Clinical trial NCT04874233
Conditions: NASH - Nonalcoholic Steatohepatitis
Sponsor: Rivus Pharmaceuticals, Inc.
Start date: 2021-04-19; Completion date: 2021-12-15
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 2a, randomized, parallel-group, placebo-controlled, double-blind, repeated-dose study to evaluate the safety and efficacy of three oral dose levels of HU6 compared to placebo over the course of 61 days in subjects with high BMI and evidence of elevated liver fat.

Detailed description:
This is a Phase 2a, randomized, parallel-group, placebo-controlled, double-blind, repeated-dose study to evaluate the safety and efficacy of three oral dose levels of HU6 compared to placebo over the course of 61 days in subjects with high BMI and evidence of elevated liver fat.

Subjects will be screened over a 45 day period to determine their eligibility based on specific history, physical, laboratory and imaging evaluations as per the Schedule of Assessments. Due to scheduling of the procedures, multiple visits will likely be necessary to complete the screening process. However, if all screening assessments and procedures, including the MRI, can be completed within 30 days of the first dose, then a single screening visit is permissible.

Arms: arm 1: HU6 is Active Study Drug arm 2: HU6 is Active Study Drug arm 3: HU6 is Active Study Drug arm 4: Non-active Study Drug
Interventions: intervention 1: HU6 intervention 2: Placebo
Intervention descriptions: intervention 1: HU6 is active study drug intervention 2: Non-active study drug N = 20

Protocol documents:
Prot_000.pdf: 
RIV-HU6-203 
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Main Title 
A 61-day Randomized, Double blind, Placebo-controlled Trial to Assess the Safety and Efficacy 
of Three Doses of HU6 in Subjects with Elevated Liver Fat and  
High Body Mass Index (28 to 45 kg/m2) 
Protocol Number: 
RIV-HU6-203 
Official Short Title: 
Phase 2a Study of HU6 in Subjects with Elevated Liver Fat and High BMI Volunteers 
Clinical Study Protocol 
Version Number:  3.0 
Date: 21 Dec 2021 
Confidentiality Statement: 
This document has been approved for publication by Rivus Pharmaceuticals, Inc. 
 
 
 


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Confidential 
SIGNATURE PAGE FOR SPONSOR 
Study No.  
 
RIV-HU6-203 
 
Protocol Title:  
A 61-day Randomized, Double blind, Placebo-controlled Trial to Assess the 
Safety and Efficacy of Three Doses of HU6 in Subjects with Elevated Liver Fat 
and High Body Mass Index (28 to 45 kg/m2). 
 
 
Approved by the following: 
 
________
_____________________ 
________________  
Shaharyar 
an, 
. .  
 
 
Date 
Chief Scientific Officer 
Rivus Pharmaceuticals, Inc. 
706b Forest Street 
Charlottesville, VA  22903 
________________________________________________ 
________________  
Roger Morgan, M.D.  
 
 
Date 
Vice President Medical Affairs 
MedSurgPI, LLC 
3700 Lark Farm Road 
Franklinton, NC  27525 
 
 
 
 
 
12-21-2021
12-21-2021


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SIGNATURE PAGE FOR INVESTIGATOR 
Study No.  
 
RIV-HU6-203 
 
Protocol Title:  
A 61-day Randomized, Double blind, Placebo-controlled Trial to Assess the 
Safety and Efficacy of Three Doses of HU6 in Subjects with Elevated Liver Fat 
and High Body Mass Index (28 to 45 kg/m2). 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of the 
protocol and in accordance with all applicable regulations, ICH and the Declaration of Helsinki. 
 
________________________ 
________________________ 
________________  
 
Investigator Name 
Signature 
 
 
Date 
 


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1 STUDY ORGANIZATIONAL STRUCTURE 
Sponsor: 
Rivus Pharmaceuticals, Inc. 
Primary Sponsor Contact: 
Shaharyar Khan, Ph.D. 
Chief Scientific Officer 
Rivus Pharmaceuticals, Inc. 
706b Forest Street 
Charlottesville, VA  22903 
  
Clinical Project Manager 
Catherine Ross MacLaren 
Clinical Project Manager 
 
 
 
24-Hour Medical Monitor Coverage 
Roger Morgan, M.D. 
Vice President Medical Affairs 
MedSurgPI, LLC 
3700 Lark Farm Road 
Franklinton, NC  27525 


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2 PROTOCOL SYNOPSIS 
TITLE:   A 61-day Randomized, Double blind, Placebo-controlled Trial to Assess the Safety 
and Efficacy of Three Doses of HU6 in Subjects with Elevated Liver Fat and High 
Body Mass Index (28.0 to 45.0 kg/m2) 
SPONSOR:  
Rivus Pharmaceuticals, Inc. 
PROTOCOL NUMBER:  
RIV-HU6-203 
CLINICAL STUDY PHASE: Phase 2a 
INVESTIGATIONAL DRUG PRODUCT:    HU6 
Name of Active Ingredient (IUPAC name):  
 
No of Study Center(s):  Up to 5 Centers 
Study Period:   
Estimated date first subject enrolled: May 2021 
Estimated last subject completed:  September 2021 
Study Duration per subject:  
Approximately 120 days (up to 45 days for screening, 61 days of dosing, up to 14 days for final 
visit after dosing completion) 
Primary Objectives:    
Efficacy: To evaluate the reduction in liver fat content, as assessed by magnetic resonance 
imaging proton density fat fraction (MRI-PDFF) from baseline to Day 61 in subjects with 
elevated Body Mass Index (BMI) treated with HU6 compared to placebo.  
Safety: To evaluate safety and tolerability of 61 days of repeated daily dosing of HU6 in 
overweight and obese subjects as defined by BMI. 
Secondary Objectives:   
 
To assess the rate and amount of body weight loss after 61 days of HU6 treatment. 
 
To assess change from baseline in whole body adiposity by MRI after 61 days of HU6 
treatment. 
 
To characterize the pharmacokinetic (PK) profile of HU6 and its metabolites, 
2,4-dinitrophenol (DNP) and M1, over 61 days of dosing in subjects with high BMI. 
 
To evaluate and correlate changes from baseline in measures of liver composition with 
changes in liver fat content after dosing with HU6. 


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 
To investigate the pharmacodynamic (PD) effects of HU6 on metabolic and 
cardiovascular risk factors. 
 
To investigate the PD effects of HU6 on metabolomic, proteomic, and lipidomic 
profiles. 
 
To characterize the dose/exposure relationships of the efficacy and PD effects of HU6, 
as data allow.  
Endpoints: 
Primary Endpoint: 
 
Relative change from baseline in liver fat content, as assessed MRI-PDFF at Day 61. 
Secondary Endpoints: 
Pharmacodynamics 
 
Change from baseline in body weight at Day 61. 
 
Change from baseline in whole body adiposity at Day 61. 
 
Changes from baseline in surrogate measures of liver inflammation and fibrosis 
Day 61: Fibroscan® Vibration-controlled Transient Elastography (VCTE), Fibroscan® 
Controlled Attenuation Parameter (CAP) score, and Enhanced Liver Fibrosis (ELF) 
score. 
 
Change from baseline in lipid parameters and cardiovascular risk biomarkers Day 61: 
serum high sensitivity C-reactive protein (hs-CRP), Lp(A), Apo B, low-density 
lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol, triglycerides, and 
free fatty acids (FFA). 
 
Change from baseline in metabolic disease parameters at Day 61: homeostatic model 
assessment for insulin resistance (HOMA-IR), fasting blood glucose concentrations, 
glycated albumin concentrations, and glycosylated hemoglobin (hemoglobin A1c 
[HbA1c]. 
Safety and Tolerability 
 
Summary of physical examinations findings over the course of the study. 
 
Adverse event (AE) assessment over the course of the study. 
 
Assessment of vital sign parameters over the course of the study. Parameters to include 
resting systolic and diastolic blood pressures, resting heart rates, resting respiratory 
rates, and oral body temperatures. 
 
Assessment of body weight over the course of the study. 
 
Safety 12-lead electrocardiograms (ECGs) over the course of the study. 
 
Assessment of clinical laboratory values (hematology, full biochemistry panel 
(including lipid panel, creatine phosphokinase [CPK], magnesium, liver function tests) 
and urinalysis (UA) over 61 days of dosing. 


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 
Assessment of ophthalmologic examination, including slit lamp, prior to and after 
61 days of dosing. 
Pharmacokinetics 
 
Population PK (PPK) analysis of HU6 parent and metabolites, DNP and M1. The 
following PK parameters will be calculated: Cmax, Tmax, t½, Tlag, AUC0-t, AUC0-∞, CL/F, 
Vd/F, λz. Other PK parameters may be calculated, as data allow and appropriate. 
 
As data permit, noncompartmental analysis of HU6 parent and metabolites, DNP and 
M1. The following PK parameters will be calculated: Cmax, AUC, and accumulation. 
 
Modeling of exposure response relationships of HU6, DNP and M1 and 
efficacy/PD endpoints, as appropriate. 
Exploratory Endpoints: 
 
Change from baseline in metabolomic and lipidomic profiles (One Way Liver- [OWL] 
metabolomic and lipidomic assays) at Day 61. 
 
Change from baseline in proteomic profiles (SomaScan®) at Day 61.  
 
Change from baseline in serum alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) concentrations at Day 61, as data allow. 
NUMBER OF SUBJECTS:  
Assuming 15% drop-out rate, approximately 80 subjects will be enrolled to achieve 
68 evaluable subjects.  
Eligible subjects will be randomized equally to 1 of the 4 following treatment groups 
(approximately 20 subjects per group): 
 
Group 1: matched placebo orally once daily for 61 days.  
 
Group 2: 150 mg HU6 orally once daily for 61 days. 
 
Group 3: 300 mg HU6 orally once daily for 61 days.  
 
Group 4: 450 mg HU6 orally once daily for 61 days.  
The randomization will be blocked and stratified by HbA1c (normal range versus between 5.7% 
and 9.0% inclusive).  
Inclusion Criteria:  Subjects must meet all the following inclusion criteria to be eligible: 
1. Adult male or females, 28 to 65 years of age (inclusive) at the time of informed 
consent with BMI between 28.0 and 45.0 kg/m2 (inclusive). 
a. Female subjects of childbearing potential must be non-lactating, not pregnant 
as confirmed by a negative urine pregnancy test at Screening and agree to 
continue using an effective method of contraception for at least 4 weeks or 
barrier method for 2 weeks prior to first study drug administration until 
30 days after the last dose of study drug.  


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b. Female subjects of childbearing potential must not donate ova during the study 
and for at least 30 days after the last dose of study drug. 
c. Female subjects of non-childbearing potential must be surgically sterile (e.g., 
hysterectomy, bilateral tubal ligation, oophorectomy) or postmenopausal (no 
menses for >1 year with follicle stimulating hormone (FSH) >40 U/L at 
Screening). 
d. Male subjects who have not had a vasectomy and/or subjects who have had a 
vasectomy but have not had 2 post surgery negative tests for sperm must agree 
to use an acceptable method of contraception from time of first dose of study 
drug until 30 days after the last dose of the study drug, and to not donate sperm 
during the study and for at least 30 days after the last dose of study drug. 
2. Inclusion as per investigator assessment of general medical status and as documented 
by medical history, physical examination, vital sign assessments, 12-lead ECG, clinical 
laboratory assessments, and general observations. 
a. Subjects must be on stable doses of medications for underlying obesity-related 
conditions for at least 2 months prior to screening. 
b. Subjects with diabetes may be treated with metformin, DPP-4 inhibitors, or 
sulfonylureas, but must be on stable doses for at least 2 months prior to 
screening. 
c. At Screening, certain laboratory values may be outside the reference range if 
commensurate with the underlying obesity or associated metabolic dysfunction 
in the eligible subject (for example, dyslipidemia and hyperglycemia), u nless 
these abnormalities suggest an underlying condition which may impact subject 
safety in the trial or interfere with the evaluation of HU6 or affect 
interpretation of the study results. 
d. Abnormalities or deviations outside the normal ranges for other assessments 
that are considered clinically significant by the Investigator (clinical laboratory 
tests, ECG, vital signs, physical examination) may be repeated once at the 
discretion of the Investigator(s). Results that continue to be outside the normal 
ranges must be judged by the investigator to be not clinically significant and 
acceptable for study participation.  
e. Subjects with elevation of unconjugated bilirubin due to presumptive Gilbert’s 
syndrome are permissible.  
f. Subject must be euthyroid as assessed by a thyroid profile utilizing thyroid 
stimulating hormone (TSH) and free thyroxine (T4) testing at screening. 
Subjects with a stable history of thyroid disease and who have been on stable 
doses of thyroid medications for a minimum of 4 months can be enrolled. 
3. Fibroscan® CAP score>300 dB/m. If the score is between >270 to 300 dB/m, it may be 
approved after discussions between the PI and Medical Monitor. 
4. ≥8% liver fat by MRI-PDFF. 


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5. Understands the procedures and requirements of the study and provides written 
informed consent and authorization for protected health information disclosure. 
6. Willing and able to comply with the requirements of the study protocol. 
Exclusion Criteria:  Subjects will be excluded from the study if any of the following criteria 
are met: 
1. Insulin-controlled diabetes. 
2. Pregnant or breastfeeding or plans to become pregnant. 
3. Intolerance to Magnetic Resonance Imaging (MRI) or with conditions contraindicated 
for MRI procedures including but not limited to inability to fit into MRI scanner or 
surgical clips/metallic implants/shrapnel. Subjects must not be claustrophobic, have a 
history of claustrophobia, or intolerance of closed or small spaces. 
4. Weight gain or loss >5% in 3 months prior to study or >10% in 6 months prior to 
screening. 
5. History of lap banding, intragastric balloon, duodenal-jejunal sleeve, or bariatric 
surgery within 5 years of screening, plans for bariatric surgery prior to conclusion of 
study participation, or plans to lose weight during this study either through a special 
diet, exercise program or both. Subjects currently maintained on a special diet or 
exercise program must be willing to discontinue that program for 30 days prior to Day 
1 and throughout the duration of the study.  
6. History of malignant hyperthermia. 
7. History of chronic serious recurrent skin rashes of unknown cause. 
8. History of or current clinically significant cardiovascular disease including but not 
limited to transient ischemic attack, stroke, cardiac arrhythmias, syncope, unstable 
angina, myocardial infarction in the 6 months prior to screening, congestive heart 
failure, or uncontrolled hypertension. (Uncontrolled hypertension is defined as a 
systolic blood pressure ≥160 mmHg or a diastolic blood pressure ≥100 mmHg)  
9. Resting heart rate <45 or >110 bpm. 
10. On screening ECG or by history: 
a. A marked baseline prolongation of QT/QTcF interval (e.g., repeated 
demonstration of a QTcF interval > 450 msec for males and >470 msec for 
females). 
b. A history of additional risk factors for Torsades de Pointes (TdP) (e.g., heart 
failure, hypokalemia, family history of Long QT Syndrome) or a family 
history of sudden cardiac death of unknown origin. 
11. Kidney disease, kidney transplant or estimated glomerular filtration rate 
(eGFR) <50 mL/min/1.73 m2 based on the CKD-EPI Creatinine Equation (NKF 2009; 
https://www.kidney.org/content/ckd-epi-creatinine-equation-2009). 


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12.  Significant lung disease requiring chronic daily medication including chronic 
obstructive pulmonary disease (COPD), emphysema, pulmonary fibrosis, or asthma.  
Documented well-controlled asthma is allowed. 
13. Untreated obesity hypoventilation syndrome (OHS) or obstructive sleep apnea (OSA). 
14. History of or active (acute or chronic) liver disease other than nonalcoholic fatty liver 
disease (NAFLD)/ nonalcoholic steatohepatitis (NASH), such as but not limited to 
autoimmune liver disease, viral hepatitis, genetic hemochromatosis, primary biliary 
cirrhosis, Wilson disease, alpha-1-antitrypsin deficiency, alcohol liver disease, acute 
fatty liver of pregnancy or drug- induced (including acetaminophen) liver disease. 
15. History of or treatment for clinically significant gastroparesis, inflammatory bowel 
disease, or any surgery of the upper gastrointestinal tract with the exception of 
cholecystectomy, or minor gastric procedures that are approved by the medical 
monitor. 
16. History of cirrhosis and/or hepatic decompensation, including ascites, hepatic 
encephalopathy, or variceal bleeding.  
17. History of acute pancreatitis within one year of screening or chronic pancreatitis of any 
cause. 
18. Serum triglyceride concentrations exceeding 500 mg/dL. 
19. HbA1c >9.0%. 
20. Familial (mother/father/sibling) and/or personal history of spontaneous retinal 
detachment any time in the past. 
21. Any history of or current diagnosis of Glaucoma. 
22. Evidence of the following pathologies on screening ophthalmologic examination: 
a. Peripheral retinal pathology requiring treatment, retinal tears, or lattice that 
require treatment. 
b. Diabetic retinopathy with macula exudates or macula edema as shown by 
optical coherence tomography (OCT) and examination. 
c. Any active macular disease that affects the vision, including macula pucker 
(epiretinal membrane) and macular degeneration. 
d. Visually significant cataract as determined by ophthalmologist. 
e. Any previous intravitreal injection of anti-VEGF agents for macular 
degeneration. 
f. History of prior vitrectomy. 
23. History of malignant neoplasms within 5 years of screening, except for basal cell or 
squamous cell skin cancer, cervical carcinoma in situ, or prostate cancer that is not 


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currently or expected to require radiation therapy, chemotherapy and/or surgical 
interventions or to initiate hormonal treatment. 
24. History of organ transplantation. 
25. Received a COVID-19 vaccine less than 1 week prior to dosing (Visit 2 / Day 1) 
and/or plans to receive a COVID-19 vaccine during the study period. 
26. History of significant drug abuse within one year prior to Screening or frequent use of 
soft drugs (such as marijuana) within 3 months prior to the Screening visit, or hard 
drugs (such as cocaine, phencyclidine [PCP], opioid derivatives including heroin, and 
amphetamine derivatives) within 1 year prior to screening. 
27. History of alcoholism in the last 2 years  or current evidence of excessive alcohol 
consumption as assessed by screening evaluation using the Alcohol Use Disorders 
Identification Test (AUDIT, Thompson 2018 [Appendix A]), and history of regular 
alcohol consumption exceeding approximately14 drinks/week for men and 
7 drinks/week for women [1 drink = 4 ounces (120 mL) of wine or 12 ounces (360 
mL) of beer or 1 ounce (30 mL) of hard liquor] within 6 months of Screening, as 
determined by the Investigator. 
28. Positive urine drug screen for drugs of abuse or positive phosphatidylethanol (PEth) 
blood test result >200 ng/mL based on tPEth 16.0/18.1 (POPEth) at Screening. In 
instances of an exclusionary PEth value, consideration for enrollment can be provided 
if the principal investigator and medical monitor agree the subject’s history is not 
consistent with alcohol abuse.  Subjects with a positive drug screen due to an approved 
medication may be allowed on a case-by-case basis by the Investigator in consultation 
with the medical monitor. 
29. Current regular vaping or more than 10 cigarettes or the equivalent per week. Use of 
nicotine patches for smoking cessation is permitted. 
30. Positive test results of hepatitis B surface antigen (HBsAg), hepatitis C virus antibody 
(HCV Ab), or human immunodeficiency virus (HIV1/2) antibody. 
31. Neutropenia, defined as absolute neutrophil count ≤1000/μL. 
32. Serum AST or ALT >5 x upper limit of normal (ULN) at screening. (One repeat test 
may be allowed within 7 days at the discretion of the Investigator). 
33. Total bilirubin > ULN, unless due to Gilbert’s syndrome or if considered normal 
variability in the absence of other clinically relevant liver impairment, as approved by 
the medical monitor. 
34. International normalized ratio (INR) ≥1.3 at screening if there is other evidence of 
potentially significant liver impairment.  
35. Participation in another clinical trial at the time of screening or exposure to any 
investigational agent, including topical, within 30 days of screening or 5 half-lives, if 
half-life known. 


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36. No tattoo or body piercings during the course of the study. 
37. Any underlying physical or psychological medical condition that, in the opinion of the 
Investigator or sponsor, would make it unlikely that the subject is able comply with the 
study requirements or would be unable to complete the study.  
38. Any condition that the investigator believes would interfere with his/her ability to 
provide written informed consent, comply with study instructions, or which might 
confound the interpretation of the study results or put the subject at undue risk.  
39.  Known or potential hypersensitivity to HU6 or its excipients. 
Prohibited Medications (Current Use): 
40. Any herbal supplement, over the counter drug, mail order or prescription drug for 
weight loss. 
41. Prescription or over the counter stimulants including: dextroamphetamine/Dexedrine, 
dextroamphetamine/amphetamine combination product/Adderall, or methylphenidate 
(Ritalin®, Concerta®). 
42. Thiazolidinediones (TZD): pioglitazone/Actos, rosiglitazone/Avandia. 
43. Glucagon-like peptide 1 (GLP1) agonists: exenatide/Byetta/Bydureon, 
lixisenatide/Adlyxin, liraglutide/Victoza, dulaglutide/Trulicity, semaglutide/Ozempic. 
44. Sodium-glucose cotransporter-2 (SGLT2) inhibitors: canagliflozin/Invokana, 
dapagliflozin/Farxiga, empagliflozin/Jardiance, ertugliflozin/Steglatro. 
45. Vitamin E: use of ursodiol or high dose vitamin E >400 IU/day for at least one month 
within in the last 6 months or started high dose vitamin E within last 3 months of 
screening. 
46. Recent (within 3 months of screening) or current use of obeticholic acid/Ocaliva, 
systemic corticosteroids, methotrexate, tamoxifen, amiodarone, or long-term use of 
tetracyclines. 
47. Warfarin, heparin, factor Xa inhibitors (dabigatran, betrixaban, edoxaban, apixaban, 
and rivaroxaban).   
48. Concomitant medications that prolong the QT/QTc interval and are known to be 
associated with increased risk of Torsade des pointes as identified in the 
https://crediblemeds.org/ website list category of ‘Known Risk’ (Appendix B). For 
subjects on medications that are listed in Appendix B, approval must be obtained from 
the Sponsor and Medical Monitor. 
 
METHODOLOGY: 
Overview of Study Design 


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Subjects will be screened over a 45 day period to determine their eligibility based on specific 
history, physical, laboratory and imaging evaluations as per the Schedule of Assessments. Due 
to scheduling of the procedures, multiple visits will likely be necessary to complete the 
screening process. However, if all screening assessments and procedures can be completed 
within 30 days of first dose that is permissible.  
Once qualified, patients will be randomly assigned to one of the HU6 treatment groups or the 
matched placebo control group and dosed once daily (fasting) for a total of 61 days. Subjects 
will return to the clinic for frequent assessment visits during the 61 days of dosing as 
demonstrated in the Schedule of Assessments (Section 8.1). A follow-up visit will occur within 
10-14 days following the completion of dosing.  
 
 
Subjects will be instructed to maintain their same diet and activity/exercise level throughout 
the study as they had prior to participation in the study.  
-45 to -3 Days
Screening / Visit 1
Dosing 
Starts 
Day 1
Baseline / Visit 2
Placebo QD (n = 20)
150 mg QD (n = 20) 
300 mg QD (n =20) 
450 mg QD (n = 20) 
Day 61
End of 
Treatment
Day 71 -
75
Follow up
10 Visits, Screening, Baseline/ First dose, Day 2, Day 7, Day 14, Day 28, Day 42,
Day 49, Day 61 / end of treatment, and Follow up at Day 71 – 75.
Visit procedures include PK and PD measures and safety assessments.


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DOSAGE, DOSE FORM, AND ROUTE OF ADMINISTRATION: 
Study drug will be supplied to the clinic as bulk capsules in a polyethylene bag contained in 
high-density polyethylene (HDPE) secondary container. The study drug is prepared by filling 
150 mg of HU6 in a size 00  HPMC capsule. Bulk drug product should be stored at controlled 
room temperature in the original container.  
Doses will be dispensed to each subject during dispensation visits in a ‘pill organizer’ with the 
appropriate pharmacy label that will include the subject’s study number. The pill organizers 
containing the study drug should be stored at controlled room temperature, away from direct 
light.  
Bulk matching placebo capsules (each size 00 HPMC capsule containing 150 mg of mannitol) 
will be supplied. The unblinded pharmacist will prepare placebo capsules in the same method 
as for the active study product. 
HU6 will be administered orally in the fasted state (after a minimum 8-hour overnight fast). 
STATISTICAL METHODS: 
Size and power assumptions 
A sample size of 17 subjects per group provides at least 80% power to detect a 30% difference 
in the mean relative change from baseline in liver fat content at Day 61, when the standard 
deviation is 30% [PASS 2020: Two sample t-test, alpha=.05]. Assuming a 15% dropout rate, 
up to 80 subjects should be enrolled to ensure that at least 68 subjects, 17 per group, are 
evaluable for the primary efficacy endpoint analysis.  
Statistical Methods 
Descriptive statistical methods will be used to summarize the data from this study, with statistical 
testing performed for the efficacy endpoints. Unless stated otherwise, the term “descriptive 
statistics” refers to number of subjects (n), mean, median, standard deviation, minimum, and 
maximum for continuous data, and frequencies and percentages for categorical data. Statistical 
testing, if performed, will be 2-sided and will be performed using a significance (alpha) level of 
0.05. There will be no adjustment for multiple comparisons for this exploratory study. All 
available data for enrolled subjects will be listed by subject. Unless otherwise noted, the data 
will be sorted first by subject number and then by date within each subject number. All statistical 
analyses will be conducted with the SAS® System, version 9.4 or higher.   
 
 
 


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TABLE OF CONTENTS 
SIGNATURE PAGE FOR SPONSOR ........................................................................................................2 
SIGNATURE PAGE FOR INVESTIGATOR ................................................................................................3 
1 
STUDY ORGANIZATIONAL STRUCTURE ........................................................................................4 
2 
PROTOCOL SYNOPSIS .................................................................................................................5 
TABLE OF CONTENTS ................................................................................................................ 15 
GLOSSARY OF TERMS AND ABBREVIATIONS ....................................................................... 20 
3 
INTRODUCTION ....................................................................................................................... 23 
3.1 
BACKGROUND ................................................................................................................................ 23 
3.2 
NONCLINICAL EXPERIENCE ................................................................................................................ 23 
3.3 
SUMMARY OF CLINICAL EXPERIENCE .................................................................................................. 23 
3.4 
RATIONALE FOR STUDY .................................................................................................................... 23 
3.5 
RATIONALE FOR SELECTED DOSES ...................................................................................................... 23 
4 
STUDY OBJECTIVES ................................................................................................................... 23 
4.1 
PRIMARY OBJECTIVES ...................................................................................................................... 23 
4.2 
SECONDARY OBJECTIVES .................................................................................................................. 23 
5 
STUDY TYPE AND DESIGN ......................................................................................................... 24 
5.1 
STUDY TYPE ................................................................................................................................... 24 
5.2 
ENDPOINTS .................................................................................................................................... 24 
5.2.1 
Primary Endpoint ................................................................................................................... 24 
5.2.2 
Secondary Endpoints .............................................................................................................. 24 
5.2.3 
Exploratory Endpoints ............................................................................................................ 25 
5.3 
STUDY DESIGN ............................................................................................................................... 25 
5.4 
STUDY DURATION ........................................................................................................................... 26 
6 
STUDY DRUG ........................................................................................................................... 27 
6.1 
SUPPLY AND STORAGE ..................................................................................................................... 27 
6.2 
ADMINISTRATION............................................................................................................................ 27 


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6.2.1 
Dosing Instructions................................................................................................................. 27 
6.2.2 
Daily Dosing Log ..................................................................................................................... 27 
6.2.3 
Compliance ............................................................................................................................. 28 
6.3 
PACKAGING AND LABELING ............................................................................................................... 28 
6.4 
ACCOUNTABILITY ............................................................................................................................ 29 
6.5 
OVERDOSE/TOXICITY MANAGEMENT ................................................................................................. 29 
6.6 
BLINDING AND RANDOMIZATION ....................................................................................................... 29 
7 
STUDY POPULATION ................................................................................................................ 30 
7.1 
NUMBER OF SUBJECTS ..................................................................................................................... 30 
7.2 
INCLUSION CRITERIA ........................................................................................................................ 30 
7.3 
EXCLUSION CRITERIA ....................................................................................................................... 31 
7.4 
WITHDRAWAL OF SUBJECTS .............................................................................................................. 35 
7.4.1 
Follow-up Procedures for Subjects Who Withdraw Prematurely .......................................... 36 
7.4.2 
Procedures for Replacing Subjects Who Withdraw Prematurely........................................... 36 
8 
TREATMENT PLAN AND METHODS ........................................................................................... 36 
8.1 
SCHEDULE OF ASSESSMENTS ............................................................................................................. 38 
8.2 
STUDY SPECIFIC PROCEDURES ........................................................................................................... 41 
8.2.1 
Screening ................................................................................................................................ 41 
8.2.2 
Baseline Visit 2 / Day 1 ........................................................................................................... 42 
8.2.3 
Visit 3 / Day 2 ......................................................................................................................... 43 
8.2.4 
Visit 4 / Day 7 (±1 day) ........................................................................................................... 44 
8.2.5 
Visit 5 / Day 14 (±1 day) ......................................................................................................... 44 
8.2.6 
Visit 6 / Day 28 (±4 days) ....................................................................................................... 45 
8.2.7 
Visit 7 / Day 42 (±4 days) ....................................................................................................... 46 
8.2.8 
Visit 8 /Day 49 (±2 days) ........................................................................................................ 46 
8.2.9 
Visit 9 / Day 61 ....................................................................................................................... 46 
8.2.10 
Visit 10/ Day 73 (±2 days) .................................................................................................. 48 
8.2.11 
Early Termination Visit ...................................................................................................... 48 


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8.3 
CONCOMITANT MEDICATIONS AND OTHER RESTRICTIONS ..................................................................... 50 
8.3.1 
Concomitant Medications ...................................................................................................... 50 
8.3.2 
Contraception and Pregnancy Avoidance Measures ............................................................. 51 
8.3.3 
Lifestyle and Dietary Restrictions ........................................................................................... 51 
9 
PHARMACOKINETIC ASSESSMENTS .......................................................................................... 52 
9.1 
PHARMACOKINETIC SAMPLE COLLECTION ........................................................................................... 52 
9.2 
HANDLING, SHIPPING, STORAGE AND ANALYSIS OF BLOOD SAMPLES ...................................................... 52 
9.3 
PHARMACOKINETIC PARAMETERS ...................................................................................................... 52 
10 
PHARMACODYNAMIC ASSESSMENTS ....................................................................................... 52 
10.1 
MAGNETIC RESONANCE IMAGING-PROTON DENSITY FAT FRACTION (MRI-PDFF) .................................... 53 
10.2 
FIBROSCAN® .................................................................................................................................. 53 
10.3 
ONE WAY LIVER ASSAYS (OWL) ....................................................................................................... 53 
10.3.1 
OWL – Metabolomics ........................................................................................................ 53 
10.3.2 
OWL – Lipidomics............................................................................................................... 53 
10.4 
SLOW OFF-RATE MODIFIED APTAMER (SOMASCAN) ............................................................................ 54 
10.5 
ENHANCED LIVER FIBROSIS (ELF) ...................................................................................................... 54 
10.6 
EXPLORATORY BIOMARKERS ............................................................................................................. 54 
11 
SAFETY ASSESSMENTS .............................................................................................................. 54 
11.1 
ADVERSE EVENTS ............................................................................................................................ 54 
11.2 
PHYSICAL EXAMINATION .................................................................................................................. 54 
11.3 
OPHTHALMOLOGIC EXAMINATION ..................................................................................................... 55 
11.4 
VITAL SIGNS ................................................................................................................................... 55 
11.5 
CLINICAL LABORATORY TESTS ............................................................................................................ 56 
11.6 
12-LEAD ELECTROCARDIOGRAM ........................................................................................................ 57 
11.7 
ADVERSE EVENTS ............................................................................................................................ 57 
11.7.1 
Definitions .......................................................................................................................... 57 
11.7.2 
Collection and Rating of Adverse Events ........................................................................... 58 
11.7.3 
Adverse Event Follow-up ................................................................................................... 59 


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11.8 
SERIOUS AND OTHER SIGNIFICANT ADVERSE EVENTS ............................................................................ 60 
11.8.1 
Definition of a Serious Adverse Event ................................................................................ 60 
11.8.2 
Serious Adverse Event Reporting by the Investigator to the Sponsor ............................... 61 
11.8.3 
Handling of Follow-up Information ................................................................................... 61 
11.8.4 
Reporting and Follow-up of Pregnancy ............................................................................. 61 
11.8.5 
Expedited Reporting of Serious Adverse Events ................................................................ 62 
12 
STATISTICAL METHODS ............................................................................................................ 62 
12.1 
GENERAL OVERVIEW OF THE STATISTICAL ANALYSIS PLAN ..................................................................... 62 
12.2 
SAMPLE SIZE DETERMINATION .......................................................................................................... 63 
12.3 
DATA ANALYSIS .............................................................................................................................. 63 
12.3.1 
Analysis Populations .......................................................................................................... 63 
12.3.2 
Efficacy Analysis ................................................................................................................. 63 
12.3.3 
Pharmacodynamic Analysis ............................................................................................... 64 
12.3.4 
Safety Analysis ................................................................................................................... 64 
12.3.5 
Pharmacokinetic Analysis .................................................................................................. 64 
12.3.6 
Pharmacokinetic/Pharmacodynamic Analyses ................................................................. 64 
12.4 
MISSING, UNUSED AND SPURIOUS DATA ............................................................................................ 65 
13 
STUDY MANAGEMENT ............................................................................................................. 65 
13.1 
PROTOCOL AMENDMENT AND PROTOCOL DEVIATION........................................................................... 65 
13.1.1 
Protocol Amendment ......................................................................................................... 65 
13.1.2 
Protocol Deviations ............................................................................................................ 65 
13.1.3 
Protocol Waivers ................................................................................................................ 65 
13.2 
ETHICS AND REGULATORY ASPECTS .................................................................................................... 65 
13.2.1 
Ethical Conduct of the Study and Regulatory Guidelines .................................................. 65 
13.2.2 
Institutional Review Board and Regulatory Approval ....................................................... 66 
13.2.3 
Subject Informed Consent .................................................................................................. 66 
13.3 
END OF STUDY AND REGULATORY NOTIFICATION ................................................................................. 66 
13.4 
DATA PROTECTION AND CONFIDENTIALITY .......................................................................................... 67 


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13.5 
MONITORING ................................................................................................................................. 67 
13.6 
QUALITY ASSURANCE AND QUALITY CONTROL ..................................................................................... 67 
13.7 
SOURCE DATA ................................................................................................................................ 67 
14 
DATA AND RECORD KEEPING .................................................................................................... 68 
14.1 
CASE REPORT FORMS ...................................................................................................................... 68 
14.2 
RECORD KEEPING ............................................................................................................................ 68 
15 
FINANCING AND INSURANCE .................................................................................................... 68 
16 
USE OF DATA AND PUBLICATION POLICY .................................................................................. 68 
17 
REFERENCES ............................................................................................................................ 69 
18 
APPENDICES ............................................................................................................................ 71 
APPENDIX A:  AUDIT QUESTIONS AND SCORING SYSTEM .................................................................. 71 
APPENDIX B: DRUGS WITH KNOWN RISK OF TORSADE DES POINTES ................................................. 73 
APPENDIX C:  ALGORITHM FOR MONITORING AND MANAGEMENT OF POSSIBLE HEPATOCELLULAR 
DILI IN PHASE 2 OR 3 NASH CLINICAL STUDIES .................................................................................. 78 
 
 
 


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GLOSSARY OF TERMS AND ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
AUC 
Area under the concentration – time curve 
AUDIT 
Alcohol Use Disorders Identification Test  
BMI 
Body mass index (kg/m2) 
BUN 
Blood urea nitrogen 
C 
Celsius 
CAP 
Controlled attenuation parameter score 
CBD 
Cannabidiol 
CI  
Confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum observed plasma drug concentration 
Css 
Steady state concentration 
COPD 
Chronic obstructive pulmonary disease 
CPK 
Creatine phosphokinase 
CRA 
Clinical research associate 
CV 
Coefficient of variation 
DILI 
Drug induced liver injury 
dL 
Deciliter 
DNP 
2,4-dinitrophenol 
ECG 
Electrocardiogram 
eCRFs 
Electronic case report forms 
eGFR 
Estimated glomerular filtration rate 
ELF 
Enhanced liver fibrosis 
F 
Fahrenheit 
FAS 
Full analysis set 


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Abbreviation 
Description 
FFA 
Free fatty acid 
FSH 
Follicle stimulating hormone 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLP 
Good Laboratory Practices 
GLP1 
Glucagon-like peptide 1  
h 
Hour(s) 
HbA1c 
Glycosylated hemoglobin (hemoglobin A1c) 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HCVab 
Hepatitis C virus antibody 
HDL 
High-density lipoprotein 
HDPE 
High-density polyethylene 
HIV 
Human immunodeficiency virus 
HOMA-IR 
Homeostatic Model Assessment for Insulin Resistance 
HPMC 
Hydroxypropyl methylcellulose 
hs-CRP 
High sensitivity C-reactive protein 
IC 
Indirect calorimetry 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous 
kg 
Kilogram 
LFTs 
Liver function tests 
LDL 
Low-density lipoprotein 
LSM 
Least square mean 
MAD 
Multiple ascending dose 
MCHC 
Mean corpuscular hemoglobin concentration 


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Abbreviation 
Description 
MCV 
Mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model for repeated measures 
MRI 
Magnetic resonance imaging  
MRI-PDFF 
Magnetic resonance imaging proton density fat fraction 
NAFLD 
Nonalcoholic fatty liver disease  
NASH 
Nonalcoholic steatohepatitis 
OCT 
Optical coherence tomography 
OHS 
Obesity hypoventilation syndrome  
OSA 
Obstructive sleep apnea  
OWL 
One Way Liver 
PCP 
Phencyclidine  
PD 
Pharmacodynamic(s) 
PEth 
Phosphatidylethanol  
PIIINP 
Procollagen III amino-terminal peptide 
PK 
Pharmacokinetic(s) 
PPK 
Population pharmacokinetic(s) 
QD 
Once daily 
QTcF 
QT interval corrected for heart rate using Fridericia cubed root formula 
RMR 
Resting metabolic rate 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SGLT2 
Sodium-glucose cotransporter-2 
SOC 
System organ class 
SomaScan 
Slow off-rate modified aptamer  
T4 
Thyroxine 
TdP 
Torsades de pointes 
TIMP-1 
Tissue inhibitor of matrix metalloproteinase 1    
Tmax 
Time to peak plasma concentration 
TSH 
Thyroid stimulating hormone 


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Abbreviation 
Description 
TZD 
Thiazolidinediones 
UA 
Urinalysis 
ULN 
Upper limit of normal 
VCTE 
Vibration-controlled transient elastography  
VLDL 
Very low-density lipoproteins 
WHO 
World Health Organization 
 
3 INTRODUCTION 
Omitted.  
4 STUDY OBJECTIVES 
4.1 
Primary Objectives 
Efficacy:  
 
To evaluate the reduction in liver fat content, as assessed by magnetic resonance imaging proton 
density fat fraction (MRI-PDFF) from baseline to Day 61 in subjects with elevated BMI treated 
with HU6 compared to placebo.  
Safety:  
 
To evaluate safety and tolerability of 61 days of repeated daily dosing of HU6 in overweight and 
obese subjects as defined by BMI. 
4.2 
Secondary Objectives 
 
To assess the rate and amount of body weight loss after 61 days of HU6 treatment. 
 
To assess change from baseline in whole body adiposity by MRI after 61 days of HU6 treatment.  
 
To characterize the PK profile of HU6 and its metabolites, DNP and M1, over 61 days of dosing 
in subjects with high BMI. 
 
To evaluate and correlate changes from baseline in measures of liver composition with changes in 
liver fat content after dosing with HU6. 
 
To investigate the pharmacodynamic (PD) effects of HU6 on metabolic and cardiovascular risk 
factors. 
 
To investigate the PD effects of HU6 on metabolomic, proteomic, and lipidomic profiles. 
 
To characterize the dose/exposure relationships of the efficacy and PD effects of HU6, as data 
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5 STUDY TYPE AND DESIGN 
5.1 
Study Type 
This is a Phase 2a, randomized, parallel-group, placebo-controlled, double-blind, repeated-dose study. 
5.2 
Endpoints 
5.2.1 
Primary Endpoint 
 
Relative change from baseline in liver fat content, as assessed by MRI-PDFF at Day 61. 
5.2.2 
Secondary Endpoints 
Pharmacodynamics 
 
Change from baseline in body weight at Day 61. 
 
Change from baseline in whole body adiposity at Day 61. 
 
Changes from baseline in surrogate measures of liver inflammation and fibrosis at Day 61: 
Fibroscan® Vibration-controlled Transient Elastography (VCTE), Fibroscan® Controlled 
Attenuation Parameter (CAP) score, and Enhanced Liver Fibrosis (ELF) score. 
 
Change from baseline in lipid parameters and cardiovascular risk biomarkers at Day 61: serum high 
sensitivity C-reactive protein (hs-CRP), Lp(A), Apo B, low-density lipoprotein (LDL), 
high-density lipoprotein (HDL), total cholesterol, triglycerides, and free fatty acids (FFA). 
 
Change from baseline in metabolic disease parameters at Day 61: homeostatic model assessment 
for insulin resistance (HOMA-IR), fasting blood glucose concentrations, glycated albumin 
concentrations, HbA1c. 
Safety and Tolerability 
 
Summary of physical examinations findings over the course of the study. 
 
Adverse event (AE) assessment over the course of the study. 
 
Assessment of vital sign parameters over the course of the study. Parameters to include resting 
systolic and diastolic blood pressures, resting heart rates, resting respiratory rates, and oral body 
temperatures. 
 
Assessment of body weight over the course of the study. 
 
Safety 12-lead ECGs over the course of the study. 
 
Assessment of clinical laboratory values (hematology, full biochemistry panel (including lipid 
panel, CPK, magnesium, liver function tests) and urinalysis (UA) over 61 days of dosing. 
 
Assessment of ophthalmologic examination, including slit lamp, prior to and after 61 days of 
dosing. 
Pharmacokinetics 


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 
Population PK analysis of HU6 parent and metabolites, DNP and M1. The following PK parameters 
will be estimated as appropriate: Cmax, Tmax, t½, Tlag, AUC0-t, AUC0-∞, CL/F, Vd/F, λz. Other PK 
parameters may be calculated, as data allow and appropriate. 
 
As data permit, noncompartmental analysis of HU6 parent and metabolites, DNP and M1. The 
following PK parameters will be calculated: Cmax, AUC, and accumulation. 
 
Modeling of exposure response relationships of HU6, DNP and M1 and efficacy/pharmacodynamic 
endpoints, as appropriate. 
5.2.3 
Exploratory Endpoints 
 
Change from baseline in metabolomic and lipidomic profiles (One Way Liver-[OWL] metabolomic 
and lipidomic assays) at Day 61. 
 
Change from baseline in proteomic profiles (SomaScan®) at Day 61. 
 
Change from baseline in serum alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) concentrations at Day 61, as data allow. 
5.3 
Study Design 
This is a Phase 2a, randomized, parallel-group, placebo-controlled, double-blind, repeated-dose study to 
evaluate the safety and efficacy of three oral dose levels of HU6 compared to placebo over the course of 
61 days in subjects with high BMI and evidence of elevated liver fat. 
Subjects will be screened over a 45 day period to determine their eligibility based on specific history, 
physical, laboratory and imaging evaluations as per the Schedule of Assessments (Section 8.1). Due to 
scheduling of the procedures, multiple visits will likely be necessary to complete the screening process. 
However, if all screening assessments and procedures, including the MRI, can be completed within 30 
days of the first dose, then a single screening visit is permissible (see Section 8.2.1).  
Once qualified, patients will be randomly assigned to one of the HU6 treatment groups or the matched 
placebo control group and dosed once daily (fasting) for a total of 61 days. Subjects will return to the 
clinic for frequent assessment visits during the 61 days of dosing. A follow-up visit will occur within 10 
to 14 days following the completion of dosing ( 
 


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Figure 1). 
 
 


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Figure 1: 
 
Study Schematic 
 
 
Subjects will be instructed to maintain their same diet and activity/exercise level throughout the study as 
they had prior to participation in the study.  
Dosing will take place once daily in a fasted state. Eligible subjects will be randomized equally (N = 20 
per group) to 1 of 4 treatment groups: 
 
Group 1: matched placebo orally once daily for 61 days.  
 
Group 2: 150 mg HU6 orally once daily for 61 days. 
 
Group 3: 300 mg HU6 orally once daily for 61 days.  
 
Group 4: 450 mg HU6 orally once daily for 61 days. 
The randomization will be blocked and stratified by HbA1c (normal range versus between 5.7% and 9.0% 
inclusive). 
5.4 
Study Duration 
For an individual subject, the study will last approximately 120 days (up to 45 days for screening, 61 days 
of dosing, up to 14 days for final visit after dosing completion.  
The entire study is estimated to last approximately 5 months: first subject in May 2021 with last subject 
anticipated being completed in September 2021.  
-45 to -3 Days
Screening / Visit 1
Dosing 
Starts 
Day 1
Baseline / Visit 2
Placebo QD (n = 20)
150 mg QD (n = 20) 
300 mg QD (n =20) 
450 mg QD (n = 20) 
Day 61
End of 
Treatment
Day 71 -
75
Follow up
10 Visits, Screening, Baseline/ First dose, Day 2, Day 7, Day 14, Day 28, Day 42,
Day 49, Day 61 / end of treatment, and Follow up at Day 71 – 75.
Visit procedures include PK and PD measures and safety assessments.


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6 STUDY DRUG 
6.1 
Supply and Storage 
Study drug will be supplied to the clinic as bulk capsules in a polyethylene bag contained in high-density 
polyethylene (HDPE) secondary container. The study drug is prepared by filling 150 mg of HU6 in a size 
00 HPMC capsule. Bulk drug product should be stored at controlled room temperature in the original 
container.  
Doses will be dispensed to each subject during dispensation visits in a ‘pill organizer’ with the 
appropriate pharmacy label that will include the subject’s study number. The pill organizers containing 
the study drug should be stored at controlled room temperature, away from direct light.  
Bulk matching placebo capsules (each size 00 HPMC capsule containing 150 mg of mannitol) will be 
supplied. The unblinded pharmacist will prepare placebo capsules in the same method as for the active 
study product. 
The unblinded pharmacist will prepare study drug such that the double-blind is maintained.  
Refer to the Pharmacy Manual for more information about study drug preparation and dispensing.  
6.2 
Administration 
6.2.1 
Dosing Instructions 
At Visit 2, clinical personnel will train subjects on dosing procedures. On Days 1-61, study drug will be 
administered once a daily in the morning after a minimum 8-hour overnight fast.  
Study drug will be administered in-clinic during each on-treatment study visit (Visits 2 through 9). 
Subjects should not take their dose of study drug at home on these mornings. Subjects should present to 
the clinic in the fasted state. Predose assessments will be conducted, and subjects will be dosed by clinical 
personnel during the on-treatment study visits. Subjects will remain fasted (from food and drink other 
than water) for at least 1-hour postdose. Capsules will be swallowed with approximately 240 mL (8 fluid 
ounces) of room temperature water.  
On all other dosing days, subjects will take their assigned dose of study drug at home in the fasted state 
(minimum 8-hour fast), and subjects should remain fasted from food until at least 1-hour postdose. Clear 
liquids are permitted.  
Study drug will be dispensed at Study Visits 3 through 8. Each subject will receive supply of study drug 
at each dispensing visit to be used until the next visit. Refer to the Study Procedures Manual for more 
information about study drug dispensing. 
6.2.2 
Daily Dosing Log 
On each dosing day, subjects will be asked to complete a daily dosing log. Subjects will be instructed in 
the use of a thermometer to document body temperature, and subjects will be trained on daily completion 
of the log. Subjects will complete the log on each dosing day to document daily dosing, body 
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with them to their study visits. The clinic staff should review the data in the log with the subject. The 
thermometer also will have recorded temperatures for the preceding 9 days and should be reviewed by the 
study coordinator with the subject. 
The log will ask for information such as: 
 
Date 
 
Did you take your dose of study drug this morning? (Yes/No) 
 
What is your body temperature? 
 
In the last 24 hours prior to this morning’s dose, did you eat Less/Same/More than you normally 
do? 
The purpose of the Daily Log is help ensure and reinforce compliance to subject instructions as a result of 
the review and discussion with the study coordinator. Individual results are not to be entered into the case 
record form (CRF). An AE that is identified by the review and discussion of the log with the subject 
should be documented appropriately (Section 11.7). 
6.2.3 
Compliance 
Subjects will be instructed to bring any used (empty bottles), partially used, or unopened bottles to each 
study visit. During the study, the clinic staff will monitor adherence by counting capsules at each visit and 
by evaluating the daily dosing log. Clinic staff will reinforce compliance with study procedures and 
troubleshoot any problem that may be influencing treatment adherence. Should there be consistently poor 
compliance with dosing, despite attempts to help the subject comply, there should be a discussion with 
the medical monitor to determine next steps. 
6.3 
Packaging and Labeling 
Study drug will be supplied to the clinic as bulk powder in a polyethylene bag contained in an HDPE 
container. 
 
The label on the bulk product will contain the following information in the English language: 
 
Protocol number: RIV-HU6-203 
 
Expiration date 
 
Lot number  
 
Contents 
 
Weight 
 
Storage conditions 
 
The sentence, Caution: New Drug Limited by Federal (US) Law to Investigational Use 
 
Name of the Investigator 
 
Name, address, and telephone number of the Sponsor. 


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6.4 
Accountability 
The Investigator or their appointed designee is responsible for ensuring that deliveries of study drug are 
correctly dispensed and recorded, that the product is handled and stored safely and properly, and that it is 
only being given to subjects in accordance with this protocol.  
Sites will keep a current log of drug accountability recording:  
 
Study drug supply received from the Sponsor. 
 
Study drug supply dispensed to each subject. 
 
Study drug supply currently in inventory. 
 
Study drug supply destroyed or returned to the Sponsor (or third party) for destruction. 
Note: Drug accountability is the responsibility of the Investigator; a written account will be required for 
all discrepancies. 
The Sponsor’s designated Monitor must verify all accountability records during periodic monitoring 
visits. Unused and used study drug must be stored on site until such accountability has taken place and 
authorization is received from the Sponsor or Sponsor’s designee that the study drug may be returned or 
destroyed. 
6.5 
Overdose/Toxicity Management 
No specific pharmacologic antagonist or antidote exists for HU6. Therefore, overdose or clinical toxicity 
should be managed with supportive care and pharmacologic treatments directed at specific symptoms (i.e. 
benzodiazepines for agitation or antipyretics for fever.)  
Should an overdose occur in the clinic which may impose on the subject significantly higher 
pharmacologic levels than have previously been studied, the subject (at the discretion of the PI or medical 
monitor) may be more intensively monitoring, including but not limited to continuous telemetry. Should 
prolongation of QTc interval be seen in excess of 500 msec, the subject should be placed on continuous 
telemetry until the interval returns to less than or equal to 500 msec. 
6.6 
Blinding and Randomization  
This is a double-blind, placebo-controlled study. The subjects, clinical personnel, and Sponsor personnel 
will be blinded. Only in the case of an emergency, when knowledge of the investigational product is 
essential for the clinical management or welfare of the subject, may the investigator unblind a subject’s 
treatment assignment. 
The investigator will, whenever possible, discuss options with the Medical Monitor, or appropriate 
Sponsor study personnel before unblinding. If the blind is broken for any reason before the investigator is 
able to contact the Medical Monitor or Sponsor, the investigator must notify the Medical Monitor or 
Sponsor as soon as possible following the unblinding incident without revealing the subject’s study 
treatment assignment, unless the information is important to the safety of subjects remaining in the study. 
In addition, the investigator will record the date, time and reason for revealing the blinded treatment 
assignment for that subject. 


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If a serious adverse event (SAE; as defined in Section 11.8.1) is reported to the Medical Monitor or 
Sponsor and unblinding is agreed upon, the Investigator may unblind the treatment assignment for the 
individual subject. If an expedited regulatory report to one or more regulatory agencies is required, the 
report will identify the subject’s treatment assignment. When applicable, a copy of the regulatory report 
may be sent to investigators in accordance with relevant regulations, Sponsor policy, or both. 
Study drug will consist of HU6 and a matching placebo. The placebo will be identical in appearance to 
the active HU6. An unblinded pharmacist (or designee) at the study site will prepare medication before 
use according to instructions provided separately. The pharmacist will be required to maintain the blind, 
and the pharmacist will not otherwise participate in this study. 
Treatment assignments will be based on a computer-generated randomization code provided by unblinded 
statistician. Sponsor personnel, including those involved in monitoring, data management, and data 
analysis, will not have access to the treatment codes during the trial. Access to the treatment codes will be 
restricted to personnel charged with generating and maintaining randomization files, preparing study 
drug, analyzing plasma concentrations, and reporting SAEs to regulatory agencies.  
Once a randomization assignment has been made for a subject, it must not be reassigned. 
7 STUDY POPULATION 
7.1 
Number of Subjects 
Assuming 15% drop-out rate, approximately 80 subjects will be randomized to achieve 68 evaluable 
subjects. 
7.2 
Inclusion Criteria 
Subjects must meet all the following inclusion criteria to be eligible: 
1. Adult male or females, 28 to 65 years of age (inclusive) at the time of informed consent with BMI 
between 28.0 and 45.0 kg/m2 (inclusive). 
a. Female subjects of childbearing potential must be non-lactating, not pregnant as confirmed by 
a negative urine pregnancy test at Screening and agree to continue using an effective method 
of contraception for at least 4 weeks or barrier method for 2 weeks prior to first study drug 
administration until 30 days after the last dose of study drug (Section 8.3.2).  
b. Female subjects of childbearing potential must not donate ova during the study and for at 
least 30 days after the last dose of study drug. 
c. Female subjects of non-childbearing potential must be surgically sterile (e.g., hysterectomy, 
bilateral tubal ligation, oophorectomy) or postmenopausal (no menses for >1 year with 
follicle stimulating hormone (FSH) >40 U/L at Screening). 
d. Male subjects who have not had a vasectomy and/or subjects who have had a vasectomy but 
have not had 2 post surgery negative tests for sperm must agree to use an acceptable method 
of contraception from time of first dose of study drug until 30 days after the last dose of the 


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study drug, and to not donate sperm during the study and for at least 30 days after the last 
dose of study drug. 
2. Inclusion as per investigator assessment of general medical status and as documented by medical 
history, physical examination, vital sign assessments, 12-lead ECG, clinical laboratory assessments, 
and general observations. 
a. Subjects must be on stable doses of medications for underlying obesity-related conditions for 
at least 2 months prior to screening. 
b. Subjects with diabetes may be treated with metformin, DPP-4 inhibitors, or sulfonylureas, but 
must be on stable doses for at least 2 months prior to screening. 
c. At Screening, certain laboratory values may be outside the reference range if commensurate 
with the underlying obesity or associated metabolic dysfunction in the eligible subject (for 
example, dyslipidemia and hyperglycemia), unless these abnormalities suggest an underlying 
condition which may impact subject safety in the trial or interfere with the evaluation of HU6 
or affect interpretation of the study results. 
d. Abnormalities or deviations outside the normal ranges for other assessments that are 
considered clinically significant by the Investigator (clinical laboratory tests, ECG, vital 
signs, physical examination) may be repeated once at the discretion of the Investigator(s). 
Results that continue to be outside the normal ranges must be judged by the investigator to be 
not clinically significant and acceptable for study participation.  
e. Subjects with elevation of unconjugated bilirubin due to presumptive Gilbert’s syndrome are 
permissible.  
f. Subject must be euthyroid as assessed by a thyroid profile utilizing thyroid stimulating 
hormone (TSH) and free thyroxine (T4) testing at screening. Subjects with a stable history of 
thyroid disease and who have been on stable doses of thyroid medications for a minimum of 
4 months can be enrolled. 
3. Fibroscan® CAP score>300 dB/m.  If the score is between >270 to 300 dB/m, it may be approved 
after discussions between the PI and Medical Monitor. 
4. ≥8% liver fat by MRI-PDFF. 
5. Understands the procedures and requirements of the study and provides written informed consent and 
authorization for protected health information disclosure. 
6. Willing and able to comply with the requirements of the study protocol. 
7.3 
Exclusion Criteria 
Subjects will be excluded from the study if any of the following criteria are met: 
1. Insulin-controlled diabetes. 
2. Pregnant or breastfeeding or plans to become pregnant. 


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3. Intolerance to Magnetic Resonance Imaging (MRI) or with conditions contraindicated for MRI 
procedures including but not limited to inability to fit into MRI scanner or surgical clips/metallic 
implants/shrapnel. Subjects must not be claustrophobic, have a history of claustrophobia, or 
intolerance of closed or small spaces. 
4. Weight gain or loss >5% in 3 months prior to study or >10% in 6 months prior to screening.  
5. History of lap banding, intragastric balloon, duodenal-jejunal sleeve, or bariatric surgery within 
5 years of screening, plans for bariatric surgery prior to conclusion of study participation, or plans to 
lose weight during this study either through a special diet, exercise program or both. Subjects 
currently maintained on a special diet or exercise program must be willing to discontinue that 
program for 30 days prior to Day 1 and throughout the duration of the study.  
6. History of malignant hyperthermia. 
7. History of chronic serious recurrent skin rashes of unknown cause. 
8. History of or current clinically significant cardiovascular disease including but not limited to transient 
ischemic attack, stroke, cardiac arrhythmias, syncope, unstable angina, myocardial infarction in the 6 
months prior to screening, congestive heart failure, or uncontrolled hypertension. (Uncontrolled 
hypertension is defined as a systolic blood pressure ≥160 mmHg or a diastolic blood pressure ≥100 
mmHg).  
9. Resting heart rate <45 or >110 bpm. 
10. On screening ECG or by history: 
a. A marked baseline prolongation of QT/QTcF interval (e.g., repeated demonstration of a QTcF 
interval > 450 msec for males and >470 msec for females). 
b. A history of additional risk factors for Torsades de Pointes (TdP) (e.g., heart failure, 
hypokalemia, family history of Long QT Syndrome) or a family history of sudden cardiac death 
of unknown origin. 
11. Kidney disease, kidney transplant, or estimated glomerular filtration rate 
(eGFR) <50 mL/min/1.73 m2 based on the CKD-EPI Creatinine Equation (NKF 2009; 
https://www.kidney.org/content/ckd-epi-creatinine-equation-2009). 
12. Significant lung disease requiring chronic daily medication including chronic obstructive pulmonary 
disease (COPD), emphysema, pulmonary fibrosis, or asthma.  Documented well-controlled asthma is 
allowed. 
13. Untreated obesity hypoventilation syndrome (OHS) or obstructive sleep apnea (OSA). 
14. History of or active (acute or chronic) liver disease other than nonalcoholic fatty liver disease 
(NAFLD)/ nonalcoholic steatohepatitis (NASH), such as but not limited to autoimmune liver disease, 
viral hepatitis, genetic hemochromatosis, primary biliary cirrhosis, Wilson disease, alpha-1-
antitrypsin deficiency, alcohol liver disease, acute fatty liver of pregnancy or drug- induced (including 
acetaminophen) liver disease. 


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15. History of or treatment for clinically significant gastroparesis, inflammatory bowel disease, or any 
surgery of the upper gastrointestinal tract with the exception of cholecystectomy, or minor gastric 
procedures that are approved by the medical monitor. 
16. History of cirrhosis and/or hepatic decompensation, including ascites, hepatic encephalopathy, or 
variceal bleeding. 
17. History of acute pancreatitis within one year of screening or chronic pancreatitis of any cause. 
18. Serum triglyceride concentrations exceeding 500 mg/dL. 
19. HbA1c >9.0%.  
20. Familial (mother/father/sibling) and/or personal history of spontaneous retinal detachment any time 
in the past. 
21. Any history of or current diagnosis of Glaucoma. 
22. Evidence of the following on screening ophthalmologic examination: 
a. Peripheral retinal pathology requiring treatment, retinal tears, or lattice that require 
treatment. 
b. Diabetic retinopathy with macula exudates or macula edema as shown by optical 
coherence tomography (OCT) and examination. 
c. Any active macular disease that affects the vision, including macula pucker (epiretinal 
membrane) and macular degeneration. 
d. Visually significant cataract as determined by ophthalmologist. 
e. Any previous intravitreal injection of anti-VEGF agents for macular degeneration. 
f. History of prior vitrectomy. 
23. History of malignant neoplasms within 5 years of screening, except for basal cell or squamous cell 
skin cancer, cervical carcinoma in situ, or prostate cancer that is not currently or expected to require 
radiation therapy, chemotherapy and/or surgical interventions or to initiate hormonal treatment. 
24. History of organ transplantation. 
25. Received a COVID-19 vaccine less than 1 week prior to dosing (Visit 2 / Day 1) and/or plans to 
receive a COVID-19 vaccine during the study period. 
26. History of significant drug abuse within one year prior to Screening or frequent use of soft drugs 
(such as marijuana) within 3 months prior to the Screening visit, or hard drugs (such as cocaine, 
phencyclidine [PCP], opioid derivatives including heroin, and amphetamine derivatives) within 
1 year prior to screening. 
27. History of alcoholism in the last 2 years  or current evidence of excessive alcohol consumption as 
assessed by screening evaluation using the Alcohol Use Disorders Identification Test (AUDIT, 
Thompson 2018 [Appendix A]), and history of regular alcohol consumption exceeding 
approximately 14 drinks/week for men and 7 drinks/week for women [1 drink = 4 ounces (120 mL) 


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of wine or 12 ounces (360 mL) of beer or 1 ounce (30 mL) of hard liquor] within 6 months of 
Screening, as determined by the Investigator.  
28. Positive urine drug screen for drugs of abuse or positive phosphatidylethanol (PEth) blood test result 
>200 ng/mL based on tPEth 16.0/18.1 (POPEth) at Screening. In instances of an exclusionary PEth 
value, consideration for enrollment can be provided if the principal investigator and medical monitor 
agree the subject’s history is not consistent with alcohol abuse.  Subjects with a positive drug screen 
due to an approved medication may be allowed on a case-by-case basis by the Investigator in 
consultation with the medical monitor. 
29. Current regular vaping or more than 10 cigarettes or the equivalent per week. Use of nicotine patches 
for smoking cessation is permitted. 
30. Positive test results of hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), or 
human immunodeficiency virus (HIV1/2) antibody. 
31.  Neutropenia, defined as absolute neutrophil count ≤1000/μL. 
32. Serum AST or ALT >5 x upper limit of normal (ULN) at screening. (One repeat test may be allowed 
within 7 days at the discretion of the Investigator). 
33. Total bilirubin > ULN, unless due to Gilbert’s syndrome or if considered normal variability in the 
absence of other clinically relevant liver impairment as approved by Medical Monitor.  
34. International normalized ratio (INR) ≥1.3 at screening if there is other evidence of potential 
significant liver impairment. 
35. Participation in another clinical trial at the time of screening or exposure to any investigational 
agent, including topical, within 30 days of screening or 5 half-lives, if half-life known. 
36. No tattoo or body piercings during the course of the study. Any underlying physical or psychological 
medical condition that, in the opinion of the Investigator or sponsor, would make it unlikely that the 
subject is able comply with the study requirements or would be unable to complete the study.  
37. Any condition that the investigator believes would interfere with his/her ability to provide written 
informed consent, comply with study instructions, or which might confound the interpretation of the 
study results or put the subject at undue risk.  
38.  Known or potential hypersensitivity to HU6 or its excipients. 
Prohibited Medications (Current Use): 
39. Any herbal supplement, over the counter drug, mail order or prescription drug for weight loss. 
40. Prescription or over the counter stimulants including: dextroamphetamine/Dexedrine, 
dextroamphetamine/amphetamine combination product/Adderall, or methylphenidate (Ritalin®, 
Concerta®). 
41. Thiazolidinediones (TZD): pioglitazone/Actos, rosiglitazone/Avandia. 
42. Glucagon-like peptide 1 (GLP1) agonists: exenatide/Byetta/Bydureon, lixisenatide/Adlyxin, 
liraglutide/Victoza, dulaglutide/Trulicity, semaglutide/Ozempic. 


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43. Sodium-glucose cotransporter-2 (SGLT2) inhibitors: canagliflozin/Invokana, dapagliflozin/Farxiga, 
empagliflozin/Jardiance, ertugliflozin/Steglatro. 
44. Vitamin E: use of ursodiol or high dose vitamin E >400 IU/day for at least one month within in the 
last 6 months or started high dose vitamin E within last 3 months of screening. 
45. Recent (within 3 months of screening) or current use of obeticholic acid/Ocaliva, systemic 
corticosteroids, methotrexate, tamoxifen, amiodarone, or long-term use of tetracyclines. 
46. Warfarin, heparin, factor Xa inhibitors (dabigatran betrixaban edoxaban, apixaban, and 
rivaroxaban). 
47. Concomitant medications that prolong the QT/QTc interval and are known to be associated with 
increased risk of Torsade des pointes as identified in the https://crediblemeds.org/ website list 
category of ‘Known Risk’ (Appendix B).  For subjects on medications that are listed in Appendix 
B, approval must be obtained from the Sponsor and Medical Monitor. 
7.4 
Withdrawal of Subjects 
A subject may withdraw from the study at any time at his/her own request or may be withdrawn at any 
time at the discretion of the Investigator for safety, behavioral, or administrative reasons. 
Reasons for withdrawal (subjects who refuse to return for any remaining study visits) or discontinuation 
(subjects who prematurely stop the treatment) at any time during the study may include, but are not 
limited, to the following: 
1. Withdrawal of subject consent. 
2. Investigator determines that withdrawal from the study is in the best interest of the subject. 
3. Major protocol violation (i.e., circumstances where confounding conditions make it impossible to 
derive sound scientific or medical conclusions from the primary endpoint data generated on a 
subject).  
4. Any condition, injury, or disease that becomes apparent during the study and necessitates the 
termination of the subject from the study. 
5. The development of an elevated temperature is not a cause for withdrawal of HU6 alone. Should a 
subject develop a temperature > 100○F, they should be instructed to repeat the measurement 
approximately 15 minutes later. If the temperature continues to be elevated, the subject should be 
instructed to contact the investigational site to be evaluated by the investigator. They should not 
take HU6 nor any anti-pyretic (acetaminophen, aspirin, nonsteroidal anti-inflammatory drugs) prior 
to evaluation by the investigator. The investigator should assess the subject medically to ascertain 
the underlying cause of the elevated temperature. Appropriate laboratory tests, including those for 
COVID-19 or influenza, may be warranted to provide a diagnosis.  
a) Should the investigator be unable to identify the cause for the elevated temperature, but the 
subject’s body temperature has returned to normal, dosing with HU6 may be restarted based 
on the medical judgment of the investigator and in discussions with the medical monitor. 
Appropriate follow-up should take place once dosing re-starts.  


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b) Subjects with persistent temperature elevations after HU6 has been stopped for 3 days may be 
discontinued from the study to allow appropriate medical care, as medically indicated. 
Restarting dosing with HU6 in subjects who have not taken the drug for greater than 4 days 
should be discussed with the medical monitor, as their participation in the study will be 
discontinued.    
6. Increased liver function tests will be evaluated in accordance with the Consensus guidelines for best 
practices for the detection, assessment, and management of suspected acute drug-induced liver 
injury (DILI) during clinical trial in patients with nonalcoholic steatohepatitis which are applicable 
to the subjects being enrolled in this trial (Regev et al., 2018). Please see Appendix C for a table 
from that Consensus that shows the algorithm for monitoring and managing of hepatocellular DILI 
in phase 2-3 NASH clinical trials in patients with normal or elevated baseline ALT, as well as the 
listing of the Consensus and Recommendations. 
7. Administrative reason (e.g., termination of the clinical study by a Regulatory Agency or the 
Sponsor). 
8. Lost to follow-up. 
9. Pregnancy. 
7.4.1 
Follow-up Procedures for Subjects Who Withdraw Prematurely 
Subjects not completing the entire study should be fully evaluated when possible. All withdrawn subjects 
will be asked to report to the clinic for the Early Termination Visit within 2 weeks after their last dose of 
the study drug.  
Subjects with ongoing AEs or AEs believed to be at least possibly related to study medication will 
continue to be followed until resolution or for 30 days as warranted by the nature of the AE.  
The Investigator must make every attempt to follow-up on subjects who have withdrawn for any reason. 
When a subject is “lost to follow-up” (i.e., fails to return for study visits), a reasonable effort 
(3 documented phone calls or 2 phone calls and 2 text messages, on separate occasions, and a follow-up 
letter sent by registered mail) should be made to contact him/her to determine a reason for the failure to 
return. If the subject cannot be reached, they should be identified as “lost to follow-up” in the eCRF. 
7.4.2 
Procedures for Replacing Subjects Who Withdraw Prematurely 
A randomized subject who withdraws prior to first dose of study drug may be replaced after consultation 
with the Sponsor. This subject will be given the same treatment assignment (by the unblinded statistician) 
as the withdrawn subject. A randomized subject who withdraws from the study after initiation of study 
drug dosing will not be replaced. 
8 TREATMENT PLAN AND METHODS 
Study procedures should be completed as designated in the Schedule of Assessments (Section 8.1). 
However, if a participant is unable to attend a visit within a specified window, the Investigator (or 
qualified designee) should discuss appropriate scheduling with the Sponsor’s Medical Monitor. 


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Blood samples for HU6, DNP, and M1 PK are required for analysis of parameters and these samples 
should be collected as close to the protocol-defined times for sample collection as possible.  
Whenever 12-lead ECGs, routine vital sign measurements, and blood draws are scheduled for the same 
time, it is preferable (but not required) that these assessments occur in the following order: 12-lead ECGs, 
vital signs, and blood draws. The timing of the assessments should allow the blood draws to occur at the 
approximate nominal time. The actual date and time should be recorded for all procedures and the 
Investigator should make every effort to perform procedures at the nominal dates and times. However, 
unscheduled procedures required for the evaluation of safety concerns take precedence over all scheduled 
routine procedures. 
 
 


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8.1 
Schedule of Assessments 
 
Screeninga 
Treatment Visits 
Follow-
up 
Early Termination 
Visit 
 
Visit 1 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 9b 
Visit  
10 
Activity/Day 
Day-45 to -
3 
Day 1: 
Predose 
Day 1: 
Postdose 
Day 
2 
Day 
7 
Day 
14 
Day 
28 
Day 
42 
Day 
49 
Day 61b 
Day  
73 
< 28 
days of 
dosing 
≥ 28 days 
of dosing 
Visit Window 
 
 
 
 
±1 
±1 
±4 
±4 
±2 
variesb 
±2 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion Criteria  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Alcohol use assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood PEth Test 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
TSH and T4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum triglycerides 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c  
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Fibroscan 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
eGFR (CKD-EPI) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation (INR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serology: HIV, HBsAg, HCV Ab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
Urine Pregnancy test (female only) 
X 
X 
  
  
X 
X 
X 
X 
 
X 
X 
X 
 X 
Laboratory U/A (dipstick) 
X 
X 
  
  
  
  
X 
  
 
X 
X 
X 
 X 
Hematology Panel (CBC) 
X 
X 
  
  
  
  
X 
  
 
X 
X 
X 
X 
Serum chemistry (includes LFTs) 
X 
X 
  
  
  
  
X 
  
 
X 
X 
X 
X 


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Screeninga 
Treatment Visits 
Follow-
up 
Early Termination 
Visit 
 
Visit 1 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 9b 
Visit  
10 
Activity/Day 
Day-45 to -
3 
Day 1: 
Predose 
Day 1: 
Postdose 
Day 
2 
Day 
7 
Day 
14 
Day 
28 
Day 
42 
Day 
49 
Day 61b 
Day  
73 
< 28 
days of 
dosing 
≥ 28 days 
of dosing 
Visit Window 
 
 
 
 
±1 
±1 
±4 
±4 
±2 
variesb 
±2 
 
 
Ophthalmologic exam 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Vital signsc and weight (InBody 
scale) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MRI/MRI-PDFF 
Xd 
 
 
 
 
 
 
 
 
X 
 
 
X 
Complete physical (includes neuro 
exam: muscle strength) 
X 
 
 
 
 
 
 
 
 
X 
 
 
X  
Targeted physical (includes neuro 
exam: muscle strength) 
 
X 
 
 
 
X 
X 
X 
 
 
X 
X 
 
Glycated Albumin 
 
 X 
  
  
 
X 
X 
X 
 
X 
 
X 
X 
hs-CRP  
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
Lipid Panel (HDL, LDL, VLDL, FFA, 
cholesterol, triglycerides) 
 
X 
  
  
  
 
X 
 
 
X 
 
 
X 
ApoB and Lp(a) 
 
X 
  
  
  
 
X 
 
 
X 
 
 
X 
HOMA-IR: glucose, insulin, and C-
peptide (3 draws 5 minutes apart) 
  
X 
  
  
  
  
X 
  
 
X 
 
 
X 
OWLiver (Metabolomics) 
 
X 
  
  
  
  
X 
  
 
X 
 
 
X 
OWL (Lipidomics) 
 
X 
  
  
  
  
X 
  
 
X 
 
 
X 
Proteomic Profile (SomaScan) 
 
X 
  
  
  
  
X 
  
 
X 
 
 
X 


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Screeninga 
Treatment Visits 
Follow-
up 
Early Termination 
Visit 
 
Visit 1 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 9b 
Visit  
10 
Activity/Day 
Day-45 to -
3 
Day 1: 
Predose 
Day 1: 
Postdose 
Day 
2 
Day 
7 
Day 
14 
Day 
28 
Day 
42 
Day 
49 
Day 61b 
Day  
73 
< 28 
days of 
dosing 
≥ 28 days 
of dosing 
Visit Window 
 
 
 
 
±1 
±1 
±4 
±4 
±2 
variesb 
±2 
 
 
Enhanced Liver Fibrosis Assay 
(ELF) 
 
X  
  
  
  
 
  
 
 
X 
 
 
X 
Exploratory biomarker (Serum 
sample) 
 
X 
  
  
  
  
X 
  
 
X 
 
 
X 
Exploratory biomarker (Plasma 
sample) 
 
X 
  
  
  
  
X 
  
 
X 
 
 
X 
Plasma sampling for PKe 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Dispense study drug  
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Administer study drug 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense Daily Log (dosing, 
temperature, diet) 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Collect Daily Log  
(dosing, temperature, diet) 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
a. 
Subjects will be screened over a 45 day period to determine their eligibility based on specific history, physical, laboratory and imaging evaluations as per the Schedule of 
Assessments. Due to scheduling of the procedures, multiple visits will likely be necessary to complete the screening process. However, if all screening assessments and 
procedures can be completed within 30 days of first dose, then a single screening visit is permissible.  
b. 
Visit 9 may be split into a series of visits to complete all assessments. Please see Section 8.2.9. Administering study drug:  if the visit occurs on Day 61.  For those 
subjects whose visit occurs on Day 62, the last dose should be taken on Day 61, with no drug administered on Day 62. 
c. 
Vital signs (body temperature, systolic and diastolic blood pressure, heart rate, and respiration rate) conducted twice (predose and prior to discharge) on Days 1, 14, and 
28. Only predose vital sign assessments on other Treatment Visit Days.  
d. 
By exception, MRI must be 30 days prior to Day 1 dosing (see Section 8.2.1) 
e. 
PK Sampling: On Day 1, 14, and 28: predose, and approximately 2, 4, and 6 hours. On Days 2, 7, 42, and 61: predose sample. One sample during Visit 10 or Early 
Termination. 


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8.2 
Study Specific Procedures 
Below is a list of procedures per visit. The description for each assessment can be found in the specific 
sections.  
8.2.1 
Screening 
Subjects will be screened over a 45 day period to determine their eligibility based on specific history, 
physical, laboratory and imaging evaluations as per the Schedule of Assessments. Due to scheduling of 
the procedures, multiple visits will likely be necessary to complete the screening process. The screening 
assessments are outlined in Section 8.2.1.1 below. However, a single screening visit or amended 
screening visit schedule may be possible as follows: 
 
If all screening assessments and procedures can be completed within 30 days of first dose, then a 
single screening visit is permissible.  
 
The baseline MRI must be conducted within 30 days of Day 1 dosing.  
 
The Investigator may repeat vital signs, ECGs and laboratory tests once to verify results as based on 
clinical judgment at the time of the subject screening evaluation. 
8.2.1.1 
Visit 1 / Screening – (-45 days to -3 days) 
Screening assessments will occur within -45 to -3 days prior to Visit 2 / Day 1.  
The following procedures will be performed: 
 
Obtain signed Informed Consent Form. 
 
Measure and record vital signs and InBody Scale for weight (Section 11.3). 
 
Evaluate subject eligibility against study inclusion/exclusion criteria. 
 
Record demographics and ethnicity. 
 
Obtain medical history including medications. 
 
Alcohol use assessment (history; current consumption; AUDIT Score) (Appendix A). 
 
Perform single 12-lead ECG (Section 11.6). 
 
Draw and process blood samples for laboratory tests (Section 11.5): 
o Comprehensive metabolic panel (includes liver function tests [LFTs] as well as routine 
chemistry panel, glucose, CPK, magnesium)  
o Hematology (CBC) 
o Serology (HIV, HepB, HCV) 
o Coagulation (INR) 
o eGFR (CKD-EPI) 
 
Collect and process urine sample for laboratory tests (Section 11.5): 


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o Routine UA (dipstick) 
o Pregnancy test (female subjects) 
o Drug screen 
 
Perform complete physical examination including a neurological examination (Section 11.2). 
 
Draw blood for laboratory tests (Section 11.5): 
o PEth Test  
o Serum triglycerides concentration  
o HbA1c  
o TSH, T4 
 
Record concomitant medications. 
 
Record any AEs. 
If eligible, continue with the following screening assessments:  
 
Perform Fibroscan prior to MRI-PDFF to assess eligibility. (Section 10.3). 
 
Perform Ophthalmologic examination (Section 11.3). 
 
Perform MRI/MRI-PDFF (Section 10.1) with 30 days of Day 1 dosing 
If eligible, schedule subject to return to for the Visit 2 / Day 1 to initiate HU6 dosing. 
8.2.2 
Baseline Visit 2 / Day 1 
Subjects will have predose assessments at Visit 2 / Day 1 prior to administering the first dose of study 
drug. Subjects should present to this study visit in the fasted state (minimum 8-hour overnight fast). 
The following predose procedures/assessments will be conducted on Day 1: 
 
Confirm eligibility against study inclusion/exclusion criteria. 
 
Medical history to determine if any changes have occurred since the Screening visit was performed. 
 
Draw and process blood samples for laboratory tests (Section 11.5): 
o Hematology (CBC) 
o Comprehensive metabolic panel (includes LFT as well as routine chemistry panel; glucose, 
CPK, magnesium)  
o Glycated albumin  
o hs-CRP  
o Low-density lipoprotein (LDL), very low-density lipoproteins (VLDL), high-density 
lipoprotein (HDL), FFA, total cholesterol, and triglycerides. 
o ApoB and Lp(a) 
o HOMA-IR - includes glucose, insulin, and C-peptide  


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 
Collect and process urine sample for laboratory tests (Section 11.5): 
o Routine UA (dipstick) 
o Pregnancy test (female subjects) 
o Drug screen 
 
Draw and process blood samples for PD assessments: 
o OWL metabolomics and OWL lipidomics (Section 10.4) 
o SomaScan proteomics (Section 10.5)  
o ELF assay (Section 10.6) 
o Exploratory biomarkers (Section 10.7) 
 
Draw and process blood sample for PK (Section 9.1). 
 
Perform targeted physical examination including a neurological examination (Section 11.2). 
 
Perform 12-lead ECG (Section 11.6). 
 
Measure and record vital signs including the InBody scale (Section 11.3). 
 
Record AEs or changes in medications since the Screening visit. 
Administer study drug (Section 6.2.1) after completion of all predose assessments. Conduct the 
following postdose procedures/assessments: 
 
Draw and process blood samples for PK (Section 9.1) at approximately 2, 4, and 6 hours postdose. 
 
Measure and record vital signs (Section 11.3) prior to discharge. 
 
Record AEs and concomitant medications. 
8.2.3 
Visit 3 / Day 2  
Subjects should present to this study visit in the fasted state (minimum 8-hour overnight fast). 
The following predose procedures/assessments will be conducted on Day 2: 
 
Record AEs and concomitant medications. 
 
Measure and record vital signs including the InBody scale (Section 11.3). 
 
Collect and process blood sample for PK (Section 9.1). 
Administer study drug (Section 6.2.1) after completion of all predose assessments. Conduct the following 
postdose procedures/assessments: 
 
Record AEs and concomitant medications. 
 
Dispense study drug. 
 
Dispense Daily Dosing Log.  


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8.2.4 
Visit 4 / Day 7 (±1 day)   
Subjects should present to this study visit in the fasted state (minimum 8-hour overnight fast). 
The following predose procedures/assessments will be conducted: 
 
Collect and Review Daily Dosing Log. 
 
Measure and record vital signs including the InBody scale (Section 11.3). 
 
Perform 12-lead ECG (Section 11.6). 
 
Collect urine sample for pregnancy test (female subjects [Section 11.5]). 
 
Draw and process blood sample for PK (Section 9.1). 
 
Record AEs and concomitant medications. 
After completing predose assessments: 
 Administer study drug (Section 6.2.1) after completion of all predose assessments. 
 Dispense study drug.  
 Dispense Daily Dosing Log.  
8.2.5 
Visit 5 / Day 14 (±1 day)   
Subjects should present to this study visit in the fasted state (minimum 8-hour overnight fast). 
The following predose procedures/assessments will be conducted: 
 
Collect and Review Daily Dosing Log. 
 
Measure and record vital signs including the InBody scale (Section 11.3). 
 
Perform 12-lead ECG (Section 11.6). 
 
Record AEs and concomitant medications. 
 
Perform targeted physical examination including a neurological examination (Section 11.2). 
 
Collect urine sample for pregnancy test (female subjects [Section 11.5]). 
 
Draw and process blood sample for glycated albumin (Section 11.5). 
 
Draw and process blood sample for PK (Section 9.1). 
Administer study drug (Section 6.2.1) after completion of all predose assessments. Conduct the 
following postdose procedures/assessments: 
 
 Draw and process blood samples for PK (Section 9.1) at approximately 2, 4, and 6 hours postdose. 
 
Record AEs and concomitant medications. 
 
Measure and record vital signs (Section 11.3) prior to discharge.  
 
Dispense study drug.  
 
Dispense Daily Dosing Log.  


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8.2.6 
Visit 6 / Day 28 (±4 days)           
Subjects should present to this study visit in the fasted state (minimum 8-hour overnight fast). 
The following predose procedures/assessments will be conducted: 
 
Collect and Review Daily Dosing Log. 
 
Draw and process blood samples for laboratory tests (Section 11.5): 
o Hematology (CBC) 
o Comprehensive metabolic panel (includes LFT as well as routine chemistry panel; glucose, 
CPK, magnesium)  
o Glycated albumin  
o hs-CRP  
o LDL, VLDL, HDL, FFA, total cholesterol, and triglycerides 
o ApoB and Lp(a) 
o HOMA-IR - includes glucose, insulin, and C-peptide  
o PEth test 
 
Collect and process urine sample for laboratory tests (Section 11.5): 
o Routine UA (dipstick) 
o Pregnancy test (female subjects) 
o Drug screen 
 
Draw and process blood samples for PD assessments: 
o OWL metabolomics and OWL lipidomics (Section 10.4) 
o SomaScan proteomics (Section 10.5)  
o Exploratory biomarkers (Section 10.7) 
 
Draw and process blood sample for PK (Section 9.1).  
 
Perform targeted physical examination including a neurological examination (Section 11.2). 
 
Measure and record vital signs including the InBody scale (Section 11.3). 
 
Perform 12-lead ECG (Section 11.6). 
 
Record AEs and concomitant medications. 
Administer study drug (Section 6.2.1) after completion of all predose assessments. Conduct the 
following postdose procedures/assessments: 
 
Draw and process blood samples for PK (Section 9.1) at approximately 2, 4, and 6 hours postdose. 
 
Measure and record vital signs (Section 11.3) prior to discharge.  
 
Record AEs and concomitant medications. 


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 
Dispense study drug.  
 
Dispense Daily Dosing Log.  
8.2.7 
Visit 7 / Day 42 (±4 days)             
Subjects should present to this study visit in the fasted state (minimum 8-hour overnight fast). 
The following predose procedures/assessments will be conducted: 
 
Collect and Review Daily Dosing Log. 
 
Measure and record vital signs including the InBody scale (Section 11.3). 
 
Perform 12-lead ECG (Section 11.6). 
 
Record AEs and concomitant medications. 
 
Perform targeted physical examination including a neurological examination (Section 11.2). 
 
Collect urine sample for pregnancy test (female subjects [Section 11.5]). 
 
Draw and process blood sample for glycated albumin (Section 11.5). 
 
Draw and process blood sample for PK (Section 9.1). 
After completing predose assessments: 
 
Administer study drug (Section 6.2.1). 
 
Dispense study drug.  
 
Dispense Daily Dosing Log.  
8.2.8 
Visit 8 /Day 49 (±2 days)           
The following procedures will be conducted: 
 
Collect and Review Daily Dosing Log. 
 
Measure and record vital signs including the InBody scale (Section 11.3). 
 
Record AEs and concomitant medications. 
 
Administer study drug (Section 6.2.1). 
 
Dispense study drug. 
 
Dispense Daily Dosing Log.  
8.2.9 
Visit 9 / Day 61  
Visit 9 may be split into multiple visits to allow for conduct of all procedures and assessments. The 
allowable visit windows along with specific assessments/procedures to be conducted within these visit 
windows is detailed below.  
8.2.9.1 
Visit 9a / Day 61 (±1 day) 
On Study Day 61 (±1 day), the following assessments will be conducted:  


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Subjects should present to this study visit in the fasted state (minimum 8-hour overnight fast). 
The following predose procedures/assessments will be conducted: 
 
Collect and Review Daily Dosing Log. 
 
Draw and process blood samples for laboratory tests (Section 11.5): 
o Hematology (CBC) 
o Comprehensive metabolic panel (includes LFT as well as routine chemistry panel; glucose, 
CPK, magnesium)  
o HbA1c 
o Glycated albumin  
o hs-CRP  
o LDL, VLDL, HDL, FFA, total cholesterol, and triglycerides 
o ApoB and Lp(a) 
o HOMA-IR - includes glucose, insulin, and C-peptide  
 
Collect and process urine sample for laboratory tests (Section 11.5): 
o Routine UA (dipstick) 
o Pregnancy test (female subjects) 
o Drug screen 
 
Draw and process blood samples for PD assessments: 
o OWL metabolomics and OWL lipidomics (Section 10.4) 
o SomaScan proteomics (Section 10.5)  
o ELF assay (Section 10.6) 
o Exploratory biomarkers (Section 10.7) 
 
Draw and process blood sample for PK (Section 9.1). 
 
Perform complete physical examination including a neurological examination (Section 11.2). 
 
Measure and record vital signs including the InBody scale (Section 11.3). 
 
Perform 12-lead ECG (Section 11.6). 
 
Record AEs and concomitant medications. 
 
Administer study drug (Section 6.2.1) if the visit occurs on Day 61.  For those subjects whose visit 
occurs on Day 62, the last dose should be taken on Day 61, with no drug administered on Day 62. 
8.2.9.2 
Visit 9b / Day 61 (-4 days to + 1 day) 
 
Perform MRI/MRI-PDFF (Section 10.1). 


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8.2.9.3 
Visit 9c / Day 61 (-5 days to + 2 days) 
 
Perform Fibroscan (Section 10.3). 
8.2.9.4 
Visit 9d / Day 61 (-5 days to + 7 days) 
 
Perform Ophthalmologic examination (Section 11.3). 
8.2.10 
Visit 10/ Day 73 (±2 days)            
The following procedures will be conducted during the follow-up visit: 
 
Collect and process urine sample for laboratory tests (Section 11.5): 
o Routine UA (dipstick) 
o Pregnancy test (female subjects) 
 
Draw and process blood samples for laboratory tests (Section 11.5): 
o Hematology (CBC) 
o Comprehensive metabolic panel (includes LFT as well as routine chemistry panel; glucose, 
CPK, magnesium)  
 
Draw and process blood sample for PK (Section 9.1). 
 
Perform targeted physical examination including a neurological examination (Section 11.2). 
 
Measure and record vital signs including the InBody scale (Section 11.3). 
 
Perform 12-lead ECG (Section 11.6). 
 
Record AEs and concomitant medications. 
8.2.11 
Early Termination Visit   
The early termination visit assessments is based on whether the subject completed < 28 days or ≥ 28 days 
of treatment. Recognizing that subjects may refuse to complete all the assessments for early termination, 
the procedures have been arranged in the order of prioritization. 
For < 28 days of dosing, the following early termination visit procedures will be conducted: 
Subjects should present to this study visit in the fasted state (minimum 8-hour overnight fast). 
The following procedures/assessments will be conducted: 
 
Collect and Review Daily Dosing Log. 
 
Draw and process blood samples for laboratory tests (Section 11.5): 
o Hematology (CBC) 
o Comprehensive metabolic panel (includes LFT as well as routine chemistry panel; glucose, 
CPK, magnesium)  
o HbA1c 
o Glycated albumin  


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 
Collect and process urine sample for laboratory tests (Section 11.5): 
o Routine UA (dipstick) 
o Pregnancy test (female subjects) 
 
Draw and process blood sample for PK (Section 9.1). 
 
Perform targeted physical examination including a neurological examination (Section 11.2). 
 
Measure and record vital signs including the InBody scale (Section 11.3). 
 
Perform 12-lead ECG (Section 11.6). 
 
Record AEs and concomitant medications. 
 
Perform Ophthalmologic examination (Section 11.3) (only if subject has been dosed for ≥14 days). 
 
Perform Fibroscan (Section 10.3). 
For ≥ 28 days of dosing, the following early termination visit procedures will be conducted: 
Subjects should present to this study visit in the fasted state (minimum 8-hour overnight fast). 
The following procedures/assessments will be conducted: 
 
Collect and Review Daily Dosing Log. 
 
Perform complete physical examination including a neurological examination (Section 11.2). 
 
Draw and process blood samples for laboratory tests (Section 11.5): 
o Hematology (CBC) 
o Comprehensive metabolic panel (includes LFT as well as routine chemistry panel; glucose, 
CPK, magnesium)  
o HbA1c 
o Glycated albumin  
o hs-CRP  
o LDL, VLDL, HDL, FFA, total cholesterol, and triglycerides 
o ApoB and Lp(a) 
o HOMA-IR - includes glucose, insulin, and C-peptide  
 
Collect and process urine sample for laboratory tests (Section 11.5): 
o Routine UA (dipstick) 
o Pregnancy test (female subjects) 
 
Draw and process blood samples for PD assessments: 
o OWL metabolomics and OWL lipidomics (Section 10.4) 
o SomaScan proteomics (Section 10.5)  
o ELF assay (Section 10.6) 


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o Exploratory biomarkers (Section 10.7) 
 
Draw and process blood sample for PK (Section 9.1). 
 
Measure and record vital signs including the InBody scale (Section 11.3). 
 
Perform 12-lead ECG (Section 11.6). 
 
Record AEs and concomitant medications. 
 
Perform Ophthalmologic examination (Section 11.3). 
 
Perform MRI/MRI-PDFF (Section 10.1). 
 
Perform Fibroscan (Section 10.3). 
8.3 
Concomitant Medications and Other Restrictions 
8.3.1 
Concomitant Medications 
Subjects must be on stable doses of medications for underlying obesity-related conditions for at least 2 
months prior to screening. 
Subjects with diabetes may be treated with metformin, DPP-4 inhibitors, or sulfonylureas, but must be on 
stable doses for at least 2 months prior to screening. 
Any concomitant medication use must have a strong clinical indication (i.e. treatment of AEs).  
The following are expressly prohibited during the study: 
a) Any herbal supplement, over the counter drug, mail order or prescription drug for weight loss. 
b) Products with CBD. 
c) Prescription or over the counter stimulants including: dextroamphetamine/Dexedrine, 
dextroamphetamine/amphetamine combination product/Adderall, or methylphenidate (Ritalin®, 
Concerta®). 
d) Thiazolidinediones (TZD): pioglitazone/Actos, rosiglitazone/Avandia. 
e) Glucagon-like peptide 1 (GLP1) agonists: exenatide/Byetta/Bydureon, lixisenatide/Adlyxin, 
liraglutide/Victoza, dulaglutide/Trulicity, semaglutide/Ozempic. 
f) Sodium-glucose cotransporter-2 (SGLT2) inhibitors: canagliflozin/Invokana, 
dapagliflozinfarxiga, empagliflozin/Jardiance, ertugliflozin/Steglatro. 
g) Vitamin E: use of ursodiol or high dose vitamin E >400 IU/day for at least one month within in 
the last 6 months or started high dose vitamin E within last 3 months of screening. 
h) Obeticholic acid/Ocaliva, systemic corticosteroids, methotrexate, tamoxifen, amiodarone, or 
long-term use of tetracyclines. 
i) Warfarin, heparin, factor Xa inhibitors (dabigatran betrixaban edoxaban, apixaban, and 
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j) Concomitant medications that prolong the QT/QTc interval and are known to be associated with 
increased risk of Torsade des pointes as identified in the https://crediblemeds.org/ website list 
category of ‘Known Risk’ (Appendix B).  
8.3.2 
Contraception and Pregnancy Avoidance Measures 
Reproductive toxicology studies have not been yet conducted and the risks of HU6 on the fetus are 
unknown. 
Male subjects are required to use one of the following acceptable forms of contraceptives during the study 
until 30 days after the last dose of study drug if they engage in sexual intercourse with a woman of 
childbearing potential: 
 
Condoms 
 
Sexual abstinence 
 
Vasectomy 
For female subjects, non-childbearing potential requires being either surgically sterile (e.g., hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy) or post-menopausal >12 months of spontaneous and 
continuous amenorrhea with a follicle stimulating hormone (FSH) level > 40 IU/L in a female). 
Women of childbearing potential are required to use one of the following acceptable forms of 
contraceptives during the study until final follow-up visit: 
 
Double-barrier methods of contraception; condoms with the use of caps (with spermicide) or with 
the use of intrauterine device (IUD) are acceptable. 
 
Hormonal contraceptives (oral, depots, patches, etc.) with a barrier method of contraception. 
 
Abstinence from sexual intercourse. 
 
A male partner who is sterile prior to the female subject's entry into the study and is the sole 
sexual partner for that female subject. 
 
Is with a same-sex partner and does not participate in bisexual activities where there is any risk 
of pregnancy. 
Male subjects must not donate sperm from day 1 of dosing and for at least 30 days after the last dose of 
study drug. 
Female subjects of childbearing potential must not donate ova during the study and for at least 30 days 
after the last dose of study drug. 
8.3.3 
Lifestyle and Dietary Restrictions 
Subjects will be instructed to maintain their same diet and activity/exercise level throughout the study as 
they had prior to participation in the study.  
 
Subjects should continue their typical dietary habits during study conduct. There is no need for 
dietary changes. Subjects should not start a weight reduction program while participating in the 
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 
Subjects should continue their typical exercise routine during study conduct. However, strenuous 
exercise should be avoided for 48 hours prior to each blood collection for clinical laboratory tests. 
Strenuous exercise includes strength (weightlifting, barre, etc.) and speed-strength (boot camp, 
cross fit, etc.) activities. Exercise such as walking or a slow jog is permitted as long as it is within 
the subject’s typical regimen. 
Subjects must not smoke or vape more than 10 cigarettes per week and cannot smoke or vape starting 
1 day before each study visit. Nicotine patches are allowed. 
Subjects should avoid ingesting alcohol for 48 hours prior to each blood collection for clinical laboratory 
tests. At other times during the study, alcohol intake should not exceed 14 drinks per week for men and 
7 drinks per week for women [1 drink = 4 ounces (120 mL) of wine or 12 ounces (360 mL) of beer or 
1 ounce (30 mL) of hard liquor].  
9 PHARMACOKINETIC ASSESSMENTS 
9.1 
Pharmacokinetic Sample Collection 
Blood samples will be collected, and plasma samples prepared at the following times: 
 
On Day 1, 14, and 28: predose (trough) and approximately 2, 4, and 6 hours postdose.  
 
On Days 2, 7, 42, and 61: predose (trough) sample.  
 
One sample during Visit 10 or Early Termination. 
9.2 
Handling, Shipping, Storage and Analysis of Blood Samples 
Please refer to the Laboratory Procedures Manual for more information about sample collection, 
processing, storage, and shipment.  
9.3 
Pharmacokinetic Parameters  
The following PK parameters will be determined from concentration-time data: 
 
Population PK (PPK) analysis of HU6 parent and metabolites (DNP and M1). The following PK 
parameters will be calculated: Cmax, Tmax, t½, Tlag, AUC0-t, AUC0-∞, CL/F, Vd/F, λz. Other PK 
parameters may be calculated, as data allow and appropriate. 
 
As data permit, noncompartmental analysis of HU6 parent and metabolites (DNP and M1). The 
following PK parameters will be calculated: Cmax, AUC, and accumulation. 
10 PHARMACODYNAMIC ASSESSMENTS 
An overview of PD assessments is provided below. Refer to Section 8 for PD blood collection time 
points. Please refer to the Study Procedure Manual for more information about sample collection, 
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10.1 Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) 
Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) is a non-invasive, quantitative 
biomarker to assess liver fat content (steatosis). The percentage of fat in the liver, or proton density fat 
fraction (PDFF), is being measured using MR: MRI-PDFF at baseline and end of treatment. Liver volume 
will be assessed from an axial T1 weighted or dual echo gradient echo images covering the entire liver.  
This advanced MRI technique measures the fraction of mobile protons in the liver attributable to liver fat 
(the PDFF), which is a direct measure of liver fat content and is a fundamental tissue property.  Subjects 
should be fasting for 4 hours prior to the MRI-PDFF being performed, however, if they are not, the scan 
can still be performed.  Should the MRI show incidental findings unrelated to the study evaluation, 
subjects will be notified of the findings and a written report provided and a recommendation for the 
subject to follow up with their primary physician. 
10.2 Abdominal MRI 
An MRI image will be taken of the abdominal region to assess total fat.  The two primary measurements 
from this scan will estimate the total visceral adipose tissue (VAT), the type of fat stored within the body 
cavity, and the subcutaneous adipose tissue (SAT), the type of fat visible right underneath the skin.   
10.3 Fibroscan® 
The Fibroscan is a non-invasive medical device which estimates liver fat content (steatosis) and liver 
stiffness (fibrosis). The assay works by measuring shear wave velocity. A 50-MHz wave is passed into 
the liver from a small transducer on the end of an ultrasound probe. The probe also has a transducer on 
the end that measure the velocity of the shear wave (in meters per second) as this wave passes through the 
liver. The shear wave velocity is converted into liver stiffness, which is expressed in kilopascals (VCTE 
score). A second measurement is also taken that estimates hepatic steatosis through measuring the 
ultrasonic attenuation of the echo wave, termed the controlled attenuation parameter (CAP).  Subjects will 
need to be fasting for 4 hours prior to the Fibroscan® being conducted. 
10.4 One Way Liver Assays (OWL) 
10.4.1 
OWL – Metabolomics 
This metabolomics assay extracts metabolites from volunteer plasma and serum to take a snapshot of 
cellular function. Liquid chromatography-mass spectrometry (LC-MS) metabolomics is used to identify 
serum biomarkers that differentiate normal liver and NAFLD and between NASH and NAFLD. The 
metabolomics profile also provides insight into cellular function and inflammation through the 
examination of various cellular metabolites that provide insight into key molecular pathways. 
10.4.2 
OWL – Lipidomics 
Lipidomics is non-invasive blood assay that analyzes and identifies lipids in plasma and serum. These 
lipids will be separated and characterized via mass spectrometry and the analysis will include fatty acids, 
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10.5 Slow Off-rate Modified Aptamer (SomaScan) 
SomaScan is a non-invasive blood assay. Blood plasma and serum samples will be assayed using 
oligonucleotide aptamers whose three-dimensional conformational shape binds specifically to a protein 
target of interest. Over seven thousand proteins will be assayed and quantified, enabling a proteomic 
snapshot of the body. Different mathematical models have been applied to large clinical data to establish 
algorithms with predictive value in cardiovascular health, metabolic rate, lean body mass, liver 
inflammation, cardiorespiratory fitness, and glucose tolerance.   
10.6 Enhanced Liver Fibrosis (ELF) 
The ELF assay is a non-invasive blood test that measures three markers of liver inflammation and 
fibrosis:  hyaluronic acid, procollagen III amino-terminal peptide (PIIINP), and tissue inhibitor of matrix 
metalloproteinase 1 (TIMP-1). The values of these three markers, when used in conjunction with 
accompanying clinical data, are highly predictive of the inflammatory and fibrotic state of the liver, as 
evidenced by correlating the data with histology in larger clinical trials. 
10.7 Exploratory Biomarkers 
Blood samples will be obtained and separated into plasma and serum components from which separate 
400 µL aliquots will be drawn, labelled, and stored for future analysis of proteins, lipids, or gene 
expression that could assist in explaining the pharmacological actions of HU6.  
11 SAFETY ASSESSMENTS 
11.1 Adverse Events  
Adverse events will be captured from the start of study-related procedures at Screening (including 
diagnostic assessments or after signing of ICF) onward during this study. Important medical events and 
conditions occurring prior to this period are not AEs; they will be captured within the medical chart and in 
the Medical History section of the Case Report Form. 
11.2 Physical Examination  
Height should be measured on a wall-mounted stadiometer at Screening.  
Refer to Section 8 for physical examination time points.  
Complete Physical:  At study visits in which a complete physical examination is required, the investigator 
should perform a thorough examination of all body systems (exception: genitourinary and reproductive 
should be symptom-directed). Neurological examination should include the assessment of strength. 
Targeted Exam:  A targeted physical exam that is symptom-based. Based upon change to subject 
symptoms or visual findings; in addition, each exam should include a limited neurological evaluation of 
the strength of muscle groups. The commonly accepted method of evaluating muscle strength is the 
Medical Research Council Manual Muscle Testing scale. This method involves testing key muscles from 
the upper and lower extremities against the examiner’s resistance and grading the patient’s strength on a 0 
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• 
0  No muscle activation 
• 
1  Trace muscle activation, such as a twitch, without achieving full range of motion 
• 
2  Muscle activation with gravity eliminated, achieving full range of motion 
• 
3  Muscle activation against gravity, full range of motion 
• 
4  Muscle activation against some resistance, full range of motion 
• 
5  Muscle activation against examiner’s full resistance, full range of motion 
11.3 Ophthalmologic Examination 
A full medical eye examination including fundus photographs of the posterior pole of eye, OCT of the 
maculas of both eyes, and slit lamp evaluations will be performed at screening and at the completion of 
dosing (approximately Day 61) to characterize the subject’s baseline status and to monitor any changes 
from baseline over the course of treatment. Pupillary dilation will be accomplished with 2.5% 
neosynephrine and 0.5% tropicamide (Mydriacyl) (unless there is a contraindication deemed by the 
ophthalmologist), one drop in each eye one time in light color eyes and up to two times, 5 minutes apart 
in dark eyes. A slit lamp is a biomicroscope with a bright light used during an eye exam and assesses 
different structures at the front of the eye and inside the eye for determination of the health and detection 
of eye disease. OCT is a non-invasive imaging technique that uses light waves to take cross-section 
pictures of the retina. Fundus photography involves photographing the rear of the eye. These procedures 
are standard tests involved in the medical evaluation of the health of the eye and should be conducted by a 
limited number of coordinating ophthalmologists to ensure consistency of evaluations.  
11.4 Vital Signs 
Refer to Section 8 for vital sign assessment time points.  
Vital signs include body temperature, systolic and diastolic blood pressure, heart rate, and respiration rate. 
All blood pressure readings must be done with a blood pressure cuff appropriate to the arm size of the 
subject. A blood pressure cuff that is too small will result in inaccurately high blood pressure 
determinations. Blood pressure and heart rate recordings will be made after the study subject has been 
supine for ≥ 5 minutes.  
The InBody scale will be used to capture weight, muscle, and body fat. This must be done predose, in the 
fasted state, and at approximately the same time of day. 
Body temperature will also be monitored daily by the subject at home utilizing a Braun Thermoscan 7 
inner ear thermometer which will be provided to them. The thermometer provides a color-coded display 
that displays the temperature as well as indicating normal, elevated (>99.9⁰ F, yellow display), or fever 
(>103⁰ F, red display) temperatures. There is an audible feedback system that ensures appropriate usage 
and alerts the user that the temperature has been acquired. Nine previous reading will be recorded on the 
thermometer. Temperature readings should be done daily at the time of dosing. Should the subject have 
symptoms that may indicate a fever, they should take their temperature and verify. For temperature 
elevations ≥100⁰ F, as indicated by the yellow or red display, the subject should stop taking HU6, avoid 
antipyretics (acetaminophen, aspirin or non-steroidal anti-inflammatory agents) and call the 


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Investigational Site. Further guidance will be provided by the medical staff (See Section 7.4 Withdrawal 
of Subjects). 
11.5 Clinical Laboratory Tests 
Refer to Section 8 for clinical laboratory blood and urine collection time points.  
Refer to the Study Procedure Manual for more information about sample collection, processing, storage, 
and shipment.  
At Screening only: 
 
Viral serology will include testing for the presence of hepatitis B antigen, anti-hepatitis C 
antibody and anti-HIV antibodies.  
 
TSH and Free T4.  
 
eGFR = CKD-EPI Creatinine Equation (NKF 2009; https://www.kidney.org/content/ckd-epi-
creatinine-equation-2009).  
Hematology testing will include erythrocyte mean corpuscular hemoglobin concentration (MCHC), 
erythrocyte mean corpuscular volume (MCV), hematocrit, hemoglobin, leukocyte count, and absolute 
counts of lymphocytes, monocytes, neutrophils, basophils, eosinophils and platelets. 
Serum chemistry analyses will include glucose, calcium, albumin, total protein, sodium, potassium, 
bicarbonate, chloride, magnesium, blood urea nitrogen (BUN), creatinine, alkaline phosphatase, 
phosphate, uric acid, lactate dehydrogenase, ALT, AST, gamma-glutamyl transferase (GGT), bilirubin 
(total and direct), amylase, and CPK.  
 
Baseline ALT and AST = while each value will be recorded, the average of screening and Day 1 
predose values will be used as the baseline value in the statistical evaluation of these parameters 
in the exploratory analysis. 
Lipid panel will include total cholesterol, HDL, LDL, VLDL, triglycerides, and FFA.  
Additional tests at select time points include glycated albumin, hs-CRP, ApoB, Lp(a), and HOMA-IR 
(includes glucose, insulin, and C-peptide; Wallace 2004), and PEth test.  
 
For HOMA-IR, 3 blood samples for the 3 analytes (blood glucose, serum insulin, and C-peptide) 
will be drawn after a minimum of 5 minutes between each sample. 
 
The PEth test is a serum biomarker that can assess recent alcohol consumption.  The value is 
dependent on both quantity of alcohol and time from consumption.  This will be assessed at 
screening and Day 28.  At the discretion of the investigator, it can be obtained at other times if 
there is concern for excessive alcohol consumption based on history, symptoms or laboratory 
evaluations (e.g. elevated liver function tests). The report lists several different assays, but this 
study will rely on the based on PEth 16.0/18.1 (POPEth) assay, which has been validated. 
Urinalysis will consist of dipstick evaluations, with a reflex microscopic evaluation if dipstick shows 
blood or protein is small (1+), moderate (2+) or large (3+). Spot urine protein and albumin to be done if 
urine > trace protein on 2 collections. 
Urine pregnancy tests will be conducted for female subjects.  


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Laboratory tests may be repeated once at screening. Additional laboratory evaluation may be performed 
at the discretion of the investigator in the assessment of an adverse event, as medically warranted. 
11.6 12-lead Electrocardiogram 
Refer to Section 8 for 12-lead ECG assessment time points.  
Single 12-Lead ECG measurements will be obtained after the subject has rested in a supine position for at 
least 10 minutes. External stimuli should be kept to a minimum. Video games, watching of TV, and 
talking will not be allowed during this time. A digital ECG machine will be utilized for the trial. If an 
ECG timepoint coincides with any blood samples, the ECGs will performed ± 10 minutes from obtaining 
the blood sample at the same timepoint. In addition, whenever possible, subjects should not have a meal 
within 2 hours prior to an ECG being performed.  
The ECGs will be measured using an ECG machine that automatically calculates the heart rate and 
measures PR, RR, QRS, QT, and QTcF (Fridericia correction formula). The same ECG machine should 
be used for the same subject throughout the study, if at all possible. ECGs should be conducted in 
adherence with a research unit SOP acceptable to the Sponsor.  
11.7 Adverse Events  
11.7.1 
Definitions  
Adverse Event  
An Adverse Event (AE) is any untoward medical occurrence in a subject or clinical investigation subject 
undergoing a study procedure or administration of a study drug. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of the study drug, whether or not considered related to the study drug. Medical 
conditions present at the initial trial visit that do not worsen in severity or frequency during the trial are 
defined as baseline conditions (medical history) and are not to be considered AEs. 
The sources of AEs include but are not limited to: 
 
The subject’s response to questions about his/her health (a standard nonleading question such as 
“How have you been feeling since your last visit?” asked at each visit). 
 
Symptoms spontaneously reported by the subject. 
 
Investigations and examinations with findings that are assessed by the Investigator to be clinically 
significant.  
 
Other information related to the subject’s health becoming known to the Investigator.  
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is considered 
as the AE rather than the procedure itself. 
Laboratory Abnormality 
A laboratory abnormality will be considered an AE when it is clinically significant and suggesting a 
disease or organ toxicity and which is of a severity requiring active management (i.e., changes of dose, 
discontinuation of drug, more frequent follow-up, medical treatment or a diagnostic investigation).  


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Pretreatment Adverse Events  
A pretreatment AE is any AE occurring during the pretreatment period (between informed consent and 
initiation of a study drug dosing).  
Treatment-emergent Adverse Events  
Treatment-emergent adverse events (TEAEs) are all AEs occurring during the treatment period or a 
pretreatment AE that worsens in intensity during the treatment period. 
11.7.2 
Collection and Rating of Adverse Events  
During the course of the study (i.e., from the signing of the ICF through the Follow-up Visit plus 30 days 
for any SAE) all AEs, irrespective of the relatedness to the study drug, will be collected and reported on 
the Adverse Event Report Form. The seriousness criteria should not be confused with the intensity of the 
event. In case of an SAE, a Serious Adverse Event Report Form must be completed and transmitted to the 
Sponsor or designee.  
Overdoses and medication errors in the presence of clinical consequences should be recorded as AEs. The 
clinical consequence should be reported as “[enter AE] due to overdose.” 
11.7.2.1 
Onset Date 
The onset date is the date when the first sign(s) or symptom(s) were first noted. For example, if the AE is 
an abnormal laboratory test (such as “platelets low”), the onset date is the date when the sample was 
taken. If the subject was hospitalized for meningitis, and symptoms such as fever, headache and nausea 
started the day before the hospitalization, the onset date is the day symptoms presented versus day of 
hospitalization. 
11.7.2.2 
Assessment of Intensity 
The intensity of each AE will be rated according to the following 3-point scale: 
 
Mild:  
Awareness of signs or symptoms, but no disruption of usual activity 
 
Moderate:  Event sufficient to affect usual activity (disturbing) 
 
Severe:  
Inability to work or perform usual activities (unacceptable) 
The CTCAE system will be used to assess the severity of the SAEs, AEs. 
11.7.2.3 
Relationship to Study Drug 
The causal relationship of the study drug to an AE will be rated according to the following 4-point scale: 
 
Unrelated: 
Clearly and incontrovertibly due only to extraneous causes, and does not meet 
criteria listed under unlikely, possible or probable 
 
Unlikely:  
Does not follow a reasonable temporal sequence from administration; may have 
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 
Possible:  
Follows a reasonable temporal sequence from administration; may have been 
produced by the subject’s clinical state or by environmental factors or other therapies 
administered 
 
Probable:  
Clear temporal association with improvement on cessation of study drug or 
reduction in dose. Reappears upon re-challenge or follows a known pattern of response to the 
study drug 
AEs considered ‘unrelated or unlikely’ will be considered unrelated causality, whereas ‘possible or 
probable’ will be considered related causality.  
11.7.2.4 
Action Taken  
The action taken toward the study drug in response to an AE will be listed as one of the following:  
 
None:  no change in study drug regimen due to the event 
 
Discontinued:  the study drug was permanently stopped due to the event 
 
Interrupted:  the study drug was temporarily interrupted due to the event 
11.7.2.5 
Outcome of Adverse Event  
The outcome of an AE will be recorded as one of the following:  
 
Recovered:  fully recovered or the condition has returned to the level observed at baseline 
 
Recovered with sequelae:  resulted in persistent or significant disability or incapacity; the nature 
of the sequelae should be specified 
 
Ongoing 
 
Death 
11.7.3 
Adverse Event Follow-up 
Adverse events requiring therapy must be treated with recognized standards of medical care to protect the 
health and well-being of the subject. 
Any subject who has any AE (whether serious or non-serious) or clinically significant (in the 
Investigator’s opinion) abnormal laboratory test values will be evaluated by the Investigator or a 
monitoring physician, and will be treated and followed up until the symptoms or values return to normal 
or acceptable levels, as judged by the Investigator and the Sponsor.  
Adverse events that are unresolved at end of study or upon early withdrawal will be tracked at least 
weekly by site staff until resolution, for 30 days, or until the subject is lost to follow-up (defined as failure 
to respond to three phone messages left on separate days and one certified letter requesting follow-up).  
Subjects will be instructed to inform site staff of any AEs occurring during the 30-day period after 
discharge or early withdrawal. 
Any follow-up information available at the time of the subject’s end of study will be included in the 
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Any SAE that is unexpected and related to the study drug occurring after the end of study should be 
forwarded to the Sponsor. These cases will be handled and submitted as expedited reports but will not be 
included in the clinical study report. 
11.8 Serious and Other Significant Adverse Events  
11.8.1 
Definition of a Serious Adverse Event 
A serious adverse event is any untoward medical occurrence that:  
 
Results in death. Death is not an event per se but rather an outcome. Note that any event 
resulting in a fatal outcome must be fully documented and reported, including deaths that occur 
within 30 days after treatment ends and irrespective of the causal relationship to the study drug. 
 
Is life-threatening. Life-threatening refers to an AE in which the subject was at immediate risk 
of death at the time of the event. It does not refer to an event, which may have caused death, if it 
was more severe. 
 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
Hospitalization means that the subject was admitted to hospital or that existing hospitalization 
was extended as a result of an event. Hospitalization describes a period of at least 24 hours. Over-
night stays for observation; stays at the emergency room or treatment on an outpatient basis does 
not constitute a hospitalization. However, medical judgment must always be exercised and, when 
in doubt, the case should be considered serious (i.e. if the case fulfills the criterion for a medically 
important event). Hospitalization for administrative or social purposes does not constitute an 
SAE. Hospital admissions and/or surgical operations planned before study inclusion are not 
considered AEs if the illness or disease existed before the subject were enrolled in the study, 
provided that the condition did not deteriorate during the study. 
 
Results in persistent or significant disability/incapacity. Disability/incapacity means a 
substantial disruption of a person’s ability to conduct normal life functions. If in doubt, the 
decision should be left to medical judgment by the Investigator. 
 
Is a congenital anomaly/birth defect. Any congenital anomaly or birth defect observed in any 
offspring of the subject conceived during treatment with the study drug. 
 
Is an important medical event. Important medical events are events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject or 
may require intervention to prevent one of the other outcomes listed in the definition above. 
Examples of important medical events include AEs that suggest a significant hazard, 
contraindication or precaution, occurrence of malignancy or development of drug dependency or 
drug abuse. Medical and scientific judgment should be exercised in deciding whether events 
qualify as medically important. 
An AE caused by an overdose or medical error is considered serious if a criterion listed in the definitions 
above is fulfilled. 
The following are not considered SAEs: 
 
A pre-existing condition that is present prior to or at the start of the study that did not worsen 


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 
Hospitalizations for treatment which were elective or preplanned, for a pre-existing condition 
unrelated to the indication under study that did not worsen 
 
Admission to a hospital or other institution for general care, not associated with any deterioration 
in condition. 
11.8.2 
Serious Adverse Event Reporting by the Investigator to the Sponsor 
Any SAE that occurs after a subject has entered the study, whether related to study drug, must be reported 
to the Sponsor or the Sponsor’s agent immediately (within 24 hours) via telephone or facsimile. If 
initially reported via telephone, this must be followed-up by a facsimile of the written SAE report. The 
Investigator must report all SAEs occurring from the time the subject signs the ICF until 30 days after last 
treatment with the study drug. 
A completed Serious Adverse Event Report Form with the best possible details must be transmitted to the 
Sponsor representative by facsimile within 24 hours of knowledge of the SAE according to contact details 
as specified below:  
Sponsor Representative and Contact Information for SAE Reporting: 
Roger Morgan, M.D. 
Vice President Medical Affairs 
MedSurgPI, LLC 
3700 Lark Farm Road 
Franklinton, NC  27525 
11.8.3 
Handling of Follow-up Information 
Follow-up information may be required, or additional information may be received by the Sponsor (e.g., 
evolution of the SAE, other signs or symptoms, final diagnosis, outcome, hospital discharge summary, or 
autopsy report). The same procedures and timelines as for initial reporting, listed above, should be 
followed for any follow-up information. If necessary, the study site will be visited to collect additional 
information. 
Follow-up information is required on all SAEs until one of the following criteria is satisfied: 
 
The outcome of the case is known 
 
The event is resolved, or the medical condition of the subject is stabilized 
 
No further information is available 
 
Sponsor assessment has been finalized 
11.8.4 
Reporting and Follow-up of Pregnancy 
When an Investigator becomes aware of the pregnancy of a female subject, the Investigator must 
withdraw the subject from the study and follow the pregnancy until termination or until the child is 1 
month old. The pregnancy will be reported immediately by telephone and by faxing a completed 
Pregnancy Report to the Sponsor within 24 hours of knowledge of the event. The pregnancy will not be 


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processed as an SAE; however, the Investigator should notify the Sponsor or the Sponsor’s agent of the 
outcome of the pregnancy by submitting a follow-up Pregnancy Report. Additionally, if the outcome of 
the pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, or congenital anomaly), the Investigator will report the event by phone 
and by faxing a completed SAE Report Form to the Sponsor within 24 hours of knowledge of the event. 
11.8.5 
Expedited Reporting of Serious Adverse Events  
11.8.5.1 
Responsibilities 
The Sponsor is responsible for ensuring the timely reporting of SAEs to Regulatory Authorities and all 
Investigators who participate in the clinical development program of the study drug. It is the 
responsibility of the Investigator to provide the Sponsor with the case information such that reporting 
timeline demands of applicable Regulatory Authorities can be met. 
11.8.5.2 
Expedited Reporting 
All AEs that are serious, unexpected, and considered related to the study drug judged by either Sponsor or 
the Investigator require expedited reporting. All available information relevant to the evaluation of the 
SAE will be reported. Serious adverse events will be considered reportable regardless of whether the 
study drug was used in accordance with the provisions in the protocol. 
Adverse events which are serious, but expected, or those which are not associated with the study drug will 
only be subjected to expedited reporting if they are required to be reported to an authority according to 
national requirements.  
11.8.5.3 
Timelines 
Fatal or life-threatening serious unexpected related cases require rapid reporting. Regulatory Authorities 
shall be notified as soon as possible but no later than 7 calendar days after first knowledge by the Sponsor 
representative, followed by as complete a report as possible within 8 additional calendar days.  
Serious unexpected related cases that are not fatal or life-threatening must be submitted as soon as 
possible, but no later than 15 calendar days after first knowledge by the Sponsor representative that the 
case meets the minimum criteria for expedited reporting. 
It is the responsibility of the Investigator to support Sponsor activities needed to meet the timelines for 
Regulatory Authority reporting in the event of an SAE. 
12 STATISTICAL METHODS 
12.1 General Overview of the Statistical Analysis Plan 
Descriptive statistical methods will be used to summarize the data from this study, with statistical testing 
performed for the efficacy endpoints. Unless stated otherwise, the term “descriptive statistics” refers to 
number of subjects (n), mean, median, standard deviation, minimum, and maximum for continuous data, 
and frequencies and percentages for categorical data. Statistical testing, if performed, will be 2-sided and 
will be performed using a significance (alpha) level of 0.05. There will be no adjustment for multiple 
comparisons for this exploratory study. All available data for enrolled subjects will be listed by subject. 


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Unless otherwise noted, the data will be sorted first by subject number and then by date within each 
subject number. All statistical analyses will be conducted with the SAS® System, version 9.4 or higher.   
Additional statistical details will be provided in the statistical analysis plan (SAP). 
In the event of higher than anticipated early terminations due to COVID-19, or other reasons, Rivus 
Pharmaceuticals, may extend enrollment in order to maintain the planned statistical power. 
12.2 Sample Size Determination 
A sample size of 17 subjects per group provides at least 80% power to detect a 30% difference in the 
mean relative change from baseline in liver fat content at Day 61, when the standard deviation is 30% 
[PASS 2020: Two sample t-test, alpha=.05]. Assuming a 15% dropout rate, up to 80 subjects should be 
enrolled to ensure that at least 68 subjects, 17 per group, are evaluable for the primary efficacy endpoint 
analysis.  
12.3 Data Analysis 
12.3.1 
Analysis Populations 
Intent-to-Treat (ITT):  includes all randomized subjects. 
Full Analysis Set (FAS): includes all randomized subjects who receive at least 1 dose of treatment.  
PK Concentration Population: includes all subjects who receive at least one dose of HU6 and have at 
least one adequately documented plasma sample obtained and analyzed for measurable HU6, DNP and 
M1 concentrations. 
PK Parameter Population: includes all subjects who have an evaluable HU6, DNP and M1 plasma 
concentration data. 
12.3.2 
Efficacy Analysis 
The primary efficacy endpoint is the reduction in liver fat content measured by the relative change from 
baseline, as assessed by MRI-PDFF at Day 61. The hypothesis of interest are 2-sided tests comparing 
each active HU6 treatment groups to the placebo. 
𝐻଴ଵ: 𝜇௣௟௔௖௘௕௢= 𝜇ு௎଺ ଵ଻଴௠௚vs 𝐻ଵଵ: 𝜇௣௟௔௖௘௕௢≠𝜇ு௎଺ ଵ଻଴௠௚    
𝐻଴ଶ: 𝜇௣௟௔௖௘௕௢= 𝜇ு௎଺ ଷସ଴௠௚vs 𝐻ଵଶ: 𝜇௣௟௔௖௘௕௢≠𝜇ு௎଺ ଷସ଴௠௚    
𝐻଴ଷ: 𝜇௣௟௔௖௘௕௢= 𝜇ு௎଺ ହଵ଴௠௚vs 𝐻ଵଷ: 𝜇௣௟௔௖௘௕௢≠𝜇ு௎଺ ହଵ଴௠௚   
Relative change from baseline in liver fat content, will be analyzed for the FAS using an analysis of 
variance (ANCOVA) model, including treatment group, HbA1c stratification (normal range versus 
between 5.7% and 9.0% inclusive) and baseline liver fat from MRI-PDFF as fixed effects. This estimand 
will include available MRI-PDFF evaluations that occur before discontinuation of treatment. The 
differences between treatment groups will be based on the least square mean (LSMean) differences 
between each HU6 group and placebo. A separate comparison of the combined HU6 groups and placebo 
may be conducted. The corresponding 95% confidence interval (CI) will be presented. 


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12.3.3 
Pharmacodynamic Analysis 
Continuous pharmacodynamic endpoints with repeated post-baseline assessments (changes from baseline 
in body weight, whole body adiposity, AVCTE, CAP, ELF, serum hs-CRP, Lp(A), Apo B, LDL, HDL, 
total cholesterol, triglycerides, FFA, plasma ceramides, HOMA-IR, fasting blood glucose concentrations, 
glycated albumin concentrations, and HbA1c) will be analyzed for the FAS using a Mixed Model for 
Repeated Measures (MMRM). This estimand will include available post-baseline response data that occur 
before discontinuation of treatment. The baseline score will be included as the covariate, and HbA1c 
stratification, treatment group, visit, and the interaction between treatment group and visit will be included 
as fixed factors in the MMRM. The difference between each HU6 level versus placebo at each visit will be 
estimated based on the LSMeans from the MMRM. 
12.3.4 
Safety Analysis 
The safety analysis will be conducted on the FAS. Should there be any subjects that receive a treatment 
other the randomized treatment, the treatment as received will be used for safety presentations. AEs will 
be assessed for toxicity grade using NCI CTCAE (Version 5 or higher) and will be coded for 
summarization using Medical Dictionary for Regulatory Activities (MedDRA® Version 10.1 or higher). 
Concomitant medications will be coded using WHO Drug Dictionary (enhanced) Format C, 15 Aug 2005 
or more recent updated version. 
Treatment-emergent AEs will be summarized by SOC and preferred term, for each dose group (including 
placebo). Further summaries by seriousness, severity, and relationship to study drug may be conducted.  
Laboratory measures will be summarized by treatment group and time-point both as absolute values and 
as change from baseline, with descriptive statistics summarizing each group and time point. Similar 
presentation will be used for vital signs and for ECG interval measurements, and changes from pre-
treatment baseline. ECG intervals will be calculated from ECG/continuous ECG recordings at each time 
point.  
A separate statistical analysis plan may be developed for exploratory evaluations of HU6 concentrations 
and QTcF.  
12.3.5 
Pharmacokinetic Analysis 
Plasma concentration-time data of HU6, DNP and M1 will be displayed in tables and/or graphs. 
Individual plasma concentration-time data will be pooled, and population pharmacokinetics will be 
performed using a currently acceptable methods as permitted by the data and based on a prospective 
analysis plan. PK parameters such as Clearance (CL) and volume of distribution (V) will be determined. 
In addition, the influence of various covariates (e.g., BMI) of the PK parameters will be examined. 
Individual PK parameter estimates will be used to calculate summary metrics of exposure including AUC 
and Cmax. 
Full details will be provided in a Pharmacokinetic Analysis Plan.  
12.3.6 
Pharmacokinetic/Pharmacodynamic Analyses 
PK/PD modeling may be conducted to better define exposure-response and dose determination for future 
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12.4 Missing, Unused and Spurious Data  
No imputation will be applied for missing data. Only non-missing values will be used for analyses.  
13 STUDY MANAGEMENT 
13.1 Protocol Amendment and Protocol Deviation 
13.1.1 
Protocol Amendment 
Administrative amendments to the protocol will be classed as amendment of typographical errors, 
clarifications of confusing wording, and other minor modifications including but not limited to name, 
address, and contact information changes that have no impact on the safety of the subject or the science of 
the study. Administrative amendments will be submitted to the Institutional Review Board (IRB) for 
information only. The Sponsor will ensure that acknowledgement is received and filed. Otherwise, an 
amendment will be classed as a substantial amendment and will be submitted to the appropriate 
Regulatory Authorities and the IRB for approval. 
13.1.2 
Protocol Deviations 
No deviations from the protocol are anticipated. Requests for deviations must be made in advance with 
the Sponsor. Should a non-anticipated protocol deviation occur, the Sponsor must be informed as soon as 
possible. All deviations and the reasons for the deviation will be documented by the Investigator or 
designated staff. Reporting of protocol deviations to the IRB and in accordance with applicable 
Regulatory Authority mandates is an Investigator responsibility. 
13.1.3 
Protocol Waivers 
Protocol waivers will not be granted by the Sponsor in this study. 
13.2 Ethics and Regulatory Aspects 
13.2.1 
Ethical Conduct of the Study and Regulatory Guidelines 
To ensure the ethical conduct of this clinical study, each Investigator is expected to conduct the study in 
accordance with the protocol; the United States IND regulations specified under 21 CFR 11, 50, 54, 56, 
and 312; the ICH Harmonized Tripartite Guideline for Good Clinical Practice (GCP); and the Guidelines 
of the Declaration of Helsinki. The Investigator will conduct all aspects of the study in accordance with 
all national, state and local laws of applicable Regulatory Authorities.  
The responsibilities of the Sponsor, the Monitor and the Investigator will be as defined in the ICH GCP 
consolidated guideline, and applicable regulatory requirements in the country where the study takes place. 
The Investigator is responsible for adhering to the GCP responsibilities of Investigators, for dispensing 
the study drug in accordance with the approved protocol or a signed amendment, and for its secure 
storage and safe handling throughout the study. 


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13.2.2 
Institutional Review Board and Regulatory Approval 
The study protocol and any amendments will be reviewed by an Independent Review Board. The IRB 
will review the written subject information sheet and the Informed Consent Form (ICF), their updates (if 
any), and any written materials given to the subjects. A listing of the membership of the IRB consulted 
and the name of the committee chair(s) or IRB registry (accreditation) number will be documented within 
the Investigator File and Trial Master File of the Sponsor. 
The Regulatory permission to perform the study must be obtained in accordance with applicable 
regulatory requirements. All ethics approvals must be obtained, and regulatory obligations met before a 
subject is exposed to any study-related procedure, including screening tests for eligibility. 
13.2.3 
Subject Informed Consent 
Subjects will be informed about the study both verbally and in writing. Each subject will be provided with 
a written subject information sheet that has been approved by the IRB and will be given a reasonable time 
to consider the study and to ask any questions they have regarding the study. The ICF must be in a 
language that the subject can understand.  
Only the Investigator, a medically qualified Sub-investigator or a suitably qualified and trained authorized 
person may be involved in the informed consent process.  
The Investigator or their suitable designee will obtain a freely given, written consent from each subject 
after an appropriate explanation of the aims, methods, potential hazards, and any other aspects of the 
study which are relevant to the decision of the subject to participate. The Investigator will explain that the 
subject is completely free to refuse to enter the study or to withdraw from it at any time, without any 
consequences for their further care and without the need to justify.  
The ICF must be signed and dated by the subject before exposure to any study-related procedure, 
including screening tests for eligibility. The subject will receive a copy of the written subject information 
sheet and the ICF. 
Each subject will be informed that a Monitor, a Quality Assurance Auditor mandated by the Sponsor, or a 
Health Authority Inspector, in accordance with applicable regulatory requirements, may review his or her 
source records and health data. Data protection will be handled in compliance with national and local 
regulations. 
If new safety information becomes available and results in significant changes in the risk to benefit 
assessment, the written subject information sheet will be revised or updated where necessary. Under these 
circumstances, all subjects (including those already being treated) should be informed of the new 
information, given a copy of the revised form and allowed to reevaluate their consent to continue in the 
study. 
13.3 End of Study and Regulatory Notification 
The study can be terminated in part or in whole at the discretion of the FDA, an applicable Regulatory 
Authority or the Sponsor.  
At the end of the study, the IRBs and Regulatory Authorities will be notified by the Sponsor according to 
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13.4 Data Protection and Confidentiality 
The confidentiality of records that could identify subjects should be protected, respecting the privacy and 
confidentiality rules in accordance with applicable regulatory requirement(s). 
13.5 Monitoring 
The study will be monitored to ensure that the study is conducted and documented properly according to 
the protocol, GCP, and all applicable regulatory requirements.  
On-site visits will be made at appropriate times during the study. Monitors must have direct access to 
source documentation in order to check the consistency of the data recorded in the CRF. 
The Investigator will make available to the Monitor source documents, medical records, and source data 
necessary to complete CRFs. In addition, the Investigator will work closely with the Monitor and, as 
needed, provide them appropriate evidence that the conduct of the study is being done in accordance with 
applicable regulations and GCP guidelines. 
13.6 Quality Assurance and Quality Control 
The Sponsor or its designee will perform the quality assurance and quality control activities of this study; 
however, responsibility for the accuracy, completeness, and reliability of the study data presented to the 
Sponsor lies with the Principal or Qualified Investigator generating the data.  
Prior to the study initiation, the Sponsor will explain the protocol, Investigator’s Brochure, and CRFs to 
Investigators. In addition, the Monitor will be available to explain applicable regulations and to answer 
any questions regarding the conduct of the study. 
At its discretion, the Sponsor may conduct audits as part of the implementation of quality assurance to 
ensure that the study is being conducted in compliance with the protocol, Standard Operating Procedures, 
GCP, and all applicable regulatory requirements. Audits will be independent of and separate from the 
routine monitoring and quality control functions. 
The study center may also be compelled to an inspection by a Regulatory Authority. 
13.7 Source Data 
Source data are defined as information in original records and certified copies of original records of 
clinical findings, observations, data, or other activities in a clinical study necessary for the reconstruction 
and evaluation of the study.  
Source documents are the original data, documents, and records. Examples include hospital records, 
laboratory reports, clinical and office charts, laboratory notes, memoranda, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, other radiographic depictions or displays, subject files, and records kept at the pharmacy, at 
the laboratories and at medico-technical departments involved in the clinical study. All source documents 
must be reviewed by the PI and the sponsor (or designee) for compliance with GCP. 
Study-specific data sheets may be used to document source information that would not normally be 
collected and documented in the routine management of the subject. Data sheets used for source 


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documentation must be verified and signed by the Investigator or a delegated study site team member and 
must be stored and archived in the subject’s clinic records (preferably) or in the Investigator File. 
The Investigator will permit study-related monitoring, audit(s), IRB review(s), and regulatory 
inspection(s), with a direct access to all the required source documents and associated records. 
14 DATA AND RECORD KEEPING 
14.1 Case Report Forms 
All data will be entered in a validated electronic data capture system using single data entry. Standard 
procedures (including following data review guidelines, manual clinical review based on subject profiles, 
computerized validation to produce queries, and maintenance of an audit file which includes all database 
modifications) will be followed to ensure accurate data. Clinical personnel will review all data listings for 
outliers, data inconsistencies, and spelling errors. 
During the course of the study, a study monitor (CRA) will make site visits to review protocol 
compliance, compare eCRFs against individual subject’s medical records, assess drug accountability, and 
ensure that the study is being conducted according to pertinent regulatory requirements. 
Electronic CRF entries will be verified with source documentation. The review of medical records will be 
performed in a manner to ensure that subject confidentiality is maintained. Checking the eCRFs for 
completeness, clarity and cross checking with source documents is required to monitor the progress of the 
study. Direct access to source data is also required for inspections and audits and will be carried out 
giving due consideration to data protection and medical confidentiality. 
14.2 Record Keeping 
Study records and source documents need to be preserved for at least 15 years after the completion or 
discontinuation of/withdrawal from the study or 2 years after the last approval of a marketing application 
of HU6 in an ICH region, whichever is the longest time period. The sponsor will be notified prior to the 
planned destruction of any study related source documents. 
15 FINANCING AND INSURANCE 
Financial aspects of the study are addressed in a separate clinical study agreement.  
The Investigator is required to have adequate current insurance to cover claims for negligence and/or 
malpractice. The Sponsor will provide insurance coverage for the clinical study as required by national 
regulations. 
16 USE OF DATA AND PUBLICATION POLICY 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
The Investigator should be aware that intellectual property rights (and related matters) generated by the 
Investigator and others performing the clinical study will be subject to the terms of a clinical study 
agreement that will be agreed between the Institution and the Sponsor or their designee. With respect to 
such rights, the Sponsor or their designee will solely own all right and interest in any materials, data and 


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intellectual property rights developed by the Investigator and others performing the clinical study 
described in this protocol, subject to the terms of any such agreement. In order to facilitate such 
ownership, the Investigator will be required to assign all such inventions either to the Institution where 
the study is conducted or directly to the Sponsor or their designee, as will be set forth in the clinical study 
agreement. This agreement will not preclude the reporting of any required data to Regulatory Authorities. 
17 REFERENCES 
Bachynsky, N. US Patent Appl. 20150056160A1, Chemically Induced Intracellular Hyperthermia, Feb. 26, 
2015. 
Code of Federal Regulations Title 21 (CFR). 2018 Available from URL: https://www.fda.gov/medical-
devices/medical-device-databases/code-federal-regulations-title-21-food-and-drugs. 
Geisler JG. 2,4 Dinitrophenol as Medicine. Cells. 2019 Mar 23;8(3):280. doi: 10.3390/cells8030280. 
PMID: 30909602; PMCID: PMC6468406. 
Golabi P, Paik JM, Arshad T, Younossi Y, Mishra A, Younossi ZM. Mortality of NAFLD According to 
the Body Composition and Presence of Metabolic Abnormalities. Hepatol Commun. 2020 May 
19;4(8):1136-1148. doi: 10.1002/hep4.1534. PMID: 32766474; PMCID: PMC7395070. 
Harper JA, Dickinson K, Brand MD. Mitochondrial uncoupling as a target for drug development for the 
treatment of obesity. Obes Rev. 2001 Nov;2(4):255-65. doi: 10.1046/j.1467-789x.2001.00043.x. PMID: 
12119996. 
International Council for Harmonisation (ICH) Harmonized Tripartite Guideline. Guideline for Good 
Clinical 
Practice 
E6 
(R2). 
Current 
Step 
5 
version. 
2017 
Available 
from 
URL: 
https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-6-r2-guideline-good-clinical-
practice-step-5_en.pdf. 
International Council for Harmonisation (ICH) Harmonized Tripartite Guideline. M3(R2) Nonclinical 
Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. 
Current version. January 2010. 
Investigator’s Brochure for HU6. Rivus Pharmaceuticals. Edition 1.0: 10July2020. 
Kinabo JL, Durnin JV. Thermic effect of food in man: effect of meal composition, and energy content. Br 
J Nutr. 1990 Jul;64(1):37-44. doi: 10.1079/bjn19900007. PMID: 2400767. 
Perry RJ, Zhang D, Zhang XM, Boyer JL, Shulman GI. Controlled-release mitochondrial protonophore 
reverses diabetes and steatohepatitis in rats. Science. 2015 Mar 13;347(6227):1253-6. doi: 
10.1126/science.aaa0672. Epub 2015 Feb 26. PMID: 25721504; PMCID: PMC4495920. 
Regev A, Palmer M, Avigan MI, Dimick-Santos L, Treem WR, Marcinak JF, Seekins D, Grishna G, Anania 
FA, Freston JW, Lewis JH, Sanyal AJ, Chalasani N. Consensus: guidelines: best practices for detection, 
assessment and management of suspected acute drug-induced liver injury during clinical trials in patients 
with nonalcoholic steatohepatitis. Aliment Pharmacol Ther. 2019; 49:702-713. DOI: 10.1111/apt.15153. 
Sarwar R, Pierce N, Koppe S. Obesity and nonalcoholic fatty liver disease: current perspectives. Diabetes 
Metab Syndr Obes. 2018;11:533-542. Published 2018 Sep 25. doi:10.2147/DMSO.S146339. 


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Tainter ML, Stockton AB, Cutting WC. 1935. Dinitrophenol in the treatment of obesity: Final report. 
JAMA 105:332-337.  
Thompson W. What is the alcohol use disorders identification test (AUDIT)? Accessed on 07Mar2021: 
https://www.medscape.com/answers/285913-41527/what-is-the-alcohol-use-disorders-identification-test-
audit. 
Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-
Fabian L, Friedman SL, Diago M, Romero-Gomez M. Weight Loss Through Lifestyle Modification 
Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015 Aug;149(2):367-
78.e5; quiz e14-5. doi: 10.1053/j.gastro.2015.04.005. Epub 2015 Apr 10. PMID: 25865049. 
Wallace TM, Levy JC, Matthews DR. Use and Abuse of HOMA Modeling. Diabetes Care. 2004; 
27:1487-1495. 
World Medical Association. (WMA) Declaration of Helsinki - Recommendations Guiding Physicians in 
Biomedical Research Involving Human Subjects, 64th WMA General Assembly, Fortaleza, Brazil, October 
2013. Available from URL https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-
principles-for-medical-research-involving-human-subjects/. 
Zhao, X., Jiang, J., Lu Y. Evaluation of efficacy of resin hemoperfusion in patients with acute 2,4-
dinitrophenol poisoning by dynamic monitoring of plasma toxin concentration. 2015. J. Zhejiang Univ-
Sci B (Biomed & Biotechnol) 16(8):720-726. 
Zitting KM, Vujovic H, Yuan RK, Isherwood CM, Medina JE, Wang W, Buxton OM, Williams JS, 
Czeisler CA, Duffy JF. Human Resting Energy Expenditure Varies with Circadian Phase. Current 
Biology 2018;28:3685–3690 e3. doi: 10.1016/j.cub.2018.10.005. Epub 2018 Nov 8. PMID: 30416064; 
PMCID: PMC6300153. 


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18 APPENDICES 
Appendix A:  AUDIT Questions and Scoring System 
Questions 
0 
Points 
1 Point 
2 Points 
3 Points 
4 Points 
1. How often do you have 
a drink containing 
alcohol? 
Never 
Monthly 
or less 
2-4 times 
a month 
2-3 
times a 
week 
4 or 
more 
times a 
week 
2. How many drinks 
containing alcohol do 
you have on a typical day 
when you are drinking? 
1 or 2 
3 or 4 
5 or 6 
7-9 
10 or 
more 
3. How often do you have 
6 or more drinks on 1 
occasion? 
Never 
Less than 
monthly 
Monthly 
Weekly 
Daily or 
almost 
daily 
4. How often during the 
past year have you found 
that you were not able to 
stop drinking once you 
had started? 
Never 
Less than 
monthly 
Monthly 
Weekly 
Daily or 
almost 
daily 
5. How often during the 
past year have you failed 
to do what was normally 
expected of you because 
of drinking? 
Never 
Less than 
monthly 
Monthly 
Weekly 
Daily or 
almost 
daily 
6. How often during the 
past year have you 
needed a first drink in the 
morning to get yourself 
Never 
Less than 
monthly 
Monthly 
Weekly 
Daily or 
almost 
daily 


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Questions 
0 
Points 
1 Point 
2 Points 
3 Points 
4 Points 
going after a heavy 
drinking session? 
7. How often during the 
past year have you had a 
feeling of guilt or 
remorse after drinking? 
Never 
Less than 
monthly 
Monthly 
Weekly 
Daily or 
almost 
daily 
8. How often during the 
past year have you been 
unable to remember what 
happened the night 
before because you had 
been drinking? 
Never 
Less than 
monthly 
Monthly 
Weekly 
Daily or 
almost 
daily 
9. Have you or has 
someone else been 
injured as a result of your 
drinking? 
No 
  
Yes, but 
not in the 
past year 
  
Yes, 
during 
the past 
year 
10. Has a relative, friend, 
or a doctor or other 
health care worker been 
concerned about your 
drinking or suggested 
you cut down? 
No 
  
Yes, but 
not in the 
past year 
  
Yes, 
during 
the past 
year 
 


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Appendix B: Drugs with Known Risk of Torsade des Pointes 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Risk 
Category Route 
Aclarubicin 
(Only on Non US 
Market) 
Aclacin, Aclacinomycine, Aclacinon, 
Aclaplastin, Jaclacin 
Anti-cancer 
Cancer 
 injection 
Amiodarone 
Cordarone, Pacerone, Nexterone 
Antiarrhythmic 
Arrhythmia 
 
oral, 
injection 
Anagrelide 
Agrylin, Xagrid 
Phosphodiesterase 
3 inhibitor 
Thrombocythemia 
 oral 
Arsenic trioxide 
Trisenox 
Anti-cancer 
Cancer (leukemia) 
 injection 
Astemizole 
(Removed from US 
Market) 
Hismanal 
Antihistamine 
Allergic rhinitis 
 oral 
Azithromycin 
Zithromax, Zmax 
Antibiotic 
Bacterial infection 
 
oral, 
injection 
Bepridil 
Vascor 
Antianginal 
Angina Pectoris 
(heart pain) 
 oral 
Cesium Chloride 
Energy Catalyst 
Toxin 
Alternative therapy 
cancer 
 
oral, 
injection 
Chloroquine 
Aralen 
Antimalarial 
Malaria 
 oral 
Chlorpromazine 
Thorazine, Largactil, Megaphen 
Antipsychotic / 
Antiemetic 
Nausea, 
Schizophrenia, many 
others 
 
oral, 
injection, 
suppository 
Chlorprothixene 
(Only on Non US 
Market) 
Truxal 
Antipsychotic 
Schizophrenia 
 
oral, 
injection 
Cilostazol 
Pletal 
Phosphodiesterase 
3 inhibitor 
Intermittent 
claudication 
 oral 
Ciprofloxacin 
Cipro, Cipro-XR, Neofloxin 
Antibiotic 
Bacterial infection 
 
oral, 
injection 
Cisapride 
(Removed from US 
Market) 
Propulsid 
GI stimulant 
Increase GI motility 
 oral 
Citalopram 
Celexa, Cipramil 
Antidepressant, 
SSRI 
Depression 
 oral 
Clarithromycin 
Biaxin, Prevpac 
Antibiotic 
Bacterial infection 
 oral, 


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Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Risk 
Category Route 
inhaled 
Cocaine 
Cocaine 
Local anesthetic 
Anesthesia (topical) 
 oral, nasal 
Disopyramide 
Norpace 
Antiarrhythmic 
Arrhythmia 
 
oral, 
injection 
Dofetilide 
Tikosyn 
Antiarrhythmic 
Arrhythmia 
 oral 
Domperidone 
(Only on Non US 
Market) 
Motilium, Motillium, Motinorm Costi, 
Nomit 
Antiemetic 
Nausea, vomiting 
 
oral, 
injection, 
suppository 
Donepezil 
Aricept 
Cholinesterase 
inhibitor 
Dementia 
(Alzheimer's Disease) 
 oral 
Dronedarone 
Multaq 
Antiarrhythmic 
Arrhythmia 
 oral 
Droperidol 
Inapsine, Droleptan, Dridol, Xomolix 
Antipsychotic / 
Antiemetic 
Anesthesia (adjunct), 
nausea 
 injection 
Erythromycin 
E.E.S., Robimycin, EMycin, Erymax, Ery- 
Tab, Eryc Ranbaxy, Erypar, Eryped, 
Erythrocin Stearate Filmtab, Erythrocot, E-
Base, Erythroped, Ilosone, MY-E, 
Pediamycin, Abboticin, Abboticin-ES, 
Erycin, PCE Dispertab, Stiemycine, 
Acnasol, Tiloryth 
Antibiotic 
Bacterial infection, 
increase GI motility 
 
oral, 
injection 
Escitalopram 
Cipralex, Lexapro, Nexito, Anxiset-E, 
Exodus, Esto, Seroplex, Elicea, Lexamil, 
Lexam, Entact, Losita, Reposil, Animaxen, 
Esitalo, Lexamil 
Antidepressant, 
SSRI 
Depression (major), 
anxiety disorders 
 oral 
Flecainide 
Tambocor, Almarytm, Apocard, Ecrinal, 
Flécaine 
Antiarrhythmic 
Arrhythmia 
 oral 
Fluconazole 
Diflucan, Trican 
Antifungal 
Fungal infection 
 
oral, 
injection 
Gatifloxacin 
(Removed from US 
Market) 
Tequin 
Antibiotic 
Bacterial infection 
 
oral, 
injection 
Grepafloxacin 
(Removed from US 
Market) 
Raxar 
Antibiotic 
Bacterial infection 
 oral 
Halofantrine 
(Only on Non US 
Market) 
Halfan 
Antimalarial 
Malaria 
 oral 


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Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Risk 
Category Route 
Haloperidol 
Haldol, Aloperidin, Bioperidolo, Brotopon, 
Dozic, Duraperidol, Einalon S, Eukystol, 
Halosten, Keselan, Linton, Peluces, 
Serenace, Serenase, Sigaperidol 
Antipsychotic 
Schizophrenia, 
agitation 
 
oral, 
injection 
Hydroquinidine 
(Dihydroquinidine) 
(Only on Non US 
Market) 
Serecor 
Antiarrhythmic 
Arrhythmia 
 oral 
Hydroxychloroquine Plaquenil, Quineprox 
Antimalarial, Anti- 
inflammatory 
Malaria, SLE, 
rheumatoid arthritis 
 oral 
Ibogaine 
(Only on Non US 
Market) 
Psychedelic 
Narcotic addiction, 
unproven 
 oral 
Ibutilide 
Corvert 
Antiarrhythmic 
Arrhythmia 
injection 
Levofloxacin 
Levaquin, Tavanic 
Antibiotic 
Bacterial infection 
 
oral, 
injection 
Levomepromazine 
(Methotrimeprazine) 
(Only on Non US 
Market) 
Nosinan, Nozinan, Levoprome 
Antipsychotic 
Schizophrenia 
 
oral, 
injection 
Levomethadyl 
acetate 
(Removed from US 
Market) 
Orlaam 
Opioid agonist 
Narcotic dependence 
 oral 
Levosulpiride 
(Only on Non US 
Market) 
Lesuride, Levazeo, Enliva 
Antipsychotic 
Schizophrenia 
 
oral, 
injection 
Meglumine 
antimoniate 
(Only on Non US 
Market) 
Glucantime 
Antiparasitic 
Leishmaniasis 
 injection 
Mesoridazine 
(Removed from US 
Market) 
Serentil 
Antipsychotic 
Schizophrenia 
 oral 
Methadone 
Dolophine, Symoron, Amidone, 
Methadose, Physeptone, Heptadon 
Opioid agonist 
Narcotic dependence, 
pain 
 
oral, 
injection 
Moxifloxacin 
Avelox, Avalox, Avelon 
Antibiotic 
Bacterial infection 
 
oral, 
injection 
Nifekalant 
Shinbit 
Antiarrhythmic 
Arrhythmia 
 injection 


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Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Risk 
Category Route 
(Only on Non US 
Market) 
Ondansetron 
Zofran, Anset, Ondemet, Zuplenz, 
Emetron, Ondavell, Emeset, Ondisolv, 
Setronax 
Antiemetic 
Nausea, vomiting 
 
oral, 
injection, 
suppository 
Oxaliplatin 
Eloxatin 
Anti-cancer 
Cancer 
injection 
Papaverine HCl (Intra- 
coronary) 
Vasodilator, 
Coronary 
Diagnostic adjunct 
 injection 
Pentamidine 
Pentam 
Antifungal 
Fungal infection 
(Pneumocystis 
pneumonia) 
 
injection, 
inhaled 
Pimozide 
Orap 
Antipsychotic 
Tourette's Disorder 
oral 
Probucol 
(Removed from US 
Market) 
Lorelco 
Antilipemic 
Hypercholesterolemia 
 oral 
Procainamide 
Pronestyl, Procan 
Antiarrhythmic 
Arrhythmia 
 injection 
Propofol 
Diprivan, Propoven 
Anesthetic, 
general 
Anesthesia 
 injection 
Quinidine 
Quinaglute, Duraquin, Quinact, Quinidex, 
Cin-Quin, Quinora 
Antiarrhythmic 
Arrhythmia 
 
oral, 
injection 
Roxithromycin 
(Only on Non US 
Market) 
Rulide, Xthrocin, Roxl-150, Roxo, Surlid, 
Rulide, Biaxsig, Roxar, Roximycinv, 
Roxomycin, Rulid, Tirabicin, Coroxin 
Antibiotic 
Bacterial infection 
 oral 
Sertindole 
(Only on Non US 
Market) 
Serdolect, Serlect 
Antipsychotic, 
atypical 
Schizophrenia, 
anxiety 
 oral 
Sevoflurane 
Ultane, Sojourn 
Anesthetic, 
general 
Anesthesia 
 inhaled 
Sotalol 
Betapace, Sotalex, Sotacor 
Antiarrhythmic 
Arrhythmia 
 oral 
Sparfloxacin 
(Removed from US 
Market) 
Zagam 
Antibiotic 
Bacterial infection 
 oral 
Sulpiride 
(Only on Non US 
Market) 
Dogmatil, Dolmatil, Eglonyl, Espiride, 
Modal, Sulpor 
Antipsychotic, 
atypical 
Schizophrenia 
 
oral, 
inhaled 


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Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Risk 
Category Route 
Sultopride 
(Only on Non US 
Market) 
Barnetil, Barnotil, Topral 
Antipsychotic, 
atypical 
Schizophrenia 
 
oral, 
injection 
Terfenadine 
(Removed from US 
Market) 
Seldane 
Antihistamine 
Allergic rhinitis 
 oral 
Terlipressin 
(Only on Non US 
Market) 
Teripress, Glypressin, Terlipin, Remestyp, 
Tresil, Teriss 
Vasoconstrictor 
Septic shock 
 injection 
Terodiline 
(Only on Non US 
Market) 
Micturin, Mictrol 
Muscle relaxant 
Bladder spasm 
 oral 
Thioridazine 
Mellaril, Novoridazine, Thioril 
Antipsychotic 
Schizophrenia 
 oral 
Vandetanib 
Caprelsa 
Anti-cancer 
Cancer (thyroid) 
 oral 
  Known Risk of TdP - Substantial evidence supports the conclusion that these drugs prolong the QT 
interval AND are clearly associated with a risk of TdP, even when taken as directed in official labeling. 
  Drugs to Avoid in Congenital Long QT - Substantial evidence supports the conclusion that these drugs 
pose a risk of TdP for patients with congenital long QT. Drugs on this list include those in the above three risk 
categories and other drugs that do not prolong the QT interval per se but they have a theoretical risk of causing 
arrhythmia that is based on their known stimulant actions on the heart. 
Last revision: 17Dec2020 
https://crediblemeds.org/ 
 
 


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               Confidential 
 
Appendix C:  Algorithm for Monitoring and Management of Possible Hepatocellular DILI in 
Phase 2 or 3 NASH Clinical Studies 
Treatment-emergent  
ALT 
Treatment-emergent  
Total Bilirubin 
Liver-related Symptoms 
Actionb 
Normal/near normal baselinea: 
Normal 
None 
Repeat ALT, AST, ALP, TBL, in 2-5 days. Follow‐
up for symptoms. Initiate evaluation for other 
etiologies of abnormal liver tests. 
ALT ≥5× ULN 
Elevated baselinea: 
Patients with Gilbert's 
syndrome: 
ALT ≥3× baseline or ≥300 U/L 
No change in baseline TBL 
(whichever occurs first) 
 
Normal/near normal baselinea: 
ALT ≥3× ULN 
Elevated baselinea: 
ALT ≥2× baseline or ≥300 U/L 
(whichever occurs first) 
Normal 
Patients with Gilbert's 
syndrome: 
No change in baseline TBL 
Severe fatigue, nausea, vomiting, 
right upper quadrant pain 
Repeat ALT, AST, ALP, TBL, in 2-5 days. Follow‐
up for symptoms. Initiate evaluation for other 
etiologies of abnormal liver tests. 
Normal/near normal baselinea: 
Normal 
None 
Interrupt study drug. Initiate close monitoring and 
workup for competing etiologies. Study drug can be 
restarted only if another etiology is identified and 
liver enzymes return to baseline. 
ALT ≥8× ULN 
Elevated baselinea: 
Patients with Gilbert's 
syndrome: 
ALT ≥5× baseline or ≥500 U/L  
No change in baseline TBL 
(whichever occurs first) 
 
Normal/near normal baselinea: 
ALT ≥3 ULN 
Elevated baselinea: 
ALT ≥2× baseline or ≥300 U/L 
(whichever occurs first) 
TBL ≥2× ULN 
None 
Interrupt study drug. Initiate close monitoring and 
workup for competing etiologies. Study drug can be 
restarted only if another etiology is identified, and liver 
enzymes return to baseline. 
Patients with Gilbert's 
syndrome: 
Doubling of direct bilirubin or increased 
INR to >1.5 
 
Normal/near normal baselinea:“ 
ALT ≥5 ULN 
Elevated baselinea: 
ALT ≥3× baseline or ≥300 U/L 
(whichever occurs first) 
Normal or elevated 
Severe fatigue, nausea, vomiting, 
right upper quadrant pain 
Interrupt study drug. Initiate close monitoring and 
workup for competing etiologies. Study drug can be 
restarted only if another etiology is identified, and liver 
enzymes return to baseline. 
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DILI, drug‐induced liver injury; INR, international normalized ratio; TBL, total bilirubin, ULN, upper 
limit of normal. 
a. 
Baseline ALT is derived from an average of two pre‐treatment ALT measurements at least 2 weeks apart. Elevated baseline is defined as ALT ≥1.5× ULN. In patients with a sizable stable 
decrease in ALT (>50% of the baseline value) during treatment, a new baseline, corresponding to the ALT nadir, should be established on an individual basis for subsequent determination 
of a DILI signal. 
b. 
The actions of close observation, monitoring, and drug interruption often overlap. Occasionally, workup is initiated after drug interruption. 
For further details, please see full Consensus and Recommendation list in Regev A et al., 2019. 

SAP_001.pdf: 
Statistical Analysis Plan 
Version 4.0 
Rivus Pharmaceuticals, Inc., Protocol RIV-HU6-203 
13 December 2021 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN (SAP) 
Protocol Number: 
RIV-HU6-203 
Protocol Title: 
A 61-day Randomized, Double-blind, Placebo-controlled 
Trial to Assess the Safety and Efficacy of Three Doses of 
HU6 in Subjects with Elevated Liver Fat and High Body 
Mass Index (28 to 45 kg/m2) 
Product Name or Number: 
HU6 
Protocol Version 
Version 2.0, 04 May 2021 
Sponsor: 
Rivus Pharmaceuticals, Inc. 
706b Forest Street,  
Charlottesville, VA  22903 USA 
SAP Prepared by: 
Kimberly T Perry, PhD 
Innovative Analytics, Inc.  
161 East Michigan Ave 
Kalamazoo, MI 49007 USA 
SAP Version Number (Date): 
Version 4.0 (13 December 2021) 
 
 
 
 
 


Statistical Analysis Plan 
Version 4.0 
Rivus Pharmaceuticals, Inc., Protocol RIV-HU6-203 
13 December 2021 
 
 
2 
TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................4 
2 
STUDY OVERVIEW ..........................................................................................................5 
3 
STUDY OBJECTIVES ........................................................................................................6 
4 
STUDY ENDPOINTS .........................................................................................................6 
4.1 
Primary Endpoint .............................................................................................................6 
4.2 
Secondary Endpoints .......................................................................................................6 
4.3 
Exploratory Endpoints .....................................................................................................8 
5 
GENERAL METHODS.......................................................................................................8 
5.1 
Analysis Populations ........................................................................................................8 
5.2 
Summarization of Data ....................................................................................................8 
5.3 
Sample Size Justification .................................................................................................8 
5.4 
Output Production and Validation ...................................................................................9 
6 
SUBJECT DISPOSITION ...................................................................................................9 
7 
DEMOGRAPHIC CHARACTERISTICS ...........................................................................9 
8 
MEDICAL HISTORY .........................................................................................................9 
9 
PHYSICAL EXAMINATION.............................................................................................9 
10 
PRIOR AND CONCOMITANT MEDICATIONS .............................................................9 
11 
EFFICACY ANALYSES ..................................................................................................10 
12 
PHARMACODYNAMICS ANALYSES ..........................................................................10 
13 
SAFETY ANALYSES.......................................................................................................11 
13.1 
Adverse Events ..............................................................................................................11 
13.2 
Laboratory Tests (Hematology, Serum Chemistry, Urinalysis, and PEth 
16.0/18.1 (POPEth)) ......................................................................................................12 
13.3 
Vital Signs ......................................................................................................................13 
13.4 
InBody Scale Measurements .........................................................................................13 
13.5 
Electrocardiograms ........................................................................................................13 
13.6 
Lipidomic (OWL Metabolomics) ..................................................................................14 
13.7 
Metabolomic (OWL Metabolomics) .............................................................................14 
13.8 
Proteomic (SomaScan® Assay) ......................................................................................14 
14 
PHARMACOKINETIC ANALYSES ...............................................................................14 


Statistical Analysis Plan 
Version 4.0 
Rivus Pharmaceuticals, Inc., Protocol RIV-HU6-203 
13 December 2021 
 
 
3 
15 
SUBJECT LISTINGS ........................................................................................................14 
16 
INTERIM ANALYSES .....................................................................................................14 
17 
FINAL SIGN-OFF FOR RIVUS PHARMACEUTICALS, INC, PROTOCOL 
RIV-HU6-203 STATISTICAL ANALYSIS PLAN ..........................................................15 
18 
REVISIONS TO STATISTICAL ANALYSIS PLAN ......................................................16 
19 
APPENDIX ........................................................................................................................17 
19.1 
Conventions for Statistical Tables and Subject Listings ...............................................17 
19.2 
Table of Contents for Mockups of Statistical Tables ....................................................18 
19.3 
Table of Contents for Mockups of Subject Listings ....................................................132 
19.4 
Table of Contents for Mockups of Figures ..................................................................184 
 


Statistical Analysis Plan 
Version 4.0 
Rivus Pharmaceuticals, Inc., Protocol RIV-HU6-203 
13 December 2021 
 
 
4 
1 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Definition 
AE 
adverse event  
ANCOVA 
analysis of covariance  
BMI 
body mass index 
CAP 
controlled attenuation parameter  
CI 
confidence interval 
Cmax 
maximum plasma drug concentration 
DNP 
2,4-dinitrophenol  
ECG 
electrocardiogram 
ELF 
enhanced liver fibrosis  
FAS 
full analysis set 
FFA 
free fatty acid 
HbA1c 
glycosylated hemoglobin (hemoglobin A1c) 
HDL 
high- density lipoprotein 
HOMA-IR 
homeostatic model assessment for insulin resistance  
hs-CRP 
high sensitivity C-reactive protein 
ITT 
intent-to-treat 
LDL 
low-density lipoprotein 
LS Means 
least squares means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures  
MRI 
magnetic resonance imaging 
MRI-PDFF 
magnetic resonance imaging proton density fat fraction 
OWL 
One Way Liver 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
POPEth 
phosphatidylethanol (PEth) 16.0/18.1 
QD 
once daily 
TEAE 
treatment-emergent adverse event 
VCTE 
vibration-controlled transient elastography  
 
 


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2 STUDY OVERVIEW 
This is a Phase 2a, multi-site, randomized, parallel-group, placebo-controlled, double-blind, 
repeated-dose study to evaluate the safety and efficacy of three oral dose levels of HU6 
compared to placebo over the course of 61 days in subjects with high body mass index (BMI) 
and evidence of elevated liver fat.  
Subjects will be screened over a 45-day period to determine eligibility based on specific history, 
physical, laboratory and imaging evaluations.  Due to scheduling of the procedures, multiple 
visits will likely be necessary to complete the screening process.  However, if all screening 
assessments and procedures, including the magnetic resonance imaging (MRI), can be completed 
within 30 days of the first dose, then a single screening visit is permissible. 
Once qualified, subjects will be randomly assigned to one of the HU6 treatment groups or the 
matched placebo control group and dosed once daily (QD) in a fasting state for a total of 61 
days. Subjects will return to the clinic for frequent assessment visits during the 61 days of 
dosing. A follow-up visit will occur within 10 to 14 days following the completion of dosing 
(Figure 1). 
Figure 1: Study Schematic 
 
Subjects will be instructed to maintain their same diet and activity/exercise level throughout the 
study as they had prior to participation in the study.  
 
Dosing will take place once daily in a fasted state. Eligible subjects will be randomized equally 
(N = 20 per group) to 1 of 4 treatment groups:  
• Group 1: matched placebo orally once daily for 61 days. 
• Group 2: 150 mg HU6 orally once daily for 61 days.  
• Group 3: 300 mg HU6 orally once daily for 61 days. 
• Group 4: 450 mg HU6 orally once daily for 61 days.  


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The randomization will be blocked and stratified by HbA1c.  Subjects will be stratified 
into two HbA1c strata: one subgroup of subjects with normal baseline HbA1c defined as 
HbA1c <5.7% and the other subgroup of subjects with high baseline HbA1c defined as 
HbA1c between 5.7% and 9.0% inclusive). 
3 STUDY OBJECTIVES 
The primary efficacy and safety objectives of this study are: 
Efficacy: 
• To evaluate the reduction in liver fat content, as assessed by magnetic resonance imaging 
proton density fat fraction (MRI-PDFF), from baseline to Day 61 in subjects with 
elevated BMI treated with HU6 compared to placebo.  
 
Safety: 
• To evaluate safety and tolerability of 61 days of repeated daily dosing of HU6 in 
overweight and obese subjects as defined by BMI.  
   The secondary objectives of this study are: 
• To assess the rate and amount of body weight loss after 61 days of HU6 treatment.  
• To assess change from baseline in whole body adiposity by MRI after 61 days of HU6 
treatment.  
• To characterize the pharmacokinetic (PK) profile of HU6 and its metabolites, DNP and 
M1, over 61 days of dosing in subjects with high BMI.  
• To evaluate and correlate changes from baseline in measures of liver composition with 
changes in liver fat content after dosing with HU6.  
• To investigate the pharmacodynamic (PD) effects of HU6 on metabolic and 
cardiovascular risk factors.  
• To investigate the PD effects of HU6 on metabolomic, proteomic, and lipidomic profiles.  
• To characterize the dose/exposure relationships of the efficacy and PD effects of HU6, as 
data allow.  
4 STUDY ENDPOINTS 
4.1 Primary Endpoint 
• Relative change from baseline in liver fat content, as assessed by MRI-PDFF at Day 61. 
4.2 Secondary Endpoints 
Pharmacodynamics  
• Change from baseline in body weight at Day 61.  


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• Change from baseline in whole body adiposity at Day 61 [i.e., total visceral adipose 
tissue (VAT) and subcutaneous adipose tissue (SAT)] 
• Changes from baseline in surrogate measures of liver inflammation and fibrosis at 
Day 61: Fibroscan® Vibration-controlled Transient Elastography (VCTE), Fibroscan® 
Controlled Attenuation Parameter (CAP) score, and Enhanced Liver Fibrosis (ELF) 
score.  
• Change from baseline in lipid parameters and cardiovascular risk biomarkers at Day 61: 
serum high sensitivity C-reactive protein (hs-CRP), Lp(A), Apo B, low-density 
lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol, triglycerides, and 
free fatty acids (FFA).  
• Change from baseline in metabolic disease parameters at Day 61: homeostatic model 
assessment for insulin resistance (HOMA-IR), fasting blood glucose concentrations, 
glycated albumin concentrations, HbA1c.  
 
Safety and Tolerability  
• Summary of physical examinations findings over the course of the study.  
• Adverse event (AE) assessment over the course of the study.  
• Assessment of vital sign parameters over the course of the study, including resting 
systolic and diastolic blood pressure, resting heart rate, resting respiratory rate, and oral 
body temperature.  
• Assessment of body weight over the course of the study.  
• Safety 12-lead electrocardiograms (ECGs) over the course of the study.  
• Assessment of clinical laboratory values (hematology, full biochemistry panel (including 
lipid panel, creatinine phosphokinase (CPK), magnesium, liver function tests, and 
urinalysis over 61 days of dosing.  
• Assessment of ophthalmologic examination, including slit lamp, prior to and after 61 
days of dosing.  
 
Pharmacokinetics  
• Population PK analysis of HU6 parent and metabolites, DNP and M1. The following PK 
parameters will be estimated as appropriate: maximum observed plasma drug 
concentration (Cmax), time to peak plasma concentration (Tmax), apparent terminal half-
life (t½), delay between the time of dosing and time of appearance of concentration in the 
sampling compartment (Tlag), area under the concentration-time curve from time zero to 
the time of the last measurable concentration (AUCt), area under the concentration-time 
curve from time zero to infinity (AUCinf), apparent oral clearance (CL/F), apparent 
volume of distribution (Vz/F), apparent terminal elimination rate constant (λz). Other PK 
parameters may be calculated, as data allow and as appropriate.  
• As data permit, noncompartmental analysis of HU6 parent and metabolites, DNP and 
M1. The following PK parameters will be calculated: Cmax, AUC, and accumulation.  


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• Modeling of exposure response relationships of HU6, DNP, and M1 and 
efficacy/pharmacodynamic endpoints, as appropriate.  
4.3 Exploratory Endpoints 
• Change from baseline in metabolomic and lipidomic profiles (One Way Liver-[OWL] 
metabolomic and lipidomic assays) at Day 61.  
• Change from baseline in proteomic profiles (SomaScan®) at Day 61.  
• Change from baseline in serum alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) concentrations at Day 61, as data allow.  
5 GENERAL METHODS 
5.1 Analysis Populations 
The analysis populations will be as follows: 
Intent-to-Treat (ITT): includes all randomized subjects. Subjects will be analyzed according to 
treatment as randomized. 
Full Analysis Set (FAS): includes all randomized subjects who receive at least 1 dose of 
treatment and have <= 10 pounds of weight gain or weight lost from screening visit to Day 1.  
Subjects will be analyzed according to treatment as randomized. 
Safety:  includes all randomized subjects who receive at least 1 dose of treatment. Subjects will 
be analyzed according to treatment as received. 
The PK concentration population and the PK parameter population will be defined in the PK 
analysis plan. 
5.2 Summarization of Data 
Study results will be summarized by treatment group (i.e., 150 mg QD, 300 mg QD, 450 mg QD, 
and Placebo) in tabular format with descriptive statistics and/or in subject listings.  
For placebo-corrected results, at each visit, the average placebo mean change from baseline will 
be subtracted from each subject’s mean change from baseline. 
Statistical testing will be 2-sided and performed using a significance (alpha) level of 0.05. There 
will be no adjustment for multiple comparisons for this exploratory study. 
No imputation of missing data will be performed.  No windowing of visits will be performed 
unless otherwise specified. 
5.3 Sample Size Justification 
A sample size of 17 subjects per group provides at least 80% power to detect a 30% difference in 
the mean relative change from baseline in liver fat content at Day 61, when the standard 
deviation is 30% [PASS 2020: Two sample t-test, alpha=.05]. Assuming a 15% dropout rate, up 


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to 80 subjects should be enrolled to ensure that at least 68 subjects, 17 per group, are evaluable 
for the primary efficacy endpoint analysis.  
5.4 Output Production and Validation 
All analyses will be performed using SAS V 9.3 or higher (SAS Institute, Inc, Cary, North 
Carolina, USA).  Validation and quality control of the tables and listings, which display the 
results of the statistical analysis of the data from this study, will follow the appropriate 
Innovative Analytics standard operating procedures (SOPs). 
6 SUBJECT DISPOSITION 
The number of subjects who are in the intent-to-treat (ITT) population, who are in the full 
analysis set (FAS) population, who are in the safety population, who complete the study, and 
who discontinue from the study, along with reason of study discontinuation, will be summarized 
in tabular format for the ITT population.  Subject disposition information will be displayed for 
the ITT population in a subject listing. 
7 DEMOGRAPHIC CHARACTERISTICS 
For quantitative variables (e.g., age, height, weight, BMI), summary statistics (n, mean, standard 
deviation, minimum, median, and maximum) will be presented for all subjects in the safety 
population.  For qualitative variables (e.g., sex, race, ethnicity), results will be summarized for 
all subjects in the safety population as counts and percentages.  Individual demographic 
information for the safety population will be displayed in subject listings. 
8 MEDICAL HISTORY 
Medical history findings will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding system (using MedDRA Version stated in Data Management Plan).  Medical 
history findings will be summarized by System Organ Class and Preferred Term.  Individual 
medical history findings will be listed for the safety population. 
9 PHYSICAL EXAMINATION 
Abnormal physical examination findings will be listed for the safety population.   
10 PRIOR AND CONCOMITANT MEDICATIONS 
Medications will be coded using World Health Organization Drug Dictionary (WHODRUG, 
version specified in the Data Management Plan).  Prior medications and concomitant 
medications will be summarized separately by Anatomical Therapeutic Chemical (ATC) Level 4 
term and Preferred Name.  Prior medications are defined as medications taken prior to the first 
dose of study drug, including those medications that were continued during the study.  
Concomitant medications will be defined as medications started after the first dose of study 
medication.  Individual medications will be displayed in subject listings. 


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11 EFFICACY ANALYSES 
The primary efficacy endpoint will be the reduction in liver fat content measured by the relative 
change from baseline, as assessed by MRI-PDFF at Day 61. The hypotheses of interest are 
2-sided tests comparing each active HU6 treatment group to the placebo group. 
𝐻01: 𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜= 𝜇𝐻𝑈6 150𝑚𝑔vs 𝐻11: 𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜≠𝜇𝐻𝑈6 150𝑚𝑔    
𝐻02: 𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜= 𝜇𝐻𝑈6 300𝑚𝑔vs 𝐻12: 𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜≠𝜇𝐻𝑈6 300𝑚𝑔    
𝐻03: 𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜= 𝜇𝐻𝑈6 450𝑚𝑔vs 𝐻13: 𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜≠𝜇𝐻𝑈6 450𝑚𝑔   
 
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values for MRI-PDFF at each time point for the FAS population, as 
described in Section 5.2, Summarization of Data.  Summary statistics will also be presented for 
the change-from-baseline values to each postbaseline time point as well as placebo-corrected 
change-from-baseline values to each postbaseline time point.  In these displays, baseline will be 
defined as the last non-missing value prior to first dose of study medication.  Figures will be 
generated appropriate to the data output. 
Mean change from baseline in liver fat content will be analyzed for the FAS population using an 
analysis of covariance (ANCOVA) model, including treatment group, HbA1c stratification 
(normal range versus between 5.7% and 9.0% inclusive) and baseline liver fat from MRI-PDFF 
as fixed effects. This estimand will include available MRI-PDFF evaluations that occur before 
discontinuation of treatment.  The difference in LS Means for the change from baseline, 
corresponding 95% CIs, and P values will be provided to assess the treatment differences 
between placebo and each HU6 treatment group. A separate comparison of the combined HU6 
groups and placebo may be conducted.  
Responder status (n, %) at Day 61 will be presented.  A subject will be deemed a responder if 
their MRI-PDFF showed a 30% or more reduction from baseline at Day 61.  Additional 
exploratory analysis may be performed such as a different threshold then the 30% or more 
reduction from baseline due to the short duration of the study. 
The above summary statistics, an ANCOVA model including treatment group and the baseline 
score of the response variable as fixed effects, and the responder status will also be presented for 
the subjects randomized only to the HbA1c between 5.7% and 9.0% subgroup. 
All MRI-PDFF results will be displayed in subject listings. 
12 PHARMACODYNAMICS ANALYSES 
For each pharmacodynamic variable, summary statistics (n, mean, standard deviation, minimum, 
median, and maximum) will be presented for the observed values at each time point for the FAS 
population, as described in Section 5.2, Summarization of Data.  Summary statistics will also be 
presented for the change-from-baseline values to each postbaseline time point.  For glycated 
albumin, placebo-corrected change-from-baseline values to each postbaseline time point will be 
presented. In these displays, baseline will be defined as the last non-missing value prior to first 
dose of study medication.  Figures will be generated appropriate to the data output. 


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For pharmacodynamic variables with only a Day 61 post-baseline assessment [i.e., ELF 
variables, HbA1c, abdominal MRI [liver volume, VAT, and SAT], and Fibroscan 
[Steatosis/VCTE and Fibrosis/CAP], summary statistics will be presented for the change-from-
baseline values for each variable at Day 61.  Placebo-corrected change-from-baseline values at 
Day 61 will be presented for abdominal MRI [liver volume, total visceral adipose tissue (VAT) 
and subcutaneous adipose tissue (SAT)], and Fibrosis/CAP.  The ELF variables will be ELF 
score, hyaluronic acid, procollagen III amino-terminal peptide (PIIINP), and tissue inhibitor of 
matrix metalloproteinase 1 (TIMP-1).  Figures will be generated appropriate to the data output. 
For each pharmacodynamic variable with only a Day 61 post-baseline assessment, mean change 
from baseline will be analyzed for the FAS population using an ANCOVA model, including 
treatment group, HbA1c stratification (normal range versus between 5.7% and 9.0% inclusive) 
and the baseline score of the response variable as fixed effects. The difference in LS Means for 
the change from baseline, corresponding 95% CIs, and P values will be provided to assess the 
treatment differences between placebo and each HU6 treatment group.  
For the abdominal MRI liver volume and adiposity, the above summary statistics, an ANCOVA 
model including treatment group and the baseline score of the response variable as fixed effects, 
and the responder status will also be presented for the subjects randomized only to the HbA1c 
between 5.7% and 9.0% subgroup. 
Continuous pharmacodynamic endpoints with repeated post-baseline assessments [changes from 
baseline in ApoB, Lp(a), glycated albumin, hs-CRP, liver panel parameters (total cholesterol, 
HDL, calculated LDL, VLDL, triglycerides, and FFA), HOMA-IR Calc (i.e., the average of the 3 
blood draws 5 minutes apart at each scheduled visit), body weight (via InBody Scale), and 
fasting blood glucose] will be analyzed for the FAS population using a mixed model for repeated 
measures (MMRM).  The estimand will include available post-baseline response data that occur 
before discontinuation of treatment.  The baseline score will be included as the covariate, and 
HbA1c stratification, treatment group, visit, and the interaction between treatment group and visit 
will be estimated based on the LSMeans from the MMRM. 
For body weight, a responder status (n, %) at Day 61 will be presented.  A subject will be 
deemed a responder if their body weight showed a 1% or more reduction from baseline at Day 
61.  Additional exploratory analysis may be performed. 
In addition, for body weight, the above summary statistics, an MMSE analysis and the responder 
status will also be presented for the subjects randomized only to the HbA1c between 5.7% and 
9.0% subgroup.  For the MMRM, the baseline score will be included as the covariate, and 
treatment group, visit, and the interaction between treatment group and visit will be estimated 
based on the LSMeans from the MMRM. 
All pharmacodynamic results will be displayed in subject listings. 
13 SAFETY ANALYSES 
13.1 Adverse Events 
Adverse events will be coded using the MedDRA coding system (using MedDRA Version stated 
in Data Management Plan).  An overall summary table will be presented to summarize all 


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treatment-emergent AEs (TEAEs), all treatment-emergent study drug-related AEs, all severe 
TEAEs, deaths, all serious TEAEs, and all study drug discontinuations due to TEAEs for all 
subjects in the safety population as described in Section 5.2, Summarization of Data.  In 
addition, frequency tables will present all TEAEs by System Organ Class and Preferred Term 
and study drug-related TEAEs by System Organ Class and Preferred Term, with a separate 
display of study-drug related TEAEs by maximum severity for all subjects in the safety 
population. 
If an AE occurs after the informed consent form has been signed and before the time of the first 
dose of study drug, it will be considered a pretreatment AE.  If an AE occurs at the time of or 
after the first dose of study drug or if the pretreatment AE worsens, it will be considered a 
treatment-emergent AE. 
If the relationship to study medication is missing, it will be assumed to be related to study 
medication for analysis purposes. 
In all displays, AEs will be displayed by MedDRA System Organ Class and Preferred Term, 
with subjects who have the same AE counted only once for that event and subjects who have 
more than one AE within a System Organ Class counted only once in that System Organ Class. 
13.2 Laboratory Tests (Hematology, Serum Chemistry, Urinalysis, and PEth 
16.0/18.1 (POPEth)) 
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values for hematology, serum chemistry, urinalysis, and PEth 
16.0/18.1 (POPEth) at each time point for the safety population, as described in Section 5.2, 
Summarization of Data.  Summary statistics will also be presented for the change-from-baseline 
values to each postbaseline time point.  In these displays, baseline will be defined as the last non-
missing value prior to first dose of study medication.  Figures will be generated appropriate to 
the data output. 
A shift table will be presented for baseline versus each post-baseline visit for absolute neutrophil 
count using following grades: 
• Normal: >=2.5 neutrophils (10**9/L); 
•  Grade 1: 1.5 to <2.5 neutrophils (10**9/L); 
•  Grade 2: 1.0 to <1.5 neutrophils (10**9/L); 
•  Grade 3: 0.5 to <1.0 neutrophils (10**9/L); 
•  Grade 4: <0.5 neutrophils (10**9/L)  
Hematology, chemistry, urinalysis, and POPEth panel results will be listed, with values falling 
outside the laboratory reference range flagged.   
Laboratory reference ranges will be provided by the laboratory site(s) and will be included in the 
clinical study report. 


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13.3 Vital Signs 
Supine vital signs will be collected.  Summary statistics (n, mean, standard deviation, minimum, 
median, and maximum) will be presented for the observed values for systolic and diastolic blood 
pressures, pulse rate, respiratory rate, body temperature, and weight at each time point for the 
safety population, as described in Section 5.2, Summarization of Data.  Summary statistics will 
also be presented for the change-from-baseline values to each postbaseline time point.  In these 
displays, baseline will be defined as the last non-missing value prior to first dose of study 
medication.  Figures will be generated appropriate to the data output. 
All vital sign results will be displayed in subject listings. 
13.4 InBody Scale Measurements 
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values for InBody scale measurements (i.e., total body water, lean 
body mass, percent body fat, body fat mass, skeletal muscle mass, dry lean mass, and visceral 
fat) at each time point for the safety population, as described in Section 5.2, Summarization of 
Data.  Summary statistics will also be presented for the change-from-baseline values to each 
postbaseline time point as well as placebo-corrected change-from-baseline values to each 
postbaseline time point.  In these displays, baseline will be defined as the last non-missing value 
prior to first dose of study medication.  Figures will be generated appropriate to the data output. 
For body fat mass and lean body mass, a responder status (n, %) at Day 61 will be presented.  A 
subject will be deemed a responder if their body fat mass showed a 1% or more reduction from 
baseline at Day 61.  The same criteria will be used for the lean body mass.  Additional 
exploratory analysis may be performed. 
The responder status will also be presented for the subjects randomized only to the HbA1c 
between 5.7% and 9.0% subgroup. 
InBody measurement results will be listed.   
13.5 Electrocardiograms 
Single 12-lead ECGs will be collected.  For the quantitative variables RR, QRS, PR, QT, QTcF 
(QT interval corrected for heart rate by Fridericia’s method), and heart rate, summary statistics 
(n, mean, standard deviation, minimum, median, and maximum) will be presented for the 
observed values at each time point, as described in Section 5.2, Summarization of Data.  
Summary statistics will also be presented for the change-from-baseline values to each 
postbaseline time point. In these displays, baseline will be defined as the last non-missing value 
prior to first dose of study medication. 
The following results will be tabulated (n, %) by treatment group: 
• Potential QTcF values of concern at any time post-baseline for: 
o    Increase from Baseline of >30 and <= 60 msec 
o    Increase from Baseline of > 60 msec 


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o    Post-baseline value > 500 msec 
All ECG results will be displayed in subject listings for the safety population. 
13.6 Lipidomic (OWL Metabolomics) 
Lipidomic analyses are not described in this statistical analysis plan.  A separate lipidomic 
analysis plan will be provided. 
13.7 Metabolomic (OWL Metabolomics) 
Metabolomic analyses are not described in this statistical analysis plan.  A separate metabolomic 
analysis plan will be provided. 
13.8 Proteomic (SomaScan® Assay) 
Proteomic (SomaScan Assay) analyses are not described in this statistical analysis plan.  A 
separate proteomic analysis plan will be provided. 
14 PHARMACOKINETIC ANALYSES 
PK analyses are not described in this statistical analysis plan.  A separate PK analysis plan will 
be provided prior to the commencement of the study. 
15 SUBJECT LISTINGS  
Data that are collected and entered into the study database but that are not displayed in the 
summary tables that are specified in the preceding sections will be presented in subject listings.  
These will include (but will not be limited to) data from the following modules: 
Dosing Information 
Inclusion/Exclusion Criteria 
Protocol Deviation 
Neurological Examination 
Ophthalmology Examination 
Concomitant Procedures 
16 INTERIM ANALYSES 
No statistical interim analysis is planned.  


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17 FINAL SIGN-OFF FOR RIVUS PHARMACEUTICALS, INC, 
PROTOCOL RIV-HU6-203 STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
Kimberly T. Perry, PhD 
Director of Clinical Services 
Innovative Analytics, Inc. 
Kalamazoo, MI 49007 
 
 
 
 
 
 
 
Date 
Roger Morgan, MD 
Vice President Medical Affairs 
MedSurgPI, LLC 
Franklinton, NC  27525 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
      


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18 REVISIONS TO STATISTICAL ANALYSIS PLAN 
Date 
Revision 
03 September 2021 
The SAP was revised to analyze the HOMA-IR Calc only (i.e., the average of 
the 3 blood draws 5 minutes apart at each scheduled visit).  Insulin, glucose, 
and C-peptide results will be listed only. 
02 December 2021 
Added summary statistics for placebo-corrected change-from-baseline values 
to each postbaseline time point for specified parameters and figures will be 
generated appropriate to the data output.  Added responder status summary 
statistics for specified parameters at Day 61. 
09 December 2021 
For subjects in HbA1c 5.7% - 9.0% subgroup only, added summary statistics 
for change-from-baseline values to each postbaseline time point for specified 
parameters, placebo-corrected change-from-baseline values to each 
postbaseline time point for specified parameters, and MMRM or ANCOVA 
analysis as appropriate.  Figures will be generated appropriate to the data 
output.  In addition, added responder status summary statistics for specified 
parameters at Day 61. 
An addition, a criterion on body weight was added to the definition of 
Full Analysis Set (FAS).