cholangitis, hepatocellular carcinoma, cardiac cirrhosis, hemochromatosis, Wilson’s 
disease, other genetic causes of liver disease.  
22. The subject has clinically significant impairment of renal function (eCLcr <45 mL/min) 
as calculated by the Cockcroft-Gault equation. 
23. The subject has a hemoglobin <8.5 mg/dL or platelets <30,000/µL. 
24. The subject has fluctuating or rapidly deteriorating hepatic function, as indicated by 
recent history or worsening of clinical (ie, abdominal pain, nausea, vomiting, anorexia, or 
fever) and/or laboratory signs of hepatic impairment, as judged by the investigator. 
25. The subject has evidence of acute viral hepatitis within 30 days before dosing with study 
drug.  
26. The subject has evidence of hepatorenal syndrome. 
27. The subject has used any prescription (excluding hormonal birth control and hormone 
replacement therapy) or over-the-counter medications, including herbal or nutritional 
supplements, within 14 days before the first dose of study drug and throughout the study, 
except those essential for the management of hepatic impairment or the treatment of 
stable concomitant medical conditions, as judged by the investigator. The dose of an 
approved medication must remain stable from 7 days before study drug dosing and 
throughout the study. 


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28. The subject has a positive test result for drugs of abuse (except positive test results 
associated with prescription medications that have been reviewed and approved by the 
investigator) at screening or before the first dose of study drug.  
STUDY TREATMENTS: 
Single Dose (Part 1): 
Aramchol will be administered as a single oral dose of 600 mg (2 × 300-mg tablets) in the 
morning on Day 1 with water approximately 30 minutes after a standardized breakfast. 
Multiple Dose (Part 2): 
Aramchol will be administered as an oral dose that will not exceed 300 mg twice daily 
(approximately 12 hours apart) for 11 days and a single AM dose on Day 12 with water 
approximately 30 minutes after a standardized meal. 
STUDY PROCEDURES: 
Pharmacokinetic Assessments and Endpoints: 
Single Dose (Part 1): 
Blood samples for analysis of concentrations of aramchol and its metabolites in plasma will 
be collected at the following time points: before dosing (0 hour) and at 1, 2, 3, 4, 5, 6, 8, 10, 
12, 14, 18, 24, 48, 72, 96, 120, 144, 168, 192, and 240 hours (the last 2 time points are for 
hepatically impaired subjects only) after administration of aramchol. 
The following plasma PK parameters will be calculated as endpoints for aramchol using 
actual sampling times rather than scheduled sampling times: 
• Area under the plasma concentration versus time curve (AUC) from time 0 to the last 
quantifiable concentration (AUC0-t) 
• AUC from time 0 extrapolated to infinity (AUC0-inf) 
• Maximum observed plasma concentration (Cmax) 
• Time to reach maximum observed plasma concentration (Tmax) 
• Time to the first measurable plasma concentration (Tlag) 
• Apparent terminal elimination half-life (t1/2) 
• Apparent oral clearance (CL/F) 
• Apparent volume of distribution (Vz/F) 
• Elimination rate constant (ke) 
Multiple Dose (Part 2): 
Blood samples for analysis of concentrations of aramchol and its metabolites in plasma will 
be collected before the AM dose on Days 1, 4, 8, 9. 10, 11, and 12 and at the following times 
after the AM dose on Day 12: 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours. 
The following plasma PK parameters on Day 12 will be calculated as endpoints for aramchol 
using actual sampling times rather than scheduled sampling times (if conducted): 
• AUC from time 0 to the dosing interval tau at steady state (AUC0-tau, ss) 


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• Maximum observed plasma concentration at steady state (Cmax, ss) 
• Time to reach maximum observed plasma concentration at steady state (Tmax, ss) 
• Minimum observed plasma concentration at steady state (Cmin, ss) 
• Time of minimum observed plasma concentration at steady state (Tmin, ss) 
• Average plasma concentration at steady state (Cavg, ss) 
Time to reach steady state will also be estimated graphically by assessing trough plasma 
concentrations (ie, pre-AM dosing on Days 1, 4, 8, 9, 10, 11, and 12) over 12 days of 
administration. 
Safety Assessments and Endpoints: 
Safety and tolerability will be assessed by the following endpoints: monitoring and recording 
of AEs, clinical laboratory test results (hematology, coagulation, serum chemistry, and 
urinalysis), vital sign measurements, 12-lead ECG results, and physical examination findings. 
STATISTICAL ANALYSIS PLANS: 
Sample Size: 
For Part 1, up to 48 subjects are planned: 8 subjects each in the mild (Cohort A), moderate 
(Cohort B), and severe (Cohort C) hepatic impairment groups, and 8 to 24 healthy control 
subjects with normal hepatic function (Cohort D). For Part 2, at least 8 subjects with mild 
and moderate or moderate and severe hepatic impairment and up to 8 healthy control subjects 
with normal hepatic function are planned. The sample size was chosen for this study based 
on clinical and practical considerations and not on a formal statistical power calculation. The 
US Food and Drug Administration Guidance for Industry, Pharmacokinetics in Patients With 
Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and 
Labeling, was used as a guide to select the sample size, which is considered sufficient to 
adequately assess the safety and PK profiles of aramchol. 
In the event of early withdrawals or discontinuations, subjects may be replaced at the 
discretion of the investigator, and after consultation with the medical monitor and sponsor if 
the number of completers will be less than 6 subjects in any cohort. 
Analysis Sets: 
The PK population will include subjects who receive at least 1 dose of aramchol and have 
sufficient concentration data to support accurate estimation of at least 1 PK parameter. In 
Part 1, subjects who experience vomiting within 6 hours after dosing will be excluded from 
the PK analysis. 
The safety population will include all subjects who receive at least 1 dose of aramchol. 
Pharmacokinetic Analyses: 
Plasma concentrations will be listed and summarized descriptively (number of subjects, 
arithmetic mean, standard deviation [SD], coefficient of variation [CV], minimum, median, 
and maximum). Plasma concentration versus actual time profiles for each subject will be 
presented graphically. The mean plasma concentration versus scheduled time profiles will be 
presented graphically. 


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Pharmacokinetic parameters derived from plasma concentration data using 
noncompartmental methods will be summarized by hepatic group using descriptive statistics 
(number of subjects, arithmetic mean, SD, CV, minimum, median, and maximum). 
Geometric mean and geometric CV will also be calculated for AUCs and Cmax. The AUC0-t, 
AUC0-inf, and Cmax values may also be expressed in terms of unbound drug concentrations. 
An analysis of variance (ANOVA) model will be performed on the natural logarithms of 
AUC0-t, AUC0-inf, and Cmax to calculate the ratio of geometric means and its 90% confidence 
interval between subjects with hepatic impairment and the corresponding healthy control 
subjects, as appropriate. The ANOVA model will include hepatic group (normal matching 
mild, mild, normal matching moderate, moderate, normal matching severe, and severe, where 
applicable) as a fixed effect. 
For AUC0-t, AUC0-inf, and Cmax, a linear regression model will be performed on the natural 
logarithms of AUC0-t, AUC0-inf, and Cmax as dependent variables and each of the following 
natural-log-transformed hepatic function estimates as independent variables: Child-Pugh 
classification score (in subjects with hepatic impairment only), baseline serum bilirubin, 
serum albumin, and prothrombin time. The regression coefficients representing the 
relationship between the PK parameters and the hepatic function estimates will be estimated 
together with their 90% confidence intervals from the regression model. 
Sensitivity analyses may be conducted to investigate the potential impact of imbalance 
existing across hepatic impairment groups in the distribution of the baseline covariates used 
in subject matching (eg, body weight) and, if data suggest, appreciable differences in PK 
exposure (AUC0-t, AUC0-inf, and Cmax) across different values of the same baseline covariate.  
Detailed descriptions of the analyses in this study will be presented in the statistical analysis 
plan. 
Safety Analyses: 
Adverse events will be coded by preferred term and system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities. All AE data will be presented in 
a data listing. Treatment-emergent AEs will be summarized by hepatic condition and overall, 
as well as by severity and relationship to study drug. Serious AEs and AEs leading to early 
discontinuation will also be presented in data listings. 
Actual values and changes from baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarized by hepatic condition at each 
time point using descriptive statistics (number of subjects, mean, SD, minimum, median, and 
maximum). Shift tables will be generated for clinical laboratory test results. Clinical 
laboratory test results, vital sign measurements, 12-lead ECG results, and physical 
examination findings will be presented in data listings. 
DATE OF PROTOCOL: 14 October 2019 


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1. 
INTRODUCTION 
1.1 
BACKGROUND 
Aramchol is a novel conjugate of cholic acid (bile acid) and arachidic acid (saturated fatty 
acid), linked by a stable amide group. It is in development for treatment of nonalcoholic 
steatohepatitis (NASH) and fibrosis. Aramchol affects stearoyl coenzyme A desaturase 1, a 
key liver enzyme involved in regulating lipid metabolism. In animal models of NASH, it 
reduces steatosis, ballooning, inflammation, and fibrosis by down-regulation of stearoyl 
coenzyme A desaturase 1 expression in hepatocytes and hepatic stellate cells. 
Aramchol is highly lipophilic and pharmacokinetic (PK) studies in humans show that plasma 
concentrations increase less than proportionally to dose due to poor absorption. Its mean 
terminal phase half-life (t1/2) is approximately 3 days but most of the drug is cleared with a 
t1/2 of about 35 hours and steady state on repeat dosing is achieved within 7 to 10 days. 
Aramchol is secreted in bile and is excreted in feces. 
 
 
 
 
 
 
 
 Two 
Phase 2 clinical studies have been completed including a placebo-controlled study in which 
subjects with NASH were treated for 52-weeks. Significantly more subjects who received 
aramchol 600 mg daily showed NASH resolution without worsening of fibrosis and a larger 
proportion of subjects showed at least a 1-point improvement in fibrosis score without 
worsening of steatohepatitis. 
 
 
 
1.2 
RATIONALE FOR STUDY 
This study will compare the effect of varying degrees of hepatic impairment on the PK, 
safety, and tolerability of a single oral dose of 600 mg (2 × 300-mg tablets) aramchol in 


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Part 1 and multiple oral doses not to exceed 300 mg twice daily for 11 days and a single 
300 mg AM dose on Day 12 in Part 2 with healthy subjects. 
Hepatic impairment associated with cirrhosis may develop in subjects with NASH. 
Therefore, it is important to assess the effect of hepatic impairment on the PK and hence 
dosage requirements and safety of aramchol. 
1.3 
RATIONALE FOR DOSE SELECTION 
A single oral dose of 600 mg aramchol in Part 1 and multiple oral doses not to exceed 
300 mg aramchol twice daily for 11 days and a single AM dose on Day 12 in Part 2 will be 
evaluated in this study based on the recommendations provided in the US Food and Drug 
Administration (FDA) Guidance for Industry, Pharmacokinetics in Patients with Impaired 
Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling 
(DHHS 2003). Though single doses up to 900 mg have been studied in healthy subjects and 
tolerated well, the single dose of 600 mg represents the highest dose likely to be used and 
was the daily dose administered in the Phase 2b study. The multiple dose of 300 mg twice 
daily has been well tolerated by healthy subjects for 10 days and is the dose to be taken daily 
by subjects participating in a Phase 3 clinical trial. 
The duration of multiple dosing is based on the apparent plasma elimination half-life of about 
35 hours and time taken to reach steady state of about 7 days in healthy subjects. A duration 
of 10 days was chosen to ensure steady state has been achieved by all the healthy subjects 
and an additional 2 days is considered appropriate for subjects with hepatic impairment 
owing to the possibility of reduced clearance in this population. 
2. 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to compare the PK profile of aramchol administered 
orally in subjects with hepatic impairment with that of healthy subjects. 
2.2 
SECONDARY OBJECTIVE 
The secondary objective of this study is to assess the safety and tolerability of aramchol 
administered orally in subjects with hepatic impairment. 


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3. 
STUDY DESIGN 
This is a Phase 1, multicenter, open-label, 2-part, single- and multiple-dose study designed to 
assess the effect of hepatic insufficiency on the PK of aramchol. 
Each part of the study will consist of a screening period, a check-in day, a treatment period, 
and an end-of-study (EOS) visit. 
In Part 1 (single-dose), up to 48 subjects are planned: 8 subjects each in the mild (Cohort A), 
moderate (Cohort B), and severe (Cohort C) hepatic impairment cohorts and 8 to 24 healthy 
control subjects with normal hepatic function (Cohort D). Enrollment of 8 subjects with mild 
hepatic impairment (Cohort A) will proceed only if there is evidence of reduced clearance of 
aramchol in Cohort B. At screening, subjects will be assigned to a study cohort according to 
the Child-Pugh classification system as follows: 
Cohort 
Hepatic Condition 
Child-Pugh Grade 
Number of Subjects 
A(a) 
Mild impairment 
Class A (Score of 5 to 6) 
8 
B 
Moderate impairment 
Class B (Score of 7 to 9) 
8 
C 
Severe impairment 
Class C (Score of 10 to 15) 
8  
D 
Healthy (control) 
— 
8 to 24 
(a) Enrollment of subjects into Cohort A will only proceed if there is evidence of reduced clearance of aramchol 
in Cohort B. 
Healthy control subjects (Cohort D) will be matched with hepatically impaired subjects 
(Cohorts A, B, and C) according to gender, age (±10 years), and body mass index (BMI) 
(±20%). 
Safety data and PK profiles of aramchol from at least 4 subjects with moderate hepatic 
impairment (Cohort B) will be obtained and reviewed while enrollment to this cohort 
continues. These 4 subjects in Cohort B must demonstrate satisfactory safety (no serious AEs 
[SAEs] or severe AEs related to aramchol) and PK results for up to 4 days after dosing before 
enrollment of subjects with severe hepatic impairment (Cohort C) is initiated. Two subjects 
with severe hepatic impairment must demonstrate satisfactory safety and tolerability (no 
SAEs or severe AEs related to aramchol) for up to 4 days after dosing before the remaining 
subjects with severe hepatic impairment may be dosed. 
Enrollment of subjects to Cohort A (mild hepatic impairment) will proceed only if there is 
evidence of reduced clearance of aramchol in the first 4 subjects in Cohort B (moderate 
hepatic impairment), defined as a reduction in apparent total oral clearance (CL/F) of greater 
than 30% compared with values in historical healthy control subjects. 


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In Part 2, a cohort of at least 8 subjects comprising of mild and moderate or moderate and 
severe hepatic impairment subjects will be administered aramchol as multiple doses to obtain 
the PK profile of aramchol at steady state. A decision on the severity of hepatic impairment 
of subjects to participate in Part 2 (multiple-dose) will be made by the sponsor based on the 
available safety and PK results from Part 1 (single-dose). 
Healthy control subjects will be matched with the hepatically impaired subjects according to 
gender, age (±10 years), and BMI (±20%). 
Single Dose (Part 1): 
On Day 1, subjects will receive a single oral dose of 600 mg aramchol administered with 
240 mL of water in the morning, after an overnight fast of at least 10 hours, and 
approximately 30 minutes after consuming a standardized breakfast. Subjects will remain 
fasted except for water for 2 hours after dosing. During the study, subjects may consume 
water on an ad libitum basis. Hepatically impaired subjects will receive a diet standardized 
for hepatic impairment and healthy control subjects will receive a similar diet. 
Serial blood samples for PK analysis of aramchol concentrations in plasma will be collected 
before dosing (0 hour) and up to 168 hours for healthy subjects and 240 hours for hepatically 
impaired subjects after administration of aramchol. 
Subjects will be confined to the clinical site from Day –1 until discharge on Day 8 for healthy 
control subjects and on Day 11 for hepatically impaired subjects. The duration of the study, 
excluding screening, is approximately 23 days. 
Multiple Dose (Part 2): 
Multiple dosing will involve twice daily (approximately 12 hours apart) oral administration 
of aramchol for 11 days with a single AM dose on Day 12 to achieve steady state. The dosage 
will not exceed 300 mg twice daily but may be adjusted to give lower exposure depending on 
review of available data on any reduction in clearance associated with hepatic impairment 
seen with single doses in Part 1. Subjects will consume a standardized meal 30 minutes prior 
to the AM and PM doses of aramchol. Subjects will remain fasted except for water for 
2 hours after dosing. During the study, subjects may consume water on an ad libitum basis. 
Hepatically impaired subjects will receive a diet standardized for hepatic impairment and 
healthy control subjects will receive a similar diet. 
Blood samples for analysis of aramchol concentrations in plasma will be collected before the 
AM dose on Days 1, 4, 8, 9, 10, 11, and 12 and at intervals to 12 hours after the AM dose on 


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Day 12. Samples of plasma will also be stored for analysis of metabolites pending results of a 
mass balance study. 
Subjects will be confined to the clinical site from Day –1 until discharge on Day 13. The 
duration of the study, excluding screening, is approximately 28 days. 




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(k) Collected for hepatically impaired subjects only. 
(l) Further details on ECG recordings are provided in Section 6.2.4. 
(m) Further details on clinical laboratory assessments, including a complete list of assessments, are provided in Section 6.2.2. 
(n) Further details on drug/alcohol screening are provided in Section 6.2.2.  
(o) Women of childbearing potential only. 
(p) The time of aramchol dosing will be called “0” hour and occurs on the day denoted with grey shading. Further dosing details are provided in Section 5.1. 
(q) Further details on the collection of blood samples for PK analysis are provided in Section 6.1. 
(r) Further details on collection and reporting of AEs are provided in Section 6.2.1. 




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(k) Women of childbearing potential only. 
(l) Aramchol dosing occurs twice daily (approximately 12 hours apart) on days denoted with grey shading. Further dosing details are provided in Section 5.1. 
(m) Further details on the collection of blood samples for PK analysis are provided in Section 6.1. 
(n) Further details on collection and reporting of AEs are provided in Section 6.2.1. 


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4. 
STUDY POPULATION 
Up to 48 male and female subjects will be enrolled across 3 centers in the United States. 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in this study: 
 The subject is male or female 18 to 79 years of age, inclusive. 
 The subject has a BMI of 19 to 40 kg/m2, inclusive, at screening. 
 Females of childbearing potential must practice a highly effective method of 
contraception throughout the study period and for 1 month after treatment 
discontinuation. Highly effective methods are defined as those that can achieve a failure 
rate of less than 1% per year when used consistently and correctly. Such methods, in 
accordance with the recommendations of the Clinical Trial Facilitation Group Working 
Group on Contraception include: hormonal contraception associated with inhibition of 
ovulation, intrauterine device, intrauterine hormonal-releasing system, bilateral tubal 
occlusion, vasectomized partner, and sexual abstinence. All female subjects must have a 
negative pregnancy test at screening and before the first dose of study drug. 
 Male subjects with female partners of childbearing potential must be vasectomized, be 
willing to use an acceptable method of birth control, or practice abstinence during the 
study. 
 The subject has a resting pulse rate of ≥40 and <100 beats per minute with no clinically 
significant deviation as judged by the investigator. 
 The subject has a QT interval corrected for heart rate using Fridericia’s formula (QTcF) 
of <500 msec. 
 The subject agrees to comply with all protocol requirements. 
 The subject is able to provide written informed consent. 
Additional Inclusion Criteria for Healthy Subjects Only (Cohort D): 
 The subject has normal hepatic function. 


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 The subject has a resting blood pressure of 90 to 150 mm Hg (systolic) and 50 to 
100 mm Hg (diastolic). 
 The subject is judged by the investigator to be in good general health, as determined by 
medical history, clinical laboratory assessments, vital sign measurements, 12-lead 
electrocardiogram (ECG) results, and physical examination findings. 
Additional Inclusion Criteria for Subjects With Hepatic Impairment Only (Cohorts A, 
B, and C): 
 The subject has cirrhosis with evidence of impaired liver function. The etiology of the 
cirrhosis may be alcoholic, autoimmune, nonalcoholic steatohepatitis, or chronic viral 
hepatitis type B or C. 
 The subject has chronic (more than 6 months) and stable hepatic impairment (ie, no acute 
episodes of illness within 30 days before screening due to deterioration of hepatic 
function) as assessed by a Child-Pugh classification score of mild (5 to 6 points), 
moderate (7 to 9 points), or severe (10 to 15 points). 
 The subject has a resting blood pressure of 90 to 155 mm Hg (systolic) and 50 to 
100 mm Hg (diastolic). 
 The subject is judged by the investigator to be in good general health, as determined by 
medical history, clinical laboratory assessments, vital sign measurements, 12-lead ECG 
results, and physical examination findings, except for findings that, as judged by the 
investigator, are consistent with the subject’s hepatic impairment or other stable 
concomitant medical conditions. 
4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
 The subject has a history or clinical manifestations of a significant neurological, renal, 
cardiovascular, gastrointestinal, pulmonary, hematologic, immunologic, or psychiatric 
disease that would preclude study participation, as judged by the investigator. 
 The subject has a positive test result for human immunodeficiency virus type 1 or 
2 antibodies at screening. 
 The subject has a history of drug abuse within 3 months before screening. 


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 The subject has a history of alcoholism within 3 months before screening, or excessive 
alcohol consumption (regular alcohol intake >15 units per week) (1 unit is equal to 
approximately ½ pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure 
[25 mL] of spirits). 
 The subject smokes >10 cigarettes daily and is unwilling to reduce to ≤5 daily from the 
time of screening through the last PK sample. 
 The subject is unable or unwilling to abstain from alcohol, caffeine, xanthine-containing 
beverages or food (eg, coffee, tea, chocolate, and caffeinated sodas, colas), grapefruit, 
grapefruit juice, Seville oranges, or products containing any of these, from 48 hours prior 
to study drug dosing until discharge. 
 The subject is involved in strenuous activity or contact sports within 24 hours of the first 
dose of study drug or during the study. 
 The subject has donated blood or blood products >450 mL within 3 months before the 
first dose of study drug. 
 The subject has a presence or history of relevant drug and/or food allergies (ie, allergy to 
aramchol, cholic acid, or any excipients, or any significant food allergy). 
 The subject has received study drug in another investigational study within 30 days of 
dosing. 
 In the opinion of the investigator, the subject is not suitable for entry into the study. 
Additional Exclusion Criteria for Healthy Subjects Only (Cohort D): 
 The subject has clinically significant findings at screening including history, physical 
examination, ECG, or laboratory values. 
 The subject has used an herbal remedy (including St John’s wort) known to interfere with 
liver enzymes during the 28 days before dosing with the study drug. 
 The subject has a past history of surgery or a medical condition that might affect 
absorption of medicines (hernia repair is acceptable). 
 The subject has a positive test result for hepatitis B surface antigen or antibodies to 
hepatitis C virus. 


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 The subject has used any prescription (excluding hormonal birth control and hormone 
replacement therapy) or over-the-counter medications (except paracetamol [up to 2 grams 
per day]), including herbal or nutritional supplements, within 14 days before the first 
dose of study drug and throughout the study. 
 The subject has a positive test result for drugs of abuse or alcohol at screening or before 
the first dose of study drug. 
Additional Exclusion Criteria for Subjects With Hepatic Impairment Only (Cohorts A, 
B, and C): 
 The subject has a current >Grade 1 (mild) encephalopathy. Subjects with a history of 
Grade 3 or 4 encephalopathy that have responded to treatment with medicines such as 
lactulose, rifaximin, or neomycin may be included with the subject receiving the point 
score for Grade 3 or 4 encephalopathy. 
 The subject has clinically demonstrable massive tense ascites. Subjects with a history of 
moderate or severe ascites that have responded to diuretics may be included with the 
subject receiving the higher score. 
 The subject has esophageal varices that have caused hemorrhage within a period of 
8 weeks prior to dosing or are considered of high risk for hemorrhage. 
 The subject has the following types of liver disease: primary biliary cirrhosis, sclerosing 
cholangitis, hepatocellular carcinoma, cardiac cirrhosis, hemochromatosis, Wilson’s 
disease, other genetic causes of liver disease.  
 The subject has clinically significant impairment of renal function (eCLcr <45 mL/min) 
as calculated by the Cockcroft-Gault equation. 
 The subject has a hemoglobin <8.5 mg/dL or platelets <30,000/µL. 
 The subject has fluctuating or rapidly deteriorating hepatic function, as indicated by 
recent history or worsening of clinical (ie, abdominal pain, nausea, vomiting, anorexia, or 
fever) and/or laboratory signs of hepatic impairment, as judged by the investigator. 
 The subject has evidence of acute viral hepatitis within 30 days before dosing with study 
drug. 
 The subject has evidence of hepatorenal syndrome. 


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 The subject has used any prescription (excluding hormonal birth control and hormone 
replacement therapy) or over-the-counter medications, including herbal or nutritional 
supplements, within 14 days before the first dose of study drug and throughout the study, 
except those essential for the management of hepatic impairment or the treatment of 
stable concomitant medical conditions, as judged by the investigator. The dose of an 
approved medication must remain stable from 7 days before study drug dosing and 
throughout the study. 
 The subject has a positive test result for drugs of abuse (except positive test results 
associated with prescription medications that have been reviewed and approved by the 
investigator) at screening or before the first dose of study drug. 
4.3 
OTHER SCREENING CONSIDERATIONS 
 For inclusion and Child-Pugh categorization, clinical laboratory test results that are 
deemed inconsistent with the usual stage of hepatic impairment may be repeated. 
 For eligibility purposes, abnormal vital sign, clinical laboratory test, or ECG results may 
be repeated if an abnormal result is observed at the initial reading. 
 In the event that the participation of a subject in the study is delayed and some screening 
procedures are performed outside of the prescribed screening window, outdated screening 
procedures may be repeated. 
 Subjects who do not qualify based on a reversible medical condition or mild intercurrent 
illness may be reevaluated after further testing/examination or rescreened after the 
condition is resolved. 
 Subjects are categorized by hepatic impairment at screening. If the Child-Pugh 
classification scores change on Day −1 due to a change in clinical status or clinical 
laboratory test results that are not clinically significant, the subject will keep their original 
score. 
4.4 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
4.4.1 
Reasons for Withdrawal 
Subjects can withdraw consent and discontinue from the study at any time, for any reason, 
without prejudice to further treatment. 


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The investigator may withdraw a subject from the study if the subject: 
1. Is noncompliant with the protocol; 
2. Experiences an SAE or intolerable AE(s) that in the investigator’s opinion requires 
withdrawal from the study; 
3. Has laboratory safety assessments that reveal clinically significant hematological or 
biochemical changes from baseline values; 
4. Develops, during the course of the study, symptoms or conditions listed in the exclusion 
criteria; 
5. Requires a medication prohibited by the protocol; or 
6. Requests an early discontinuation for any reason. 
The investigator can also withdraw a subject upon the request of the sponsor, or if the 
sponsor terminates the study. Upon occurrence of an intolerable SAE or intolerable AE, the 
investigator will confer with the sponsor. If a subject is discontinued because of an AE, the 
event will be followed until it is resolved, stable, or judged by the investigator to be not 
clinically significant. 
4.4.2 
Handling of Withdrawals 
Subjects are free to withdraw from the study at any time upon request. Subject participation 
in the study may be stopped at any time at the discretion of the investigator or at the request 
of the sponsor. 
When a subject withdraws from the study, the reason(s) for withdrawal shall be recorded by 
the investigator on the relevant page in the electronic case report form (eCRF). Whenever 
possible, any subject who withdraws from the study prematurely will undergo all EOS 
assessments. Any subject who fails to return for final assessments will be contacted by the 
site in an attempt to have them comply with the protocol. The status of subjects who fail to 
complete final assessments will be documented in the eCRF. 


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4.4.3 
Replacements 
At the discretion of the investigator, and after consultation with the medical monitor and 
sponsor, any subject who withdraws before completing the study may be replaced to retain 
the target of 6 evaluable subjects based on clinical considerations. Any replacement subject 
will be assigned to receive the same treatment as the subject he or she is replacing. 
5. 
STUDY TREATMENTS 
5.1 
TREATMENTS ADMINISTERED 
All doses of study drug will be administered by mouth with 240 mL of room temperature 
water. During the study, subjects may consume water on an ad libitum basis. 
Hepatically impaired subjects will receive a diet standardized for hepatic impairment and 
healthy control subjects will receive a similar diet. Subjects should receive these meals at the 
same time during each part of the study. 
Single Dose (Part 1): 
On Day 1, all subjects will receive a single oral dose of 600 mg (2 × 300-mg tablets) 
aramchol in the morning, after an overnight fast of at least 10 hours and approximately 
30 minutes after a standardized breakfast. 
Multiple Dose (Part 2): 
Starting on Day 1, all subjects will receive an oral dose of aramchol that will not exceed 
300 mg twice daily (approximately 12 hours apart) for 11 days and a single AM dose on 
Day 12 approximately 30 minutes after a standardized meal. The dose may be adjusted to 
give lower exposure depending on the review of available data on any reduction in clearance 
associated with hepatic impairment seen with single doses in Part 1. 
5.2 
INVESTIGATIONAL PRODUCTS 
Aramchol will be supplied as 300-mg tablets. 
 
 
 


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5.2.1 
Study Drug Packaging and Storage 
The sponsor will provide the investigator and clinical site with adequate quantities of 
aramchol. The clinical site pharmacy will prepare the study treatments for each subject 
according to the schedule of events for Parts 1 and 2 (Section 3.1 and Section 3.2, 
respectively). 
All study drugs must be stored according to the labeled instructions in a secure cabinet or 
room with access restricted to necessary site personnel. The site will be required to keep a 
temperature log to establish a record of compliance with storage conditions. 
5.2.2 
Study Drug Accountability 
The investigator will maintain accurate records of receipt of all study drugs, including dates 
of receipt. Accurate records will be kept regarding when and how much study drug is 
dispensed and used by each subject in the study. Reasons for departure from the expected 
dispensing regimen must also be recorded. At the completion of the study, and to satisfy 
regulatory requirements regarding drug accountability, all study drugs will be reconciled and 
retained or, with approval of the sponsor, destroyed according to applicable regulations. 
5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT 
GROUPS 
This is a nonrandomized study. At screening, hepatically impaired subjects will be assigned 
to a study group based on their level of hepatic function according to the Child-Pugh 
classification system, as shown in Table 5–1. To allocate subjects to the appropriate cohort of 
hepatic impairment severity, a history of higher severity that has responded to medication 
will be taken into account. Thus, subjects with a history of Grade 3 or 4 encephalopathy that 
have responded to treatment with medicines such as lactulose or neomycin may be included 
with the subject receiving the point score for Grade 3 or 4 encephalopathy. Similarly, subjects 
with a history of moderate or severe ascites that have responded to diuretics may be included 
with the subject receiving the higher score. 


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Table 5–1 
Child-Pugh Classification System 
Points(a) 
Bilirubin 
(mg/dL) 
Albumin 
(g/dL) 
Prothrombin Time  
(seconds prolonged) 
Encephalopathy 
(grade)(b) 
Ascites  
(grade) 
1 
<2.0 
>3.5 
<4 
None (Grade 0) 
Absent 
2 
2.0 to 3.0 
2.8 to 3.5 
4 to 6 
1 or 2 
Slight 
3 
>3.0 
<2.8 
>6 
3 or 4 or subjects receiving 
medication(s) to prevent 
encephalopathy 
Moderate or severe 
subjects on 
medication(s) to 
control ascites 
Abbreviation: INR, international normalized ratio. 
(a) For each category (bilirubin, albumin, prothrombin time or INR, encephalopathy grade, and ascites), points 
are assigned based on the subject’s condition and the criterion met. The Child-Pugh class is assigned based 
on the sum of these points as follows: Child-Pugh Class A or mild hepatic impairment if the sum is 5 or 
6 points; Child-Pugh Class B or moderate hepatic impairment if the sum is 7 to 9 points; and Child-Pugh 
Class C or severe hepatic impairment if the sum is 10 to 15 points. 
(b) Grade 0: normal consciousness, personality, neurological examination, electroencephalogram. 
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 count-per-second 
waves. 
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves. 
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves. 
Grade 4: unarousable coma, no personality/behavior, decerebrate, slow 2-3 count-per-second delta activity. 
Hepatically impaired subjects (Cohorts A, B, and C) will be enrolled as they become eligible 
and receive their allocated subject numbers in the order in which they are enrolled into their 
respective cohorts. 
5.4 
BLINDING 
This is an open-label study. 
5.5 
TREATMENT COMPLIANCE 
All doses of the study drug will be administered in the clinical site under direct observation 
of site personnel and recorded in the eCRF. Clinic personnel will confirm that the subject has 
received the entire dose of study drug. 
The date and time of study drug dosing will be recorded on the appropriate page in the eCRF. 
If a subject is not administered study drug, the reason for the missed dose will be recorded. 
5.5.1 
Prior and Concomitant Medications 
Restrictions for prior and concomitant medications and therapies are provided in Section 4.1 
and Section 4.2. Prior and concomitant medications and therapies will be coded using the 
latest version of the World Health Organization Drug Dictionary available at initiation of the 
study. 


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5.5.1.1 
Prior Medications 
Information regarding prior medications taken by the subject within the 30 days before 
signing the informed consent form (ICF) will be recorded in the subject’s eCRF. 
5.5.1.2 
Concomitant Medications 
Any concomitant medication deemed necessary for the welfare of the subject during the 
study may be given at the discretion of the investigator. If a concomitant medication is taken, 
a joint decision will be made by the investigator and the sponsor to continue or discontinue 
the subject based on the time the medication was administered, its pharmacology and PK, 
and whether the use of the medication will compromise the safety of the subject or the 
interpretation of the data. The investigator is responsible for ensuring that details regarding 
the medication are adequately recorded in the eCRF. 
6. 
STUDY PROCEDURES 
Before performing any study procedures, all potential subjects will sign an ICF as outlined in 
Section 9.2.2.3. Subjects will undergo study procedures at the time points specified in the 
schedule of events for Parts 1 and 2 (Section 3.1 and Section 3.2, respectively). 
The total amount of blood collected from each subject over the duration of the study, 
including any extra assessments that may be required, will not exceed 500 mL. 
6.1 
PHARMACOKINETIC ASSESSMENTS AND ENDPOINTS 
Single Dose (Part 1): 
Blood samples for analysis of concentrations of aramchol and its metabolites in plasma will 
be collected at the following time points: before dosing (0 hour) and at 1, 2, 3, 4, 5, 6, 8, 10, 
12, 14, 18, 24, 48, 72, 96, 120, 144, 168, 192, and 240 hours (the last 2 time points are for 
hepatically impaired subjects only) after administration of aramchol. Acceptable time 
deviations are ±5 minutes for 0 to 4 hours, ±10 minutes for >4 to 8 hours, ±15 minutes for 
>8 to 24 hours, ±30 minutes for >24 to 72 hours, and ±60 minutes for >72 hours to 
240 hours. 
The following plasma PK parameters will be calculated as endpoints for aramchol using 
actual sampling times rather than scheduled sampling times: 
• AUC from time 0 to the last quantifiable concentration (AUC0-t) 


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• AUC from time 0 extrapolated to infinity (AUC0-inf) 
• Maximum observed plasma concentration (Cmax) 
• Time to reach maximum observed plasma concentration (Tmax) 
• Time to the first measurable plasma concentration (Tlag) 
• Apparent terminal elimination half-life (t1/2) 
• Apparent oral clearance (CL/F) 
• Apparent volume of distribution (Vz/F) 
• Elimination rate constant (ke) 
Multiple Dose (Part 2): 
Blood samples for analysis of concentrations of aramchol and its metabolites in plasma will 
be collected before the AM dose on Days 1, 4, 8, 9, 10, 11, and 12 and at the following times 
after the AM dose on Day 12: 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours. Acceptable time deviations 
are ±5 minutes for 0 to 4 hours, ±10 minutes for >4 to 8 hours, and ±15 minutes for >8 to 
12 hours. 
The following plasma PK parameters on Day 12 will be calculated as endpoints for aramchol 
using actual sampling times rather than scheduled sampling times (if conducted): 
• AUC from time 0 to the dosing interval tau at steady state (AUC0-tau, ss) 
• Maximum observed plasma concentration at steady state (Cmax, ss) 
• Time to reach maximum observed plasma concentration at steady state (Tmax, ss) 
• Minimum observed plasma concentration at steady state (Cmin, ss) 
• Time of minimum observed plasma concentration at steady state (Tmin, ss) 
• Average plasma concentration at steady state (Cavg, ss) 
Time to reach steady state will also be estimated graphically by assessing trough plasma 
concentrations (ie, pre-AM dosing on Days 1, 4, 8, 9, 10, 11, and 12) over 12 days of 
administration. 


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6.1.1 
Pharmacokinetic Sample Collection 
Details for the collection, processing, storage, and shipping of PK samples will be provided 
to the clinical site separately. 
6.1.2 
Pharmacokinetic Sample Analysis 
Pharmacokinetic samples will be analyzed using a validated liquid chromatography coupled 
with tandem mass spectrometry assay for aramchol in human plasma. Assay results and 
validation details will be provided in a separate bioanalytical report. Stored samples of 
plasma will also be analyzed for aramchol metabolites pending results of a mass balance 
study. 
6.2 
SAFETY ASSESSMENTS AND ENDPOINTS 
Safety and tolerability will be assessed by the following endpoints: monitoring and recording 
of AEs, clinical laboratory test results (hematology, coagulation, serum chemistry, and 
urinalysis), vital sign measurements, 12-lead ECG results, and physical examination findings. 
For all safety assessments, the investigator will determine whether results are clinically 
significant, which is defined as any variation in a result that has medical relevance and may 
result in an alteration in medical care (eg, active observation, diagnostic measures, or 
therapeutic measures). If clinical significance is noted, the result and reason for significance 
will be documented and an AE reported on the AE page in the subject’s eCRF. The 
investigator will monitor the subject until the result has reached the reference range or the 
result at screening, or until the investigator determines that follow-up is no longer medically 
necessary. 
6.2.1 
Adverse Events 
Adverse events will be assessed from the time the subject signs the ICF until EOS and should 
be followed until they are resolved, stable, or judged by the investigator to be not clinically 
significant. 
The investigator is responsible for ensuring that all AEs and SAEs are recorded in the eCRF 
and SAEs are reported to the sponsor, regardless of their relationship to study drug or clinical 
significance. If there is any doubt as to whether a clinical observation is an AE, the event 
should be reported. 


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6.2.1.1 
Adverse Event Definitions 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. Subjects will be instructed to contact the 
investigator at any time after signing the ICF if any symptoms develop. 
A treatment-emergent AE is defined as any event not present before exposure to study drug 
or any event already present that worsens in intensity or frequency after exposure. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
study drug caused the AE. For the purposes of investigational new drug safety reporting, 
“reasonable possibility” means that there is evidence to suggest a causal relationship between 
the study drug and the AE. A suspected adverse reaction implies a lesser degree of certainty 
about causality than an adverse reaction. 
An adverse reaction is any AE caused by a study drug. Adverse reactions belong to a subset 
of all suspected adverse reactions and indicate that there are reasons to conclude that the 
study drug caused the event. 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator’s brochure or if it occurs with specificity or severity that has not been previously 
observed with the study drug being tested. 
An AE or suspected adverse reaction is considered an SAE/suspected unexpected serious 
adverse reaction if, in the view of either the investigator or sponsor, it results in any of the 
following outcomes: 
• Death 
• Life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• Congenital anomaly or 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 subject and may require medical or surgical intervention to prevent 


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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. 
An AE or suspected adverse reaction is considered “life threatening” if, in the view of either 
the investigator or sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE or suspected adverse reaction that might have caused death if it had 
been more severe. 
6.2.1.2 
Eliciting and Documenting Adverse Events 
Subjects will be asked a standard question to elicit any medically related changes in their 
well-being. They will also be asked if they have been hospitalized, had any accidents, used 
any new medications, or changed concomitant medication regimens (both prescription and 
over-the-counter medications). 
In addition to subject observations, AEs will be documented from any data collected on the 
AE page in the eCRF (eg, laboratory values, physical examination findings, and ECG 
changes) or other documents that are relevant to subject safety. 
6.2.1.3 
Reporting Adverse Events 
All AEs reported or observed during the study will be recorded in the source documentation 
and on the AE page in the eCRF. Information to be collected includes drug treatment, type of 
event, time of onset, dosage, investigator-specified assessment of severity and relationship to 
study drug, time of resolution of the event, seriousness, any required treatment or 
evaluations, and outcome. Any AEs resulting from concurrent illnesses, reactions to 
concurrent illnesses, reactions to concurrent medications, or progression of disease states 
must also be reported. All AEs will be followed until they are resolved, stable, or judged by 
the investigator to be not clinically significant. The Medical Dictionary of Regulatory 
Activities will be used to code all AEs. 
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE but will be recorded as medical history. However, 
if it deteriorates at any time during the study, it should be recorded as an AE. 
Any AE that is considered serious by the investigator or that meets SAE criteria 
(Section 6.2.1.1) must be reported to the sponsor (or the sponsor’s designee) following the 


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guidelines provided on the study SAE form as soon as site personnel/investigator have 
become aware of the event and no later than 24 hours regardless of the relationship to the 
study drug. The investigator will assess whether there is a reasonable possibility that the 
study drug caused the SAE.  
Serious AE report form completion and reporting must not be delayed even when 
information is incomplete at the time of the initial report. Any additional (follow-up) 
information that becomes available after the initial reporting should be forwarded in a 
follow-up SAE report form by the site personnel within 24 hours of the information 
becoming available. 
All SAEs should be followed until resolution or stabilization of all parameters (including 
laboratory) return to baseline or until the investigator assesses them as stable or until the 
subject is lost to follow-up. 
The sponsor will be responsible for notifying the relevant regulatory authorities of any SAE 
as outlined in US Title 21 Code of Federal Regulations (CFR) Parts 312 and 320. The 
investigator is responsible for notifying the institutional review board (IRB) directly. 
For this study, the following contact information will be used for SAE reporting: 
6.2.1.4 
Assessment of Severity 
The severity (or intensity) of an AE refers to the extent to which it affects the subject’s daily 
activities and will be classified as mild, moderate, or severe using the following criteria: 
• Mild: These events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
• Moderate: These events result in a low level of inconvenience or require minor 
therapeutic measures. Moderate events may cause some interference with normal 
functioning. 
• Severe: These events interrupt a subject’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating. 
Changes in the severity of an AE should be documented to allow the duration of the event at 
each level of intensity to be assessed. An AE characterized as intermittent does not require 
documentation of the onset and duration of each episode. 


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6.2.1.5 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process but is not a factor in determining what is or is not reported in the 
study. 
The investigator will assess causality (ie, whether there is a reasonable possibility that the 
study drug caused the event) for all AEs and SAEs. The relationship will be classified as 
follows: 
• Not related: There is not a reasonable possibility of relationship to study drug. The AE 
does not follow a reasonable temporal sequence from study drug administration or can be 
reasonably explained by the subject’s clinical state or other factors (eg, disease under 
study, concurrent diseases, and concomitant medications). 
• Related: There is a reasonable possibility of relationship to study drug. The AE follows a 
reasonable temporal sequence from study drug administration and cannot be reasonably 
explained by the subject’s clinical state or other factors (eg, disease under study, 
concurrent diseases, or concomitant medications), represents a known reaction to the 
study drug or other drugs in its class, is consistent with the known pharmacological 
properties of the study drug, and/or resolves with discontinuation of the study drug 
(and/or recurs with rechallenge, if applicable). 
6.2.1.6 
Follow-up of Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed until 
they are resolved, stable, or judged by the investigator to be not clinically significant. 
6.2.2 
Clinical Laboratory Testing 
Clinical laboratory tests will be performed by the clinical sites’ local laboratories. Blood and 
urine samples will be collected and prepared using standard procedures.  
Repeat clinical laboratory tests may be performed at the discretion of the investigator, if 
necessary, to evaluate inclusion and exclusion criteria or clinical laboratory abnormalities. 
The clinical laboratory that will perform the tests will provide the reference ranges for all 
clinical laboratory parameters. Abnormal clinical laboratory values will be flagged as either 
high or low (or normal or abnormal) based on the reference ranges for each laboratory 
parameter. 


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Single Dose (Part 1): 
Clinical laboratory testing will occur at screening; check-in; on Day 4; prior to discharge on 
Day 8 (healthy subjects) or Day 11 (hepatically impaired subjects); and at EOS. 
Multiple Dose (Part 2): 
Clinical laboratory testing will occur at screening; check-in; Days 4, 8, and 12; and at EOS. 
The following clinical laboratory assessments will be performed for Parts 1 and 2: 
Hematology 
Absolute neutrophil count and differential, hematocrit, hemoglobin, 
mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, leukocyte count and differential (basophils, 
eosinophils, lymphocytes, monocytes, and neutrophils [absolute and 
differential]), mean corpuscular volume, platelet count, red blood 
cell count, and red blood cell distribution width 
Coagulation 
 
International normalized ratio, partial thromboplastin time, and 
prothrombin time 
Serum chemistry 
Alanine aminotransferase, albumin, alkaline phosphatase, aspartate 
aminotransferase, bilirubin (total), blood urea nitrogen, calcium, 
carbon dioxide, chloride, cholesterol (total, high-density lipoprotein, 
and calculated low-density lipoprotein), creatinine, 
gamma-glutamyltransferase, globulin, glucose, lactate 
dehydrogenase, phosphorus, potassium, sodium, total protein, 
triglycerides, and uric acid 
Urinalysis 
Bilirubin, color, glucose, ketones, leukocyte esterase, reflex 
microscopy (performed if dipstick is positive for protein or the blood 
value is 1+ or greater; and includes bacteria, casts, crystals, epithelial 
cells, red blood cells, and white blood cells), nitrites, occult blood, 
pH, protein, specific gravity, turbidity, and urobilinogen 
Serology 
Hepatitis B surface antigen, hepatitis C virus antibody, and human 
immunodeficiency virus antibody types 1 and 2 (screening only) 
Other analyses 
All subjects: Urine drug screen (alcohol, amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine metabolites, 
methamphetamines, methylenedioxymethamphetamine, and opiates 
[including heroin, codeine, and oxycodone]) 
Female subjects: Follicle-stimulating hormone (postmenopausal 
women; screening only), urine pregnancy test (human chorionic 
gonadotropin) (screening, check-in, and EOS [or early termination]) 


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6.2.3 
Vital Sign Measurements 
All vital signs will be measured after the subject has been in the seated position for at least 
5 minutes. Vital signs will include systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature. 
Single Dose (Part 1): 
Vital signs will be measured at screening and check-in; prior to aramchol dosing; 4, 12, and 
24 hours after dosing; Days 3 and 4; prior to discharge on Day 8 (healthy subjects) or Day 11 
(hepatically impaired subjects); and at EOS.  
Multiple Dose (Part 2): 
Vital signs will be measured at screening and check-in, prior to the AM aramchol dosing on 
Day 1; 4 hours after the AM dose on Days 1 through 12; prior to discharge on Day 13; and at 
EOS.  
6.2.4 
Electrocardiograms 
All ECGs will be measured after the subject has been in the supine position for at least 
5 minutes. A single repeat measurement is permitted at screening for eligibility 
determination.  
Electrocardiogram assessments will include comments on whether the tracings are normal or 
abnormal, rhythm, presence of arrhythmia or conduction defects, morphology, any evidence 
of myocardial infarction, or ST-segment, T-wave, and U-wave abnormalities. In addition, 
measurements of the following intervals will be measured and reported: RR interval, 
PR interval, QRS width, QT interval, and QTcF. 
Single Dose (Part 1): 
Single 12-lead ECG recordings will be made at screening and check-in; at 6, 12, and 
24 hours after dosing; on Day 4; prior to discharge on Day 8 (healthy subjects) or Day 11 
(hepatically impaired subjects); and at EOS. 
Multiple Dose (Part 2): 
Single 12-lead ECG recordings will be made at screening and check-in; on Days 4, 8, and 12; 
and at EOS. 


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6.2.5 
Physical Examinations 
Subjects will undergo a physical examination at the time points specified in the schedule of 
events for Parts 1 and 2 (Section 3.1 and Section 3.2, respectively). A full physical 
examination will include, at minimum, assessment of skin, head, ears, eyes, nose, throat, 
neck, thyroid, lungs, heart, cardiovascular system, abdomen, lymph nodes, and 
musculoskeletal system/extremities. A brief physical examination will include, at minimum, 
assessment of skin, lungs, cardiovascular system, and abdomen (liver and spleen). Interim 
physical examinations may be performed at the discretion of the investigator, if necessary, to 
evaluate AEs or clinical laboratory abnormalities. 
Height and weight will be measured, and BMI will be calculated at screening only. Only 
weight will be measured at check-in and EOS (or early termination). 
7. 
STATISTICAL ANALYSIS PLANS 
7.1 
SAMPLE SIZE CALCULATIONS 
For Part 1, up to 48 subjects are planned: 8 subjects each in the mild (Cohort A), moderate 
(Cohort B), and severe (Cohort C) hepatic impairment cohorts and 8 to 24 healthy control 
subjects with normal hepatic function (Cohort D). For Part 2, at least 8 subjects with mild 
and moderate or moderate and severe hepatic impairment and up to 8 healthy control subjects 
with normal hepatic function are planned. The sample size was chosen for this study based 
on clinical and practical considerations and not on a formal statistical power calculation. The 
US Food and Drug Administration Guidance for Industry, Pharmacokinetics in Patients With 
Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and 
Labeling (DHHS 2003) was used as a guide to select the sample size, which is considered 
sufficient to adequately assess the safety and PK profiles of aramchol. 
In the event of early withdrawals or discontinuations, subjects may be replaced at the 
discretion of the investigator, and after consultation with the medical monitor and sponsor if 
the number of completers will be less than 6 subjects in any cohort. 
7.2 
ANALYSIS SETS 
The analysis populations are as follows: 
• The PK population will include subjects who receive at least 1 dose of aramchol and have 
sufficient concentration data to support accurate estimation of at least 1 PK parameter. In 


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Part 1, subjects who experience vomiting within 6 hours after study drug dosing will be 
excluded from the PK analysis. 
• The safety population will include all subjects who receive at least 1 dose of aramchol. 
7.3 
STATISTICAL ANALYSIS 
Details of all statistical analyses will be described in a statistical analysis plan. All data 
collected will be presented in data listings. Data from subjects excluded from an analysis 
population will be presented in the data listings but not included in the calculation of 
summary statistics. 
For categorical variables, frequencies and percentages will be presented. Continuous 
variables will be summarized using descriptive statistics (number of subjects, mean, standard 
deviation [SD], minimum, median, and maximum). 
Baseline demographic and background variables will be summarized by hepatic condition for 
all subjects. The number of subjects who enroll in the study and the number and percentage 
of subjects who complete the study will be presented. Frequency and percentage of subjects 
who withdraw or discontinue from the study, and the reason for withdrawal or 
discontinuation, will also be summarized. 
7.3.1 
Pharmacokinetic Analyses 
Plasma concentrations will be listed and summarized descriptively (number of subjects, 
arithmetic mean, SD, coefficient of variation [CV], minimum, median, and maximum). 
Plasma concentration versus actual time profiles for each subject will be presented 
graphically. The mean plasma concentration versus scheduled time profiles will be presented 
graphically. 
Pharmacokinetic parameters derived from plasma concentration data using 
noncompartmental methods with Phoenix® WinNonlin® (Certara USA Inc, Princeton, New 
Jersey) Version 8.0 or higher will be summarized by hepatic group using descriptive statistics 
(number of subjects, arithmetic mean, SD, CV, minimum, median, and maximum). 
Geometric mean and geometric CV will also be calculated for AUCs and Cmax. The AUC0-t, 
AUC0-inf, and Cmax values may also be expressed in terms of unbound drug concentrations. 
An analysis of variance (ANOVA) model will be performed on the natural logarithms of 
AUC0-t, AUC0-inf, and Cmax to calculate the ratio of geometric means and its 90% confidence 
interval between subjects with hepatic impairment and the corresponding healthy control 


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subjects, as appropriate. The ANOVA model will include hepatic group (normal matching 
mild, mild, normal matching moderate, moderate, normal matching severe, and severe, where 
applicable) as a fixed effect. 
For AUC0-t, AUC0-inf, and Cmax, a linear regression model will be performed on the natural 
logarithms of AUC0-t, AUC0-inf, and Cmax as dependent variables and each of the following 
natural-log-transformed hepatic function estimates as independent variables: Child-Pugh 
classification score (in subjects with hepatic impairment only), baseline serum bilirubin, 
serum albumin, and prothrombin time. The regression coefficients representing the 
relationship between the PK parameters and the hepatic function estimates will be estimated 
together with their 90% confidence intervals from the regression model. 
Sensitivity analyses may be conducted to investigate the potential impact of imbalance 
existing across hepatic impairment groups in the distribution of the baseline covariates used 
in subject matching (eg, body weight) and, if data suggest, appreciable differences in PK 
exposure (AUC0-t, AUC0-inf, and Cmax) across different values of the same baseline covariate.  
Detailed descriptions of the analyses in this study will be presented in the statistical analysis 
plan. 
7.3.2 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities. All AE data will be presented in 
a data listing. Treatment-emergent AEs will be summarized by hepatic condition and overall, 
as well as by severity and relationship to study drug. Serious AEs and AEs leading to early 
discontinuation will also be presented in data listings. 
Actual values and changes from baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarized by hepatic condition at each 
time point using descriptive statistics (number of subjects, mean, SD, minimum, median, and 
maximum). Shift tables will be generated for clinical laboratory test results. Clinical 
laboratory test results, vital sign measurements, 12-lead ECG results, and physical 
examination findings will be presented in data listings. 
7.4 
HANDLING OF MISSING DATA 
Plasma concentrations that are below the limit of quantification (BLQ) will be treated as zero 
for descriptive statistics. Mean BLQ concentrations will be presented as BLQ, and the SD 


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and CV will be reported as not applicable. Missing concentrations will be excluded from the 
calculations. 
For the PK analysis, BLQ values will be treated as zero with the exception that a BLQ value 
between 2 quantifiable concentrations will be set as missing. Missing concentrations will be 
treated as missing from the PK parameter calculations. If consecutive BLQ concentrations 
are followed by quantifiable concentrations in the terminal phase, those concentrations after 
BLQ concentrations will be treated as missing. 
7.5 
INTERIM ANALYSES 
No formal interim analyses will be performed in this study. 


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8. 
REFERENCE LIST 
Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research, Center for Biologics Evaluation and Research (US). 
Guidance for industry: Pharmacokinetics in patients with impaired hepatic function: Study 
design, data analysis, and impact on dosing and labeling. May 2003 [cited 10 Jul 2019]. 
Available from: https://www.fda.gov/media/71311/download 
Aramchol. Investigator’s brochure, 3rd ed. Tel Aviv (Israel); 2019. 125 p. 


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9. 
APPENDICES 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ANOVA 
analysis of variance 
AUC 
area under the plasma concentration versus time curve 
AUC0-inf 
area under the plasma concentration versus time curve from time 0 
extrapolated to infinity 
AUC0-t 
area under the plasma concentration versus time curve from time 0 
to the last quantifiable concentration 
AUC0-tau, ss 
area under the plasma concentration versus time curve from time 0 
to the dosing interval tau at steady state 
BLQ 
below the limit of quantification 
BMI 
body mass index 
Cavg, ss 
average plasma concentration at steady state 
CFR 
Code of Federal Regulations 
CL/F 
apparent total oral clearance 
Cmax 
maximum observed plasma concentration 
Cmax, ss 
maximum observed plasma concentration at steady state 
Cmin, ss 
minimum observed plasma concentration at steady state 
CV 
coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end of study 
FDA 
Food and Drug Administration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IRB 
institutional review board 
ke 
elimination rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
NASH 
nonalcoholic steatohepatitis 
PK 
pharmacokinetic(s) 
QTcF 
QT corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SD 
standard deviation 
t1/2 
apparent terminal phase half-life 
Tlag 
time to the first measurable plasma concentration 
Tmax 
time to reach maximum observed plasma concentration 
Tmax, ss 
time to reach maximum observed plasma concentration at steady 
state 
Tmin, ss 
time of minimum observed plasma concentration at steady state  
Vz/F 
apparent volume of distribution 


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9.2 
APPENDIX 2: STUDY GOVERNANCE 
9.2.1 
Data Quality Assurance 
This study will be conducted using the quality processes described in applicable procedural 
documents. The quality management approach to be implemented will be documented and 
will comply with current International Council for Harmonisation (ICH) guidance on quality 
and risk management. All aspects of the study will be monitored for compliance with 
applicable government regulatory requirements, current Good Clinical Practice, the protocol, 
and standard operating procedures. The monitor will maintain current personal knowledge of 
the study through observation, review of study records and source documentation, and 
discussion of the conduct of the study with the investigator and staff. Electronic CRFs and 
electronic data capture will be utilized. The electronic data capture system is validated and 
compliant with US Title 21 CFR Part 11. Each person involved with the study will have an 
individual identification code and password that allows for record traceability. 
Important protocol deviations, should they occur during the study, will be presented in 
Section 10.2 of the clinical study report. 
9.2.2 
Investigator Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study and may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB 
but will not result in protocol amendments. 
9.2.2.1 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the subject (or the subject’s legal guardian), except as necessary for monitoring 
and auditing by the sponsor, its designee, the FDA, or the IRB. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study, any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 


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9.2.2.2 
Institutional Review 
Federal regulations and ICH guidelines require that approval be obtained from an IRB before 
participation of human subjects in research studies. Before study onset, the protocol, ICF, 
advertisements to be used for the recruitment of study subjects, and any other written 
information regarding this study that is to be provided to the subject or the subject’s legal 
guardian must be approved by the IRB. Documentation of all IRB approvals and of the IRB 
compliance with the ICH harmonised tripartite guideline E6(R2): Good Clinical Practice will 
be maintained by the site and will be available for review by the sponsor or its designee. 
All IRB approvals should be signed by the IRB chairman or designee and must identify the 
IRB name and address, the clinical protocol by title or protocol number or both, and the date 
approval or a favorable opinion was granted. 
9.2.2.3 
Subject Consent 
Written informed consent in compliance with US Title 21 CFR Part 50 shall be obtained from 
each subject before he or she enters the study or before performing any unusual or nonroutine 
procedure that involves risk to the subject. If any institution-specific modifications to 
study-related procedures are proposed or made by the site, the consent should be reviewed by 
the sponsor or its designee or both before IRB submission. Once reviewed, the investigator 
will submit the ICF to the IRB for review and approval before the start of the study. If the 
ICF is revised during the course of the study, all active participating subjects must sign the 
revised form. 
Before recruitment and enrollment, each prospective subject or his/her legal guardian will be 
given a full explanation of the study and will be allowed to read the approved ICF. Once the 
investigator is assured that the subject/legal guardian understands the implications of 
participating in the study, the subject/legal guardian will be asked to give his or her consent 
to participate in the study by signing the ICF. A copy of the signed ICF will be provided to 
the subject/legal guardian. 
9.2.2.4 
Study Reporting Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in this protocol. In addition, the investigator agrees to 
submit annual reports to his or her IRB as appropriate. 


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9.2.2.5 
Financial Disclosure and Obligations 
The investigator is required to provide financial disclosure information to allow the sponsor 
to submit the complete and accurate certification or disclosure statements required under US 
Title 21 CFR Part 54. In addition, the investigator must provide to the sponsor a commitment 
to promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the sponsor nor the sponsor’s designee is financially responsible for further testing or 
treatment of any medical condition that may be detected during the screening process. In 
addition, in the absence of specific arrangements, neither the sponsor nor the sponsor’s 
designee is financially responsible for further treatment of the disease under study. 
9.2.2.6 
Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH 
E6(R2) Section 8.2 and US Title 21 of the CFR by providing essential documents, including 
but not limited to, the following: 
• IRB approval. 
• An original investigator-signed investigator agreement page of the protocol. 
• Form FDA 1572, fully executed, and all updates on a new fully executed 
Form FDA 1572. 
• Curriculum vitae for the principal investigator and each subinvestigator listed on Form 
FDA 1572. Current licensure must be noted on the curriculum vitae. Curriculum vitae 
will be signed and dated by the principal investigators and subinvestigators at study 
start-up, indicating that they are accurate and current. 
• Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under US Title 21 CFR Part 54. In 
addition, the investigators must provide to the sponsor a commitment to promptly update 
this information if any relevant changes occur during the course of the investigation and 
for 1 year after the completion of the study. 
• An IRB-approved ICF, samples of site advertisements for recruitment for this study, and 
any other written information about this study that is to be provided to the subject or legal 
guardians. 


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• Laboratory certifications and reference ranges for any local laboratories used by the site, 
in accordance with US Title 42 CFR Part 493. 
9.2.2.7 
Study Conduct 
The investigator agrees to perform all aspects of this study in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, ICH E6(R2): Good Clinical 
Practice; the protocol; and all national, state, and local laws or regulations. 
9.2.2.8 
Case Report Forms and Source Documents 
Site personnel will maintain source documentation, enter subject data into the eCRF as 
accurately as possible, and rapidly respond to any reported discrepancies. 
Electronic CRFs and electronic data capture will be utilized. The electronic data capture 
system is validated and compliant with US Title 21 CFR Part 11. Each person involved with 
the study will have an individual identification code and password that allows for record 
traceability. Thus, the system, and any subsequent investigative reviews, can identify 
coordinators, investigators, and individuals who have entered or modified records, as well as 
the time and date of any modifications. There may be an internal quality review audit of the 
data and additional reviews by the monitor. 
Each eCRF is presented as an electronic copy, allowing data entry by site personnel, who can 
add and edit data, add new subjects, identify and resolve discrepancies, and view records. 
This system provides immediate direct data transfer to the database, as well as immediate 
detection of discrepancies, enabling site coordinators to resolve and manage discrepancies in 
a timely manner. 
Paper copies of the eCRFs and other database reports may be printed and signed by the 
investigator. This system provides site personnel, monitors, and reviewers with access to 
hardcopy audits, discrepancy reviews, and investigator comment information. 
9.2.2.9 
Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol, in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 


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9.2.2.10 
Reporting Adverse Events 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the timeline and method outlined in this protocol. In addition, the investigator agrees to 
submit annual reports to his or her IRB as appropriate. The investigator also agrees to 
provide the sponsor with an adequate report, if applicable, shortly after completion of the 
investigator’s participation in the study. 
9.2.2.11 
Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB with a summary of the study’s 
outcome and the sponsor and regulatory authorities with any reports required. 
9.2.2.12 
Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study drug. These documents should be 
retained for a longer period, however, if required by applicable regulatory requirements or by 
an agreement with the sponsor. The sponsor is responsible for informing the 
investigator/institution when these documents no longer need to be retained. 
9.2.2.13 
Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and any other related issues. The sponsor has final approval authority over 
all such issues. 
Data are the property of the sponsor and cannot be published without their prior 
authorization, but data and any publication thereof will not be unduly withheld. 


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9.2.3 
Study Management 
9.2.3.1 
Monitoring 
9.2.3.1.1 
Monitoring of the Study 
The monitor, as a representative of the sponsor, is obligated to follow the study closely. In 
doing so, the monitor will visit the investigator and clinical site at periodic intervals in 
addition to maintaining necessary telephone and email contact. The monitor will maintain 
current personal knowledge of the study through observation, review of study records 
including eCRFs and source documentation, and discussion of the conduct of the study with 
the investigator and staff. 
All aspects of the study will be carefully monitored by the sponsor or its designee for 
compliance with applicable government regulation with respect to current ICH E6(R2) 
guidelines and standard operating procedures. 
9.2.3.1.2 
Inspection of Records 
The investigator and institution involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records. 
In the event of an audit, the investigator agrees to allow the sponsor, their representatives, the 
FDA, or other regulatory agencies access to all study records. 
The investigator should promptly notify the sponsor and clinical sites of any audits scheduled 
by any regulatory authorities and promptly forward copies of any audit reports received to 
the sponsor. 
9.2.3.2 
Management of Protocol Amendments and Deviations 
9.2.3.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent 
immediate hazard to the subject, must be reviewed and approved by the sponsor or designee. 
Amendments to the protocol must be submitted in writing to the investigator’s IRB for 
approval before subjects are enrolled into an amended protocol. 


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9.2.3.2.2 
Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change to, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB for review and approval, to the sponsor for agreement, and to 
the regulatory authorities, if required. 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. An important deviation (sometimes referred to as a major 
or significant deviation) is a subset of protocol deviations that leads to a subject being 
discontinued from the study, or significantly affects the subject’s rights, safety, or well-being 
and/or the completeness, accuracy, and reliability of the study data. An important deviation 
can include nonadherence to inclusion or exclusion criteria or nonadherence to FDA 
regulations or ICH E6(R2) guidelines. 
Protocol deviations will be documented by the monitor throughout the course of monitoring 
visits. Any additional protocol deviations that are found by the monitor during the course of 
monitoring visits will also be recorded by the monitor. The investigator will be notified in 
writing by the monitor of deviations. The IRB should be notified of all protocol deviations, if 
appropriate, in a timely manner. 
9.2.3.3 
Study Termination 
Although the sponsor has every intention of completing the study, they reserve the right to 
discontinue it at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last subject completes the last visit 
(including the EOS visit). Any additional long-term follow-up that is required for monitoring 
of the resolution of an AE or finding may be appended to the clinical study report. 
9.2.3.4 
Final Report 
Regardless of whether the study is completed or prematurely terminated, the sponsor will 
ensure that clinical study reports are prepared and provided to the regulatory agency as 
required by the applicable regulatory requirement. The sponsor will also ensure that clinical 
study reports in marketing applications meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and content of clinical study reports. 


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Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review complete study results. 
Upon completion of the clinical study report, the investigators will be provided with the final 
approved clinical study report, as appropriate.