Clinical trial NCT04052516
Conditions: Non Alcoholic Steatohepatitis (NASH)
Sponsor: NorthSea Therapeutics B.V.
Start date: 2019-07-17; Completion date: 2022-12-19
Enrollment: 280 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2b study to evaluate the efficacy of different doses of NST-4016 on the resolution of NASH without worsening of fibrosis

Detailed description:
This is a 62 week (including screening and follow-up), multicenter, randomized, double blind, placebo-controlled, parallel group study in male and female patients with a histological diagnosis of NASH. The study includes a screening period, double blind treatment period, and post-treatment follow up

Arms: arm 1: Placebo oral capsules taken one daily for 52 weeks arm 2: Icosabutate 300mg oral capsule taken once daily for 52 weeks arm 3: Icosabutate 600mg oral capsules taken once daily for 52 weeks
Interventions: intervention 1: Icosabutate intervention 2: Placebo
Intervention descriptions: intervention 1: Icosabutate oral capsule once daily intervention 2: Matching placebo oral capsule

Protocol documents:
Prot_000.pdf: 
 
CLINICAL STUDY PROTOCOL 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study of NST-4016 in Patients With Nonalcoholic 
Steatohepatitis (NASH) 
Investigational Product: NST-4016 Icosabutate 
Protocol Number: NST-02 
 
 
Sponsor: 
 
 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6, 1105 BP  
Amsterdam, The Netherlands 
Telephone: +31 35 760 65 05 
 
 
 
Version Number: 8.0 
Original Protocol: 25 January 2019 
Amendment 1: 06 May 2019 
Amendment 2: 22 May 2019 
Amendment 3: 21 January 2020 
Amendment 4: 20 February 2020 
Amendment 5: 16 July 2020 
Amendment 6: 28 July 2021 
Amendment 7: 21 July 2022 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of NorthSea Therapeutics B.V. (hereinafter NorthSea) except to the extent that 
disclosure would be required by law and for the purpose of evaluating and/or conducting a 
clinical study for NorthSea. You are allowed to disclose the contents of this document only to 
your Institutional Review Board and study personnel directly involved with conducting this 
protocol. Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to NorthSea and that it may not be further disclosed to third parties. 


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NorthSea Therapeutics B.V. 
Clinical Study Protocol NST-02 
Confidential & Proprietary 
 
Version 8.0, 21 July 2022 
3 
INVESTIGATOR AGREEMENT 
By signing below, I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by NorthSea Therapeutics B.V. (hereinafter NorthSea) to study personnel under my supervision. I 
will discuss this material with them to ensure they are fully informed about the study product and 
study procedures. I will let them know that this information is confidential and proprietary to 
NorthSea and that it may not be further disclosed to third parties. I understand that the study may 
be terminated, or enrollment suspended at any time by NorthSea, with or without cause, or by me 
if it becomes necessary to protect the best interests of the study patients. 
I agree to conduct this study in full accordance with Food and Drug Administration regulations, 
Institutional Review Board regulations, and International Council for Harmonisation Guidelines 
for Good Clinical Practice. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 


NorthSea Therapeutics B.V. 
Clinical Study Protocol NST-02 
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4 
SYNOPSIS 
TITLE: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of 
NST-4016 in Patients With Nonalcoholic Steatohepatitis (NASH) 
PROTOCOL NUMBER: NST-02 
INVESTIGATIONAL PRODUCT: NST-4016 Icosabutate 
PHASE: 2b 
INDICATION: Nonalcoholic steatohepatitis (NASH) without cirrhosis 
OBJECTIVES: 
The primary objective is to evaluate the efficacy of different doses of NST-4016 on the resolution 
of NASH without worsening of fibrosis. 
The secondary objective is to determine the safety and tolerability of NST-4016 in patients with 
NASH without cirrhosis. 
POPULATION: 
Inclusion Criteria 
A patient who meets all of the following criteria will be eligible to participate in the study: 
1. Provides signed written informed consent and agrees to comply with the study protocol. 
2. Is a male or female aged 18 to 75 years, inclusive. 
3. Has a histological diagnosis of NASH without cirrhosis prior to study entry, as confirmed by 
either of the following: 
a. A historical liver biopsy within 6 months of screening (and has not received any NASH 
treatment since the biopsy). The histology slides from the historical biopsy must be 
evaluable and available for review by the central pathology reader. Historical liver biopsies 
obtained during the course of a prior investigational drug study must not be utilized if 
obtained within 3 months or 5 half-lives of the last dose of the prior investigational drug, 
whichever is longer. 
OR 
b. A contemporaneous liver biopsy during the screening period (Week -8 to Week -1). 
Patients without a historical biopsy must also have a FibroScan vibration-controlled 
transient elastography (VCTE) measurement 8.5 kPa and a controlled attenuation 
parameter (CAP) for steatosis with cut-off values 300 dB/m at screening or a historical 
FibroScan (with eligible VCTE and CAP values) within 90 days of screening (prior to 
moving forward with the magnetic resonance imaging [MRI]-proton density-fat fraction 
[PDFF] and subsequent liver biopsy). 


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Note: Prior to performing a contemporaneous liver biopsy, patients must have 3 or more 
of the following metabolic risk factors: 
 Type 2 diabetes. 
 Elevated fasting glucose (100 mg/dL). 
 Elevated blood pressure (systolic 130 mmHg or diastolic 85 mmHg or on 
antihypertensive drug treatment). 
 Fasting high-density lipoprotein-cholesterol (40 mg/dL in men or 50 mg/dL in 
women or on drug treatment). 
 Elevated fasting triglycerides (150 mg/dL but 300 mg/dL or on drug treatment). 
 Elevated waist circumference (40 inches in men and 35 inches in women) present 
before performing the biopsy. 
4. Has a Nonalcoholic Fatty Liver Disease Activity Score (NAS) 4, with a score of at least 1 in 
each component (steatosis, lobular inflammation, and ballooning), as per the central pathology 
reader. 
5. Has a fibrosis score F1 to F3, inclusive (F1 capped at 20%), on liver biopsy as per the central 
pathology reader. 
6. Has a PDFF 8% on MRI at screening, per the central imaging reader. The MRI-PDFF criteria 
will not apply if the patient has a qualifying historical liver biopsy. 
7. Has alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <5  upper limit 
of normal (ULN) and AST 20 U/L in men and 17 U/L for women upon entry into the study. 
A documented AST 30 U/L by a local laboratory within 60 days of screening will also be 
acceptable. The minimum AST criteria will not apply if the patient has a qualifying historical 
liver biopsy.  
8. Has stable baseline liver enzymes, including serum ALT, AST, alkaline phosphatase (ALP), 
and total bilirubin values that are established by at least 2 samples demonstrating the 
following: 
a. Values of an enzyme in the 2 samples are within 1.5  ULN ranges. 
OR 
b. If one of the enzyme levels is 1.5 × ULN, the variability between the 2 samples of ALT 
and AST does not exceed 50% and the variability between the 2 samples of ALP and total 
bilirubin does not exceed 30%.  
Notes:  
o The 2 samples need to be obtained 2 to 16 weeks apart.  
o One sample can be obtained from the patient’s medical history and 1 sample can be 
obtained during the screening period, or both samples can be obtained during the screening 
period.  


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o A third sample may be collected if the variability between the first 2 samples exceeds the 
limits in Inclusion Criterion 8b and one of these values is deemed spurious. 
9. Has no other cause of chronic liver disease (eg, autoimmune disorder, alcoholic liver disease, 
drug-induced liver disease, primary biliary cholangitis, primary sclerosing cholangitis, 
hepatitis B virus, hepatitis C virus [HCV], Wilson’s disease, -1-antitrypsin deficiency, 
hemochromatosis) and has not had a liver transplant. 
10. If the patient has type 2 diabetes mellitus (T2DM), he/she has stable T2DM, defined as 
hemoglobin A1c 9.5% at screening and no new symptoms associated with decompensated 
diabetes in the previous 3 months. 
11. Has a stable body weight, defined by no more than a 5% loss in initial body weight for at least 
3 months or since the liver biopsy was performed, whichever is longer. 
12. Has a body mass index 25 kg/m2 and 50 kg/m2. 
13. Is willing to undergo a liver biopsy after 52 weeks of treatment. 
14. Is not of childbearing potential or, if of childbearing potential, is not pregnant as confirmed by 
a negative serum human chorionic gonadotropin test at screening and is not planning a 
pregnancy during the course of the study. 
Note: A woman is considered of childbearing potential following menarche and until 
becoming postmenopausal unless permanently sterile (permanent sterilization methods 
include 
hysterectomy, 
bilateral 
salpingectomy, 
and 
bilateral 
oophorectomy). 
A 
postmenopausal state is defined as no menses for 12 consecutive months without an 
alternative medical cause. A follicle-stimulating hormone level in the postmenopausal range 
will be used to confirm a postmenopausal state in women 55 years of age. 
15. Male and female patients of childbearing potential must agree to use a dual method of 
contraception (a highly effective method of contraception in conjunction with a barrier 
contraception) consistently and correctly from the first dose of study drug until 90 days after 
the last dose of study drug. Highly effective methods of contraception are those that result in 
a failure rate of less than 1% per year when used consistently and correctly and include the 
following: hormonal intrauterine devices; hormonal contraceptives (oral birth control pills, 
depo, patch, or injectable); male sterilization performed more than 6 months prior to screening; 
and complete abstinence from sexual intercourse (if this is the patient’s usual and preferred 
lifestyle). Barrier methods of contraception include male or female condoms used in 
combination with a separate spermicide product (eg, foam, gel, film, cream, or suppository). 
16. Male patients must agree to abstain from sperm donation from the first dose of study drug until 
90 days after the last dose of study drug. 


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Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from participation in the study: 
1. Has a known history of alcohol abuse or daily heavy alcohol consumption (females: more than 
14 units of alcohol per week; males: more than 21 units of alcohol per week [1 unit of alcohol 
is equivalent to a half pint of beer {285 mL}, 1 measure of spirits {25 mL}, or 1 glass of wine 
{125 mL}]). Alcohol abuse will be defined as having an Alcohol Use Disorders Identification 
Test-Concise (AUDIT-C) score of 3 points for men and women AND a full Alcohol Use 
Disorders Identification Test (AUDIT) score of 8 points at screening. 
Note: Only patients with AUDIT-C scores 3 points at screening will receive the full AUDIT 
and will be excluded if they score 8 points on the full AUDIT. Patients with AUDIT-C scores 
<3 points will not receive the full AUDIT. 
2. Has had bariatric surgery within the past 5 years or has bariatric surgery planned to occur 
during the study. 
3. Has significant systemic or major illnesses other than liver disease, including pulmonary 
disease, renal failure, organ transplantation, serious psychiatric disease, or malignancy that, in 
the opinion of the Investigator, would preclude treatment with NST-4016 or confound the 
study results. This would include any malignancy under evaluation, or diagnosed and/or 
treated within the past 2 years except for squamous or non-invasive basal skin cell or cervical 
carcinoma in-situ. 
4. Has a recent (within 6 months) history of cardiac dysrhythmias and/or cardiovascular disease, 
including congestive heart failure (class C and D of the American Heart Association), unstable 
coronary artery disease, cerebrovascular disease, or myocardial infarction. 
5. Has uncontrolled arterial hypertension. 
6. Has hepatitis B surface antigen >0, HCV antibody and HCV polymerase chain reaction 
(PCR) >0 (HCV PCR only required for patients who test positive for HCV antibody; patients 
with a confirmed history of HCV infection can be included if HCV PCR has been negative for 
at least the last 2 years), or human immunodeficiency virus infection. 
7. Has type 1 diabetes mellitus. 
8. Has diabetic ketoacidosis. 
9. Has a history of liver decompensation, such as ascites, esophageal varices, and hepatic 
encephalopathy. 
10. Has any of the following exclusionary laboratory results upon entry into the study: 
a. Hemoglobin 11 g/dL for females and 12 g/dL for males. 
b. White blood cell count 2.5 K/L. 
c. Neutrophil count 1.5 K/µL. 
d. Platelet count 150 K/µL. 
e. Total bilirubin 1.3 mg/dL. Patients with total bilirubin 1.3 mg/dL can be included if 
direct bilirubin is within normal ranges in the setting of Gilbert’s syndrome. 


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f. Albumin <3.6 g/L. 
g. International Normalized Ratio 1.3, unless due to anti-coagulant therapy. 
h. Thyroid-stimulating hormone >1.5  ULN. 
i. Estimated glomerular filtration rate <60 mL/min/1.73 m2. 
j. Fasting triglyceride level >300 mg/dL. 
Note: Repeat testing may be performed in consultation with the Medical Monitor if any of the 
above laboratory parameters are outside the specified ranges. 
11. Has a hemostasis disorder. 
12. Has any contraindication to liver biopsy or MRI. 
13. Has any clinically significant electrocardiogram (ECG) abnormality at screening. 
14. Has participated in any other investigational drug study within the previous 3 months or 
5 half-lives of the last dose of the investigational drug, whichever is longer. 
15. Has a known hypersensitivity to any of the ingredients or excipients of the study drug.  
16. Has used any drug known to produce hepatic steatosis, including systemic corticosteroids, 
methotrexate, tetracycline, amiodarone, tamoxifen, estrogens at doses greater than those used 
for hormone replacement, anabolic steroids, or valproic acid, for more than 2 weeks in the 
6 months prior to screening. Local corticosteroid injection for musculoskeletal disorders is 
permitted, including epidural corticosteroid administration. 
17. Is unable to comply with the following concomitant medication restrictions: 
a. Lipid-lowering therapies must be stable for 3 months at screening. Fish oil and other 
omega-3 compounds must also be stable for 3 months at screening if the dose is 
1000 mg per day. 
b. Antidiabetic drugs, including insulin regimens, must be stable for 3 months at screening, 
with the exception of sodium-glucose cotransporter-2 inhibitors, and glucagon-like 
peptide-1 agonists, which must be stable for 6 months at screening. 
c. No vitamin E >400 U/d, pioglitazone, obeticholic acid, or antiobesity drugs for 3 months 
prior to screening or since the liver biopsy, whichever is longer.  
18. Has any other condition that, in the opinion of the Investigator, would impede competence or 
compliance or possibly hinder completion of the study. 
19. Uses any prohibited medications or any concomitant medications used to treat an exclusionary 
medical condition. 
STUDY DESIGN AND DURATION: 
This is a 62-week (including screening and follow-up), multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study in male and female patients with a histological diagnosis 
of NASH. 
The study includes a screening period, double-blind treatment period, and post-treatment 
follow-up. The Screening Visit will occur up to 8 weeks prior to randomization at Visit 2 


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(Week 0); more than 1 Screening Visit may be necessary to perform all required procedures. The 
double-blind treatment period will entail 52 weeks of dosing with study drug and will be followed 
by a Safety Follow-up Visit 2 weeks after the last dose of study drug. 
Approximately 264 patients who meet the eligibility criteria will be randomized into 1 of 3 parallel 
treatment groups, each of which will contain approximately 88 patients. Patients in Group 1 will 
receive 300 mg NST-4016, patients in Group 2 will receive 600 mg NST-4016, and patients in 
Group 3 will receive placebo. Patients will be stratified by biopsy fibrosis score (2 levels: F1 
versus F2 or F3). 
Baseline assessments will include hepatic imaging (MRI-PDFF and iron-corrected T1 [cT1]), liver 
biopsy, vital signs (blood pressure, pulse rate, and body temperature), physical examinations, 
laboratory evaluations (hematology, biochemistry, coagulation, and lipid panels and urinalysis), 
and 12-lead ECGs. Historical liver biopsy within 6 months of screening may be used for eligibility 
if evaluable histology slides are available for review by the central pathology reader. Historical 
liver biopsies obtained during the course of a prior investigational drug study must not be utilized 
if obtained within 3 months or 5 half-lives of the last dose of the prior investigational drug, 
whichever is longer. Patients who screen fail may be rescreened once. With the exception of 
MRI-PDFF, cT1, and liver biopsy, baseline assessments will be collected at Visit 2 (Week 0, 
Day 0), prior to dosing; for MRI-PDFF, cT1, and liver biopsy, the assessments performed during 
screening will provide the baseline data. 
Study drug dosing will begin at Visit 2 (Week 0, Day 0) and will continue daily for 52 weeks. 
During the 52-week treatment period, patients will return to the clinic for study visits every 1 to 
3 months. The following assessments will occur at every study visit during the treatment period: 
adverse events, concomitant medications, body weight, vital signs, physical examinations, 
laboratory evaluations (hematology, biochemistry, coagulation, and lipid panels and urinalysis), 
and trough pharmacokinetic (PK) sampling. For a subset of patients (approximately 8 patients per 
group) at pre-identified sites, blood samples for analysis of additional PK parameters will also be 
collected predose and up to 24 hours postdose at Visit 2. In addition, hepatic imaging will be 
performed at Visit 5 (after 16 weeks of treatment) and Visit 9 (after 52 weeks of treatment).  
Evaluation of liver inflammation and fibrosis biomarkers (Homeostatic Model Assessment for 
Insulin Resistance [HOMA-IR], high-sensitivity C-reactive protein [hsCRP], N-terminal type 3 
collagen propeptide [Pro-C3], and enhanced liver fibrosis [ELF] panel) will be performed at 
Visits 2, 5, and 9. Twelve-lead ECGs will be performed at Visits 2, 5, 7, and 9, and a liver biopsy 
will also be performed at Visit 9. Throughout the study, patients will be monitored for suspected 
drug-induced liver injury. 
A Safety Follow-up Visit (Visit 10) will occur 14 days after the last dose of study drug to assess 
adverse events, concomitant medications, body weight, vital signs, physical examination findings, 
laboratory parameters, and 12-lead ECGs. Lipid parameters will be monitored throughout the 
follow-up period and will be managed by the Investigator. 
Patients who discontinue early from the study for any reason prior to completion of the treatment 
period will be requested to return to the clinic for an Early Termination (ET) Visit as soon as 
possible after their last intake of study drug. Patients who discontinue early from the study for any 
reason after completion of the treatment period and before the Safety Follow-up Visit will be 


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requested to return to the clinic for an ET Visit as soon as possible and no later than the planned 
Safety Follow-up Visit. 
From screening through follow-up, the total study duration for each patient who completes the 
entire treatment period will be approximately 62 weeks. 
An external, independent Data Safety Monitoring Committee (DSMC) will review all available 
unblinded preliminary safety and biomarker results per the DSMC Charter. 
In addition, the following data was comprehensively reviewed during an interim analysis, which 
was performed after 90 patients had completed 16 weeks of treatment: ALT, AST, HOMA-IR, 
Pro-C3, ELF panel, MRI-PDFF, cT1, and lipid parameters. 
This study protocol includes contingency measures to manage disruptions due to Coronavirus 
Disease 2019 (COVID-19) control measures; see Appendix G for details. In the absence of a 
COVID-19 impact, it is expected that Investigators and patients follow the protocol requirements 
as set forth. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
All patients will take 2 capsules of study drug (either 300 mg NST-4016 and/or matching placebo) 
orally in the morning with water once daily for 52 weeks. 
EFFICACY VARIABLES:  
The primary efficacy parameter is the percentage of patients with resolution of NASH, defined as 
disappearance of ballooning (score = 0) with lobular inflammation score 0 or 1, with no worsening 
of fibrosis. 
The secondary efficacy parameters include the following: 
 Change from baseline in NAS 
 Changes in individual histological scores for steatosis, ballooning, inflammation, and fibrosis 
 Changes in the liver enzymes AST, ALT, gamma glutamyl transferase, and bilirubin 
 Changes in the imaging parameters MRI-PDFF and cT1 
 Changes in the inflammation marker hsCRP 
 Changes in the fibrosis activity markers Pro-C3 and ELF panel 
 Changes in HOMA-IR, a measure of insulin resistance and metabolic status 
Exploratory Biomarker Analysis 
The exploratory parameters include the following (in a subgroup of patients): 
 Profile and characterization of lipid species on End of Treatment Visit liver biopsy 
 Profile and characterization of lipid species on baseline and End of Treatment serum samples 


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PHARMACOKINETIC VARIABLES: 
For all patients, blood samples for evaluation of trough plasma PK concentrations of NST-4016 
will be collected predose at Visits 2 to 9 (or the ET Visit, if applicable). 
For those patients participating in the intensive PK subset, PK blood samples will be collected in 
relation to the first dose of study drug at Visit 2. Samples will be taken at the following timepoints: 
predose (within 1 hour prior to the first dose), followed by 1, 2, 3, 4, 6, and 8 hours postdose 
(10 minutes) at Visit 2 (Day 0) and 24 hours postdose (1 hour, but prior to the second dose of 
study drug on Day 1). 
For the intensive PK subset of patients, the following PK parameters will be calculated in order to 
further characterize the PK of NST-4016 after the first dose: 
 AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last 
observed concentration 
 AUC0-inf: area under the plasma concentration-time curve from time 0 extrapolated to infinity 
 CL/F: apparent plasma clearance  
 Cmax: maximum observed plasma concentration 
 Tmax: time to reach the maximum observed plasma concentration 
 Vz/F: apparent volume of distribution 
Additional PK parameters may be determined, if deemed appropriate. 
SAFETY VARIABLES: 
Safety assessments will include the monitoring of adverse events, serious adverse events (SAEs), 
vital signs (blood pressure, pulse rate, and body temperature), physical examinations, 12-lead 
ECGs, and clinical laboratory parameters (hematology, biochemistry, coagulation, and lipid 
panels and urinalysis). 
Throughout the study, all treatment-emergent adverse events (TEAEs), clinical assessments, and 
clinical laboratory parameters will be closely monitored against the criteria for suspected 
drug-induced liver injury. 
STATISTICAL ANALYSES: 
Full details of the analyses will be provided in the Statistical Analysis Plan, which will be finalized 
prior to database lock and unblinding. 
Analysis Populations 
The Randomized Population will include all patients who are randomized to the study. 
The Intent-to-Treat (ITT) Population will include all patients who are randomized and receive at 
least 1 dose of study drug. 
The Modified ITT (mITT) Population will include all patients from the ITT Population who have 
valid baseline and Week 52 (or ET, if applicable) liver biopsy measurements. 


NorthSea Therapeutics B.V. 
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The Per-Protocol (PP) Population will include all patients from the mITT Population who 
complete the 52-week treatment period without any major protocol violations. 
The Trough PK Population will include all patients who received at least 1 dose of NST-4016 and 
have at least 1 measurable trough PK concentration. 
The Intensive PK Population will include all patients who received at least 1 dose of NST-4016 
and have at least 1 measurable non-trough intensive PK sample. 
The Safety Population will include all patients who receive at least 1 dose of study drug. 
Efficacy Analysis 
The efficacy analysis will be performed on the ITT Population; missing values for continuous 
endpoints will be imputed using multiple imputation methods. 
Baseline will be defined as the value at the Screening Visit for measurements from the liver biopsy 
and imaging data and as the predose value at Visit 2 (Week 0) for the biomarker data. For other 
efficacy endpoints, baseline will be defined as the predose value at Visit 2 (Week 0); if this value 
is missing, then the latest predose value will be used. 
Primary Efficacy Analysis 
The primary endpoint (ie, the percentage of patients with resolution of NASH without worsening 
fibrosis) will be analyzed using the ITT Population. Patients without a Week 52 (or ET, if 
applicable) liver biopsy will be imputed as nonresponders. The number and percentage of patients 
meeting the criteria for the primary endpoint will be summarized by treatment group. 
The primary analysis will be conducted using the data from the 600 mg NST-4016 and placebo 
groups using the Cochran-Mantel-Haenszel test, stratified by biopsy fibrosis score (2 levels: F1 
versus F2 or F3). The primary analysis will be based on the use of a 2-sided test at the 
alpha=0.05 level of significance. 
If the primary analysis is statistically significant (p<0.05), the key secondary analysis of the 
primary endpoint will be conducted using the data from the 300 mg NST-4016 and placebo groups, 
again using the Cochran-Mantel-Haenszel test, stratified by biopsy fibrosis score (2 levels: F1 
versus F2 or F3). Due to the use of this fixed-sequence testing procedure, the key secondary 
analysis will be based on the use of a 2-sided test at the alpha=0.05 level of significance. However, 
if the primary analysis is not statistically significant, the comparison between the 300 mg 
NST-4016 and placebo groups will be exploratory rather than confirmatory. 
A sensitivity analysis for the primary endpoint will be carried out using a logistic regression model 
with treatment group (300 mg NST-4016, 600 mg NST-4016, or placebo) and biopsy fibrosis 
score (2 levels: F1 versus F2 or F3) as factors. Pairwise treatment comparisons will be estimated 
in this model as odds ratios (NST-4016 versus placebo) along with their 95% confidence intervals 
and p-values. 
The primary, key secondary, and sensitivity analyses of the primary endpoint will be repeated on 
the mITT and PP Populations. 
Secondary Efficacy Analysis 
Continuous efficacy variables will be summarized using descriptive statistics for the observed data 
and change and/or percent change from baseline by treatment group and visit as appropriate. 


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Change from baseline to Week 52 in NAS and individual histological scores will be analyzed in 
an analysis of covariance model, adjusting for treatment (300 mg NST-4016, 600 mg NST-4016, 
or placebo), biopsy fibrosis score (2 levels: F1 versus F2 or F3), and respective baseline score. 
Pairwise treatment comparisons between each NST-4016 dose and placebo will be estimated in 
this model using least square (LS) means, standard errors, 95% confidence intervals, and p-values. 
A similar analysis will be carried out for the imaging parameters at Week 16 and Week 52. 
Efficacy variables measured at multiple timepoints will be analyzed with Mixed Model Repeated 
Measures methods, with change (or percent change) from baseline as the dependent variable, 
adjusting for treatment (300 mg NST-4016, 600 mg NST-4016, or placebo), biopsy fibrosis score 
(2 levels: F1 versus F2 or F3), and baseline score. Pairwise treatment comparisons between each 
NST-4016 dose and placebo at Week 52 will be estimated using LS means, standard errors, 
95% confidence intervals, and p-values. 
Exploratory Biomarker Analysis 
The analysis of exploratory endpoints will be further described in the Statistical Analysis Plan. 
Pharmacokinetic Analysis 
Trough plasma PK concentrations at Visits 3 to 9 will be summarized descriptively by visit for 
the Trough PK Population. 
For the subset of patients with intensive PK sampling data, additional PK parameters will be 
summarized by treatment using descriptive statistics for the Intensive PK Population. No formal 
statistical analysis of PK parameters will be performed. 
Safety Analysis 
Safety variables will be tabulated and presented for the Safety Population. 
Baseline will be defined as the predose value at Visit 2 (Week 0); if this value is missing, then the 
latest predose value will be used. 
A TEAE is defined as a new or worsening adverse event after the first dose of study drug. The 
number and percentage of patients with at least 1 TEAE will be summarized by treatment group 
by system organ class and preferred term. Similar summaries will be presented for study 
drug-related TEAEs and SAEs. 
Safety laboratory parameters, vital signs, and ECGs will be summarized by treatment group by 
visit. Change from baseline values by visit will also be presented for the continuous parameters. 
The number (and percentage) of patients with abnormalities based on predefined normal ranges 
will be tabulated by treatment group. 
Interim Analysis 
An interim analysis was planned for this study after 90 patients had completed 16 weeks of 
treatment. This analysis was reviewed by the DSMC according to the DSMC Charter. The interim 
analysis included a comprehensive review of the following data: ALT, AST, HOMA-IR, Pro-C3, 
ELF panel, MRI-PDFF, cT1, and lipid parameters. The conclusions and recommendations of the 
DSMC were shared blindly with the Sponsor and clinical sites. A separate interim analysis plan 
was finalized prior to conducting the interim analysis. 


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Data Safety Monitoring Committee 
An external, independent DSMC will review all available unblinded preliminary safety and 
biomarker results, as described in the DSMC Charter. The DSMC Charter will describe the overall 
guidelines, composition and roles, and responsibilities of the independent DSMC for the NST-02 
study, including the selection of DSMC members, timing of meetings, methods of providing 
information to and from the DSMC, frequency and format of meetings, data analysis 
recommendations, and DSMC relationships with other parties participating in the conduct of this 
study. Patient accrual will continue throughout the period of the DSMC review. The DSMC will 
advise on the accrual of the remaining patients per protocol or any amendments that are necessary 
for safety reasons. 
SAMPLE SIZE DETERMINATION: 
A sample size of 88 patients per treatment group provides 80% power to detect a 40% responder 
rate for active versus placebo, assuming a placebo response rate of 18% and a dropout rate of 25%. 
SITES: Approximately 50 sites in the United States 
SPONSOR CONTACTS: 
Stephen J. Rossi, PharmD 
Chief Development Officer 
NorthSea Therapeutics B.V. 
Mobile: +1-415-572-0596 
Email: stephen.rossi@northseatherapeutics.com 
 
Kathline Kim 
Senior Clinical Trial Manager 
NorthSea Therapeutics B.V. 
Mobile: +1-510-282-3024 
Email: kathline.kim@northseatherapeutics.com 


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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 15 
List of Tables ................................................................................................................................ 19 
List of Figures ............................................................................................................................... 20 
List of Abbreviations and Definition of Terms............................................................................. 21 
1  Introduction and Background Information ............................................................................. 23 
1.1 
Rationale ........................................................................................................................ 23 
1.2 
Coronavirus Disease 2019 Impacts ............................................................................... 24 
1.3 
Non-Clinical Studies ..................................................................................................... 24 
1.4 
Clinical Studies ............................................................................................................. 25 
1.4.1  Pre-Specified Interim Analysis of the Ongoing Phase 2b Study in 
Non-Cirrhotic Patients With NASH (Study NST-02) ....................................... 25 
1.4.1.1  Overview of interim analyses ............................................................. 25 
1.4.1.2  Clinical pharmacodynamics ................................................................ 25 
1.4.1.3  Clinical safety ..................................................................................... 26 
1.5 
Risk/Benefit ................................................................................................................... 27 
2  Study Objectives ..................................................................................................................... 28 
2.1 
Primary Objective ......................................................................................................... 28 
2.2 
Secondary Objective ..................................................................................................... 28 
3  Study Description.................................................................................................................... 29 
3.1 
Summary of Study Design ............................................................................................ 29 
3.1.1  Coronavirus Disease 2019 Contingency Measures ........................................... 30 
3.2 
Study Indication ............................................................................................................ 31 
4  Selection and Withdrawal of Patients ..................................................................................... 32 
4.1 
Inclusion Criteria ........................................................................................................... 32 
4.2 
Exclusion Criteria .......................................................................................................... 34 
4.3 
Withdrawal Criteria ....................................................................................................... 36 
5  Study Treatments .................................................................................................................... 37 
5.1 
Treatment Groups .......................................................................................................... 37 


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5.2 
Rationale for Dosing ..................................................................................................... 37 
5.3 
Randomization and Blinding ......................................................................................... 37 
5.4 
Breaking the Blind ........................................................................................................ 37 
5.5 
Drug Supplies ................................................................................................................ 38 
5.5.1  Formulation and Packaging ............................................................................... 38 
5.5.2  Study Drug Preparation and Dispensing ........................................................... 38 
5.5.3  Study Drug Administration ............................................................................... 38 
5.5.4  Treatment Compliance ...................................................................................... 38 
5.5.5  Storage and Accountability ............................................................................... 39 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 39 
5.6.1  Excluded Medications and/or Procedures ......................................................... 39 
5.6.2  Restricted Medications and/or Procedures ........................................................ 39 
5.6.3  Documentation of Prior and Concomitant Medication Use .............................. 42 
6  Study Procedures .................................................................................................................... 43 
6.1 
Informed Consent .......................................................................................................... 43 
6.2 
Screening Visit (Visit 1, Week -8 to Week -1) ............................................................. 43 
6.3 
Treatment Period – Visit 2 to Visit 9 (Week 0 to Week 52) ......................................... 44 
6.3.1  Visit 2 (Week 0) ................................................................................................ 44 
6.3.2  Visit 3 (Week 4) ................................................................................................ 45 
6.3.3  Visit 4 (Week 10) .............................................................................................. 46 
6.3.4  Visit 5 (Week 16) .............................................................................................. 46 
6.3.5  Visit 6 (Week 24) .............................................................................................. 47 
6.3.6  Visit 7 (Week 32) .............................................................................................. 47 
6.3.7  Visit 8 (Week 40) .............................................................................................. 48 
6.3.8  Visit 9 (Week 52) .............................................................................................. 48 
6.4 
Safety Follow-up Visit (Visit 10, Week 54) ................................................................. 49 
6.5 
Early Termination Visit and Withdrawal Procedures ................................................... 50 
7  Efficacy Assessments .............................................................................................................. 51 
7.1 
Efficacy Variables ......................................................................................................... 51 
7.1.1  Primary Efficacy Variable ................................................................................. 51 
7.1.2  Secondary Efficacy Variables ........................................................................... 51 
7.1.3  Exploratory Biomarker Analysis ....................................................................... 51 


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8  Safety Assessments ................................................................................................................. 52 
8.1 
Adverse Events .............................................................................................................. 52 
8.1.1  Adverse (Drug) Reaction .................................................................................. 53 
8.1.2  Unexpected Adverse Drug Reaction ................................................................. 53 
8.1.3  Assessment of Adverse Events by the Investigator .......................................... 53 
8.1.4  Adverse Events of Special Interest .................................................................... 54 
8.2 
Serious Adverse Events ................................................................................................. 54 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 55 
8.4 
Pregnancy Reporting ..................................................................................................... 56 
8.5 
Expedited Reporting ...................................................................................................... 56 
8.6 
Special Situation Reports .............................................................................................. 57 
8.7 
Clinical Laboratory Evaluations .................................................................................... 57 
8.8 
Vital Signs ..................................................................................................................... 58 
8.9 
Electrocardiograms ........................................................................................................ 58 
8.10  Physical Examinations .................................................................................................. 58 
8.11  Imaging Assessments .................................................................................................... 58 
8.12  Liver Biopsies ............................................................................................................... 59 
8.12.1  Nonalcoholic Fatty Liver Disease Activity Score ............................................. 59 
8.12.2  Re-Reading of Central Pathologist Assessment of Eligible Patients Based on a 
Qualifying Historical Biopsy ............................................................................ 59 
8.13  Pharmacodynamic Assessments .................................................................................... 59 
8.14  Pharmacokinetic Assessments ....................................................................................... 59 
9  Statistics .................................................................................................................................. 61 
9.1 
Analysis Populations ..................................................................................................... 61 
9.2 
Statistical Methods ........................................................................................................ 61 
9.2.1  Analysis of Efficacy .......................................................................................... 61 
9.2.1.1  Primary efficacy analysis .................................................................... 61 
9.2.1.2  Key secondary analysis of the primary endpoint ................................ 61 
9.2.1.3  Sensitivity analysis of the primary endpoint ....................................... 62 
9.2.1.4  Secondary efficacy analysis ................................................................ 62 
9.2.1.5  Exploratory biomarker analysis .......................................................... 62 
9.2.1.6  Pharmacokinetic analysis .................................................................... 62 
9.2.2  Analysis of Safety ............................................................................................. 62 


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9.2.3  Interim Analysis ................................................................................................ 63 
9.2.4  Data Safety Monitoring Committee .................................................................. 63 
9.2.5  Sample Size Determination ............................................................................... 63 
10  Data Management and Record Keeping ................................................................................. 64 
10.1  Data Management ......................................................................................................... 64 
10.1.1  Data Handling ................................................................................................... 64 
10.1.2  Computer Systems ............................................................................................. 64 
10.1.3  Data Entry ......................................................................................................... 64 
10.1.4  Medical Information Coding ............................................................................. 64 
10.1.5  Data Validation ................................................................................................. 64 
10.2  Record Keeping ............................................................................................................. 64 
10.3  End of Study .................................................................................................................. 65 
11  Investigator Requirements and Quality Control ..................................................................... 66 
11.1  Ethical Conduct of the Study ........................................................................................ 66 
11.2  Institutional Review Board ............................................................................................ 66 
11.3  Informed Consent .......................................................................................................... 66 
11.4  Study Monitoring Requirements ................................................................................... 66 
11.5  Disclosure of Data ......................................................................................................... 67 
11.6  Retention of Records ..................................................................................................... 67 
11.7  Publication Policy ......................................................................................................... 67 
11.8  Financial Disclosure ...................................................................................................... 68 
12  Study Administrative Information .......................................................................................... 69 
12.1  Protocol Amendments ................................................................................................... 69 
13  References ............................................................................................................................... 70 
Appendix A: Schedule of Procedures ........................................................................................... 71 
Appendix B: Clinical Laboratory Analytes .................................................................................. 74 
Appendix C: Alcohol Use Disorders Identification Test-Concise ................................................ 76 
Appendix D: Alcohol Use Disorders Identification Test: Interview Version ............................... 78 
Appendix E: Drug-Induced Liver Injury Monitoring Plan ........................................................... 79 
Appendix F: 2018 American Heart Association/American College of Cardiology Guideline on 
the Management of Blood Cholesterol ................................................................................... 83 
Appendix G: Coronavirus Disease 2019 Contingency Measures ................................................. 84 


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LIST OF TABLES 
Table 1. 
Placebo-Adjusted Absolute Changes in Non-Invasive Biomarkers ........................... 25 
Table 2. 
Overview of TEAEs by Treatment Arm in Study NST-02 ......................................... 26 
Table 3. 
Study Treatment Groups and Dosing Regimens ......................................................... 37 
 


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LIST OF FIGURES 
Figure 1.  Study Design ............................................................................................................... 29 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
AA 
Arachidonic acid 
ACC 
American College of Cardiology 
AESI 
Adverse events of special interest 
AHA 
American Heart Association 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ASCVD 
Atherosclerotic Cardiovascular Disease 
AST 
Aspartate aminotransferase 
AUDIT 
Alcohol Use Disorders Identification Test 
AUDIT-C 
Alcohol Use Disorders Identification Test-Concise 
BMI 
Body mass index 
CAP 
Controlled attenuation parameter 
CFR 
Code of Federal Regulations 
COVID-19 
Coronavirus Disease 2019 
CRA 
Clinical Research Associate 
CSR 
Clinical Study Report  
cT1 
Iron-corrected T1 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DAG 
Diglyceride 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
eGFR 
Estimated glomerular filtration rate 
EIU 
Exposure In Utero 
ELF 
Enhanced liver fibrosis 
EPA 
Eicosapentaenoic acid 
ET 
Early Termination 
FPG 
Fasting plasma glucose 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GLP-1 
Glucagon-like peptide-1 
HbA1c 
Hemoglobin A1c 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 


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Abbreviation 
Definition 
HETE 
Hydroxyeicosatetraenoic acid 
HIV 
Human immunodeficiency virus 
HOMA-IR 
Homeostatic Model Assessment for Insulin Resistance 
hsCRP 
High-sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
LDL-C 
Low-density lipoprotein-cholesterol 
LS 
Least square 
mITT 
Modified Intent-to-Treat 
MRI 
Magnetic resonance imaging 
n-3 FA 
Omega-3 fatty acid 
NAS 
Nonalcoholic Fatty Liver Disease Activity Score 
NASH 
Nonalcoholic steatohepatitis  
PCR 
Polymerase chain reaction 
PCSK9 
Proprotein convertase subtilisin kexin 9 
PD 
Pharmacodynamic 
PDFF 
Proton density-fat fraction 
PK 
Pharmacokinetic(s) 
PP 
Per-Protocol 
PPAR 
Peroxisome proliferator-activated receptor alpha 
Pro-C3 
N-terminal type 3 collagen propeptide 
SAE 
Serious adverse event 
SEDDS 
Self-Emulsifying Drug Delivery System 
SGLT2 
Sodium-glucose cotransporter-2 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T2DM 
Type 2 diabetes mellitus 
TEAE 
Treatment-emergent adverse event 
TNF- 
Tumor necrosis factor alpha 
ULN 
Upper limit of normal 
VCTE 
Vibration-controlled transient elastography 
WHO 
World Health Organization 


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1 
INTRODUCTION AND BACKGROUND INFORMATION  
NorthSea Therapeutics B.V. (hereinafter NorthSea) is developing the drug substance icosabutate 
(International Nonproprietary Name) (development code NST-4016). Icosabutate is a novel, orally 
administered, semisynthetic fatty acid for the treatment of lipid disorders (hypertriglyceridemia, 
mixed dyslipidemia, and hypercholesterolemia) and nonalcoholic steatohepatitis (NASH).  
1.1 
Rationale 
Icosabutate is a novel, orally administered, highly potent, semisynthetic fatty acid for the treatment 
of various dyslipidemias and NASH. Structural modification of the natural omega-3 fatty acid 
(n-3 FA) eicosapentaenoic acid (EPA) is designed to potentiate the pharmacological effects of 
naturally occurring n-3 FA by increasing direct hepatic delivery through the portal vein following 
absorption, reducing the incorporation into complex lipids, and increasing availability for fatty 
acid intracellular signaling pathways regulating metabolism, inflammation, and fibrosis. 
The clinical experience with icosabutate shows potent hypolipidemic effects along with 
improvements in glycemic control. Additionally, marked decreases in elevated liver enzymes 
suggest that icosabutate has additional hepatoprotective effects not typically seen with 
hypolipidemic drugs. Similarly, the significant improvements in glycemic control observed in 
patients with severe hypertriglyceridemia in response to treatment with icosabutate is not observed 
with either unmodified EPA or cholesterol-lowering drugs. Beneficial effects on both plasma lipids 
and glycemic control with icosabutate are important attributes for the treatment of patients with 
NASH given the strong association of NASH with both cardiovascular disease and diabetes. 
The nonclinical experience with icosabutate thus far indicates potent reductions in hepatic 
steatosis, inflammation, and fibrosis in multiple differentiated NASH models. There are likely 
multiple contributors to the observed pharmacodynamic (PD) effects of icosabutate in NASH. 
Although icosabutate is a partial peroxisome proliferator-activated receptor alpha (PPARα) 
agonist, the activation of which may underlie its beneficial effects on plasma triglycerides, the 
beneficial effects in fibrosing NASH are likely mediated via other mechanisms. However, PPARα 
activation does likely contribute to the increase in hepatic fatty acid β-oxidation and increase in 
ketone formation, which in turn may reduce the hepatic lipid load. Reductions in hepatic 
diglycerides (DAGs) and cholesteryl ester may also be partially related to PPARα, although 
icosabutate has potent effects upon hepatic cholesterol not seen with synthetic PPARα agonists. 
Icosabutate induces highly significant improvements in hepatic inflammation, including 
reductions in proinflammatory gene expression along with decreases in hepatic inflammatory 
cellular infiltrates and galectin-3 content in rodent NASH models. The mechanisms underlying 
these effects may involve significant reductions in the hepatic levels of proinflammatory bioactive 
arachidonic acid (AA)-derived metabolites (ie, hydroxyeicosatetraenoic acids [HETEs]), which 
are associated with NASH in humans and rodents. The ability of icosabutate to remain as a free 
acid and avoid incorporation into complex lipids is believed to underlie its ability to potently target 
the AA cascade versus unmodified EPA.  
Icosabutate also decreases the hepatic expression of pivotal genes regulating HETE and 
leukotriene formation (eg, 5-lipoxygenase activation protein and cytosolic phospholipase A2). In 
addition to the effects on hepatic inflammation, the reductions in proinflammatory AA metabolites 
may also underlie the improvements in insulin resistance and reductions in NASH-associated 
hepatic lipids such as DAGs. The formation of anti-inflammatory omega-3 cytochrome P450 


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(CYP) epoxides is also seen with icosabutate, which in concert with the reductions in AA 
metabolites, leads to a reversal of the balance between hepatic proinflammatory and 
anti-inflammatory fatty acid metabolites derived from the AA cascade. 
Icosabutate significantly reduces, and even reverses, fibrosis in rodent models of NASH in 
association with a marked reduction in collagen fiber number. Significant reductions in the 
expression of pivotal profibrotic genes, such as COL1A1 and PDGFR1, are also observed in 
concert with the reduction in hepatic fibrosis. The reduction in hepatic fibrosis is likely secondary 
to the significant reduction in the number of proliferating stellate cells (ie, myofibroblasts) in the 
livers of rodents with established NASH after treatment with icosabutate. These effects are likely 
to be at least partially related to the above-mentioned anti-inflammatory effects. However direct 
antiproliferative effects are seen in isolated human stellate cells, which suggests that icosabutate 
has direct antifibrotic effects independent of effects on inflammatory cell types such as 
macrophages and/or dying hepatocytes. 
The mechanism underlying the direct antifibrotic effects of icosabutate is not clarified. However, 
icosabutate functions as a potent hepatic antioxidant, inducing significant decreases in the amount 
of hepatic oxidized glutathione in multiple rodent NASH models. This occurs in concert with a 
highly significant increase in the reduced to oxidized glutathione ratio and increases in the hepatic 
expression of enzymatic antioxidant genes, such as SOD1, SOD2, and catalase. As oxidative stress 
sensitizes stellate cells to multiple proliferation-inducing stimuli such as tumor necrosis factor 
alpha (TNF-), and increases the proliferative response per se, a reduction in oxidative stress and 
improvements in redox status may play a key role in the antifibrotic effects of icosabutate. A 
reduction in oxidative stress may also be involved in the significant reduction in proinflammatory 
genes regulated by the redox-sensitive transcription factor nuclear factor-B, such as TNF-α. The 
ability of icosabutate to be rapidly excreted via the avoidance incorporation into complex lipids 
may play a key role in mediating the reduced oxidative stress. 
For more information, refer to the icosabutate Investigator’s Brochure.1 
1.2 
Coronavirus Disease 2019 Impacts 
In March 2020, the Coronavirus Disease 2019 (COVID-19), caused by infection with severe acute 
respiratory syndrome coronavirus 2, was characterized as a pandemic by the World Health 
Organization (WHO). The COVID-19 pandemic has impacted clinical studies worldwide due to 
quarantines, site closures, travel limitations, diversion of resources, and/or general interruptions in 
study-related procedures.  
This study protocol includes contingency measures to manage disruptions due to COVID-19 
control measures; see Appendix G for details. The impacts of these implemented contingency 
measures on the outcomes of this study, including any protocol deviations that result from 
COVID-19 illness and/or COVID-19 control measures, will be discussed in the Clinical Study 
Report (CSR). 
1.3 
Non-Clinical Studies 
Please see the Investigator’s Brochure for detailed summaries of the nonclinical studies conducted 
with icosabutate.1 


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1.4 
Clinical Studies 
The completed clinical studies to date in the icosabutate clinical development program include 
5 Phase 1 studies and 2 Phase 2 studies. The Phase 1 studies included a first-in-human 
pharmacokinetic (PK) and safety study in healthy volunteers (CTN4016 11101), a mass-balance 
study (CTN4016 14102), a drug-to-drug interaction study (CTN4016 14103), a thorough QTc 
study (NST-01), and a Phase 1b PK/PD and safety study in patients with mixed dyslipidemia 
(CTN4016 14104). The 2 Phase 2 studies evaluated treatment with icosabutate for 12 weeks in 
patients with high triglycerides (CTN4016 13201) and mixed dyslipidemia (CTN4016 13202). 
These studies are supportive of the clinical development of icosabutate in patients with NASH 
without cirrhosis. Please refer to the Investigator’s Brochure for additional detailed information 
on these studies. Additional clinical data not included in the Investigator’s Brochure are 
summarized in the following sections. 
1.4.1 
Pre-Specified Interim Analysis of the Ongoing Phase 2b Study in Non-Cirrhotic 
Patients With NASH (Study NST-02) 
1.4.1.1 
Overview of interim analyses 
A pre-specified interim analysis was performed in this ongoing Phase 2b study in patients with 
biopsy-confirmed NASH. This interim analysis was performed after 90 patients had randomized 
and completed 16 weeks of treatment. The purpose of this interim analysis was to evaluate safety 
as well as multiple non-invasive biomarkers relevant for NASH, fibrosis, metabolic syndrome, 
lipid metabolism, and cardiovascular risk. The individual patient disposition remains blinded to 
both the Investigators and the Sponsor but was unblinded to an independent Data Safety 
Monitoring Committee (DSMC) as part of their standard review. The baseline patient populations 
of the 90 patients in the interim analysis cohort were reflective of those enrolled into NASH 
clinical trials and generally well balanced across the treatment arms (Study NST-02 interim 
analysis; data on file). 
1.4.1.2 
Clinical pharmacodynamics 
Rapid, sustained, and significant dose-dependent decreases were seen in alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), and alkaline 
phosphatase (ALP) at levels predictive of histologic improvement (see Table 1). Both doses 
showed significant reductions in N-terminal type 3 collagen propeptide (Pro-C3) and enhanced 
liver fibrosis (ELF) score (both total score and individual components) supporting an effect on 
fibrogenesis. High -sensitivity C-reactive protein (hsCRP) significantly decreased by 52% with 
600 mg, in conjunction with improvements in glycemic control and key atherogenic lipoproteins. 
There were no changes in weight or body mass index (BMI), suggesting a treatment effect 
independent of weight loss. Liver fat content was unchanged with both doses, consistent with the 
icosabutate mechanism of action. 
Table 1. 
Placebo-Adjusted Absolute Changes in Non-Invasive Biomarkers 
Biomarker (Unit) 
Icosabutate 300 mg 
(n=33) 
Icosabutate 600 mg 
(n=35) 
ALT (U/L) 
-19* 
-25.4* 
AST (U/L) 
-9.4# 
-13.5# 
GGT (U/L) 
-16.9# 
-28.6* 
ALP (U/L) 
-12.7* 
-19.6* 


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Table 1. 
Placebo-Adjusted Absolute Changes in Non-Invasive Biomarkers (Continued) 
Biomarker (Unit) 
Icosabutate 300 mg 
(n=33) 
Icosabutate 600 mg 
(n=35) 
Bilirubin (mg/dL) 
-0.0 
-0.14# 
Pro-C3 (ng/mL) 
-4.5* 
-4.6* 
ELF 
-0.4# 
-0.6* 
hsCRP (mg/L) 
-1.2 
-2.3# 
HbA1c (%) 
0.0 
-0.3 
HOMA-IR 
-1.5 
-2.1 
LDL-C (mg/dL) 
5.5 
-3.9 
HDL-C (mg/dL) 
3.2# 
2.3 
Remnant-C (mg/dL) 
-6.1# 
-8.0* 
ApoC3 (mg/dL) 
-1.6# 
-2.7* 
TG (mg/dL) 
-27.1# 
-34.0# 
* = p0.001, # = p0.05 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; ApoC3 = apolipoprotein C3; AST = aspartate 
aminotransferase; ELF = enhanced liver fibrosis; GGT = gamma glutamyl transferase; HbA1c = hemoglobin A1c; 
HDL-C = high-density lipoprotein-cholesterol; HOMA-IR = Homeostatic Model Assessment of Insulin Resistance; 
hsCRP = high-sensitivity C-reactive protein; LDL-C = low-density lipoprotein-cholesterol; Pro-C3 = N-terminal type 3 
collagen propeptide; TG = triglyceride. 
Source: Study NST-02 interim analysis (data on file) 
1.4.1.3 
Clinical safety 
A safety review was performed of the 157 patients screened at the time of the Week 16 interim 
analysis with the treatment-emergent adverse events (TEAEs) presented in Table 2. There was no 
notable difference in the frequency, severity, or causality of the overall safety profile between 
placebo and either 300 mg or 600 mg of icosabutate for up to 16 weeks. The majority of TEAEs 
were mild to moderate in severity and generally comparable across the study arms. The treatment 
was well tolerated and comparable to placebo, with the exception of mild nausea (4.3%, 9.0%, and 
21.3% in placebo, 300 mg, and 600 mg, respectively). 
Table 2. 
Overview of TEAEs by Treatment Arm in Study NST-02 
 
Placebo 
(n=46) 
Icosabutate 300 mg 
(n=46) 
Icosabutate 600 mg 
(n=47) 
Any TEAE (n [%]) 
37 (80.4%) 
30 (65.2%) 
37 (78.75%) 
Maximum severity 
Grade 1 (n [%]) 
12 (26.1%) 
7 (15.2%) 
9 (19.1%) 
Grade 2 (n [%]) 
24 (52.2%) 
22 (47.8%) 
20 (42.6%) 
Grade 3 (n [%]) 
1 (2.2%) 
1 (2.2%) 
4 (8.5%) 
Grade 4 (n [%]) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Grade 5 (n [%]) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Drug-related TEAE (n [%]) 
7 (15.2%) 
7 (15.2%) 
8 (17.0%) 
SAE (n [%]) 
1 (2.2%) 
1 (2.2%) 
3 (6.4%) 
Drug-related SAE (n [%]) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
SAE = serious adverse event; TEAE = treatment-emergent adverse event. 
Source: Study NST-02 interim analysis (data on file) 
No confirmed drug-induced liver injury, cardiovascular events, or worsening of diabetes were 
observed during the study period. Laboratory values remained stable or improved and there were 
no clinically relevant changes in vital signs or electrocardiograms (ECGs). No safety or tolerability 
signals of concern were observed during the study period as confirmed by an independent 
unblinded DSMC review. In summary, the safety and tolerability of icosabutate remains favorable 
and similar to that observed in other patient populations. 


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1.5 
Risk/Benefit 
Clinical studies conducted so far suggest that icosabutate is safe and well tolerated and confers 
clinically significant changes in triglycerides, atherogenic cholesterol, and other atherosclerotic 
risk markers such as apolipoprotein C3. The reduction in elevated liver enzymes seen in Phase 2 
dyslipidemia studies, coupled with extensive animal models of NASH, suggest that icosabutate 
can be an important therapeutic option for the treatment of NASH. 
In the clinical experience with icosabutate in patients with a lipid disorder, the overall incidence 
of adverse events throughout clinical studies has generally been low, and there have been no 
apparent treatment- or dose-related trends in the number of adverse events reported or the number 
of patients reporting adverse events. The most common adverse events seen in these patients were 
mild nausea and gastrointestinal bloating. Similarly, the interim analysis of the ongoing NST-02 
study showed similar frequency and severity of overall adverse events in patients with NASH 
without cirrhosis. The most common adverse events, again, were gastrointestinal symptoms (other 
than an increase in mild gastrointestinal disturbance at supratherapeutic doses). There have been 
no other findings of clinical importance in the clinical laboratory evaluations, vital signs, 12-lead 
ECGs, telemetry, physical examinations, or body weight observed during the clinical studies. None 
of the nonclinical safety findings have been observed in the clinical studies, with no evidence of 
ophthalmic effects in human studies. A thorough QT study has demonstrated no effect of 
icosabutate on QT interval at supratherapeutic doses. 
Based on the nonclinical and clinical experience to date, icosabutate has a favorable safety and 
tolerability profile with the potential for addressing common comorbid conditions in patients with 
NASH without cirrhosis. The potential benefits of icosabutate treatment in patients with NASH 
without cirrhosis outweigh any potential harm. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective is to evaluate the efficacy of different doses of NST-4016 on the resolution 
of NASH without worsening of fibrosis. 
2.2 
Secondary Objective 
The secondary objective is to determine the safety and tolerability of NST-4016 in patients with 
NASH without cirrhosis. 


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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is a 62-week (including screening and follow-up), multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study in male and female patients with a histological diagnosis 
of NASH. 
The study includes a screening period, double-blind treatment period, and post-treatment 
follow-up. The Screening Visit will occur up to 8 weeks prior to randomization at Visit 2 (Week 0); 
more than 1 Screening Visit may be necessary to perform all required procedures. The 
double-blind treatment period will entail 52 weeks of dosing with study drug and will be followed 
by a Safety Follow-up Visit 2 weeks after the last dose of study drug.  
Approximately 264 patients who meet the eligibility criteria will be randomized into 1 of 3 parallel 
treatment groups, each of which will contain approximately 88 patients. Patients in Group 1 will 
receive 300 mg NST-4016, patients in Group 2 will receive 600 mg NST-4016, and patients in 
Group 3 will receive placebo. Patients will be stratified by biopsy fibrosis score (2 levels: F1 versus 
F2 or F3). For a schematic of the study design, see Figure 1.  
Figure 1. Study Design 
Baseline assessments will include hepatic imaging (magnetic resonance imaging [MRI]-proton 
density-fat fraction [PDFF] and iron-corrected T1 [cT1]), liver biopsy, vital signs (blood pressure, 
pulse rate, and body temperature), physical examinations, laboratory evaluations (hematology, 
biochemistry, coagulation, and lipid panels and urinalysis), and 12-lead ECGs. Historical liver 
biopsy within 6 months of screening may be used for eligibility if evaluable histology slides are 
available for review by the central pathology reader. Historical liver biopsies obtained during the 
course of a prior investigational drug study must not be utilized if obtained within 3 months or 
5 half-lives of the last dose of the prior investigational drug, whichever is longer. Patients who 
screen fail may be rescreened once. With the exception of MRI-PDFF, cT1, and liver biopsy, 


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baseline assessments will be collected at Visit 2 (Week 0, Day 0), prior to dosing; for MRI-PDFF, 
cT1, and liver biopsy, the assessments performed during screening will provide the baseline data. 
Study drug dosing will begin at Visit 2 (Week 0, Day 0) and will continue daily for 52 weeks. 
During the 52-week treatment period, patients will return to the clinic for study visits every 1 to 
3 months. The following assessments will occur at every study visit during the treatment period: 
adverse events, concomitant medications, body weight, vital signs, physical examinations, 
laboratory evaluations (hematology, biochemistry, coagulation, and lipid panels and urinalysis), 
and trough PK sampling. For a subset of patients (approximately 8 patients per group) at 
pre-identified sites, blood samples for analysis of additional PK parameters will also be collected 
predose and up to 24 hours postdose at Visit 2. In addition, hepatic imaging will be performed at 
Visit 5 (after 16 weeks of treatment) and Visit 9 (after 52 weeks of treatment).  
Evaluation of liver inflammation and fibrosis biomarkers (Homeostatic Model Assessment for 
Insulin Resistance [HOMA-IR], hsCRP, Pro-C3, and ELF panel) will be performed at Visits 2, 5, 
and 9. Twelve-lead ECGs will be performed at Visits 2, 5, 7, and 9, and a liver biopsy will also be 
performed at Visit 9. Throughout the study, patients will be monitored for suspected drug-induced 
liver injury. 
A Safety Follow-up Visit (Visit 10) will occur 14 days after the last dose of study drug to assess 
adverse events, concomitant medications, body weight, vital signs, physical examination findings, 
laboratory parameters, and 12-lead ECGs. Lipid parameters will be monitored throughout the 
follow-up period and will be managed by the Investigator. 
Patients who discontinue early from the study for any reason prior to completion of the treatment 
period will be requested to return to the clinic for an Early Termination (ET) Visit as soon as 
possible after their last intake of study drug. Patients who discontinue early from the study for any 
reason after completion of the treatment period and before the Safety Follow-up Visit will be 
requested to return to the clinic for an ET Visit as soon as possible and no later than the planned 
Safety Follow-up Visit. 
From screening through follow-up, the total study duration for each patient who completes the 
entire treatment period will be approximately 62 weeks. For a summary of procedures to be 
performed at each visit, refer to the Schedule of Procedures in Appendix A. 
An external, independent DSMC will review all available unblinded preliminary safety and 
biomarker results per the DSMC Charter.  
In addition, the following data was comprehensively reviewed during an interim analysis, 
which was performed after 90 patients had completed 16 weeks of treatment: ALT, AST, 
HOMA-IR, Pro-C3, ELF panel, MRI-PDFF, cT1, and lipid parameters. 
3.1.1 
Coronavirus Disease 2019 Contingency Measures 
This study protocol includes contingency measures to manage disruptions due to COVID-19 
control measures; see Appendix G for details. The impacts of these implemented contingency 
measures on the outcomes of this study, including any protocol deviations that result from 
COVID-19 illness and/or COVID-19 control measures, will be discussed in the CSR. In the 
absence of a COVID-19 impact, it is expected that Investigators and patients follow the protocol 
requirements as set forth. 


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3.2 
Study Indication 
The indication for this study is the treatment of patients with NASH without cirrhosis. 


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4 
SELECTION AND WITHDRAWAL OF PATIENTS  
4.1 
Inclusion Criteria 
A patient who meets all of the following criteria will be eligible to participate in the study: 
1. Provides signed written informed consent and agrees to comply with the study protocol. 
2. Is a male or female aged 18 to 75 years, inclusive. 
3. Has a histological diagnosis of NASH without cirrhosis prior to study entry, as confirmed by 
either of the following: 
a. A historical liver biopsy within 6 months of screening (and has not received any NASH 
treatment since the biopsy). The histology slides from the historical biopsy must be 
evaluable and available for review by the central pathology reader. Historical liver biopsies 
obtained during the course of a prior investigational drug study must not be utilized if 
obtained within 3 months or 5 half-lives of the last dose of the prior investigational drug, 
whichever is longer. 
OR 
b. A contemporaneous liver biopsy during the screening period (Week -8 to Week -1). 
Patients without a historical biopsy must also have a FibroScan vibration-controlled 
transient elastography (VCTE) measurement 8.5 kPa and a controlled attenuation 
parameter (CAP) for steatosis with cut-off values 300 dB/m at screening or a historical 
FibroScan (with eligible VCTE and CAP values) within 90 days of screening (prior to 
moving forward with the MRI-PDFF and subsequent liver biopsy). 
Note: Prior to performing a contemporaneous liver biopsy, patients must have 3 or more 
of the following metabolic risk factors: 
 Type 2 diabetes. 
 Elevated fasting glucose (100 mg/dL). 
 Elevated blood pressure (systolic 130 mmHg or diastolic 85 mmHg or on 
antihypertensive drug treatment). 
 Fasting high-density lipoprotein-cholesterol (40 mg/dL in men or 50 mg/dL in 
women or on drug treatment).  
 Elevated fasting triglycerides (150 mg/dL but 300 mg/dL or on drug treatment). 
 Elevated waist circumference (40 inches in men and 35 inches in women) present 
before performing the biopsy. 
4. Has a Nonalcoholic Fatty Liver Disease Activity Score (NAS) 4, with a score of at least 1 in 
each component (steatosis, lobular inflammation, and ballooning), as per the central pathology 
reader. 
5. Has a fibrosis score F1 to F3, inclusive (F1 capped at 20%), on liver biopsy as per the central 
pathology reader. 
6. Has a PDFF 8% on MRI at screening, per the central imaging reader. The MRI-PDFF criteria 
will not apply if the patient has a qualifying historical liver biopsy. 


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7. Has ALT and AST <5  upper limit of normal (ULN) and AST 20 U/L in men and 17 U/L 
for women upon entry into the study. A documented AST 30 U/L by a local laboratory within 
60 days of screening will also be acceptable. The minimum AST criteria will not apply if the 
patient has a qualifying historical liver biopsy. 
8. Has stable baseline liver enzymes, including serum ALT, AST, ALP, and total bilirubin values 
that are established by at least 2 samples demonstrating the following: 
a. Values of an enzyme in the 2 samples are within 1.5  ULN ranges. 
OR 
b. If one of the enzyme levels is 1.5 × ULN, the variability between the 2 samples of ALT 
and AST does not exceed 50% and the variability between the 2 samples of ALP and total 
bilirubin does not exceed 30%.  
Notes:  
o The 2 samples need to be obtained 2 to 16 weeks apart.  
o One sample can be obtained from the patient’s medical history and 1 sample can be 
obtained during the screening period, or both samples can be obtained during the screening 
period.  
o A third sample may be collected if the variability between the first 2 samples exceeds the 
limits in Inclusion Criterion 8b and one of these values is deemed spurious. 
9. Has no other cause of chronic liver disease (eg, autoimmune disorder, alcoholic liver disease, 
drug-induced liver disease, primary biliary cholangitis, primary sclerosing cholangitis, 
hepatitis B virus, hepatitis C virus [HCV], Wilson’s disease, -1-antitrypsin deficiency, 
hemochromatosis) and has not had a liver transplant. 
10. If the patient has type 2 diabetes mellitus (T2DM), he/she has stable T2DM, defined as 
hemoglobin A1c (HbA1c) 9.5% at screening and no new symptoms associated with 
decompensated diabetes in the previous 3 months. 
11. Has a stable body weight, defined by no more than a 5% loss in initial body weight for at least 
3 months or since the liver biopsy was performed, whichever is longer. 
12. Has a BMI 25 kg/m2 and 50 kg/m2. 
13. Is willing to undergo a liver biopsy after 52 weeks of treatment. 
14. Is not of childbearing potential or, if of childbearing potential, is not pregnant as confirmed by 
a negative serum human chorionic gonadotropin (hCG) test at screening and is not planning a 
pregnancy during the course of the study. 
Note: A woman is considered of childbearing potential following menarche and until becoming 
postmenopausal unless permanently sterile (permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy). A postmenopausal state 
is defined as no menses for 12 consecutive months without an alternative medical cause. A 
follicle-stimulating hormone (FSH) level in the postmenopausal range will be used to confirm 
a postmenopausal state in women 55 years of age. 


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15. Male and female patients of childbearing potential must agree to use a dual method of 
contraception (a highly effective method of contraception in conjunction with a barrier 
contraception) consistently and correctly from the first dose of study drug until 90 days after 
the last dose of study drug. Highly effective methods of contraception are those that result in a 
failure rate of less than 1% per year when used consistently and correctly and include the 
following: hormonal intrauterine devices; hormonal contraceptives (oral birth control pills, 
depo, patch, or injectable); male sterilization performed more than 6 months prior to screening; 
and complete abstinence from sexual intercourse (if this is the patient’s usual and preferred 
lifestyle). Barrier methods of contraception include male or female condoms used in 
combination with a separate spermicide product (eg, foam, gel, film, cream, or suppository). 
16. Male patients must agree to abstain from sperm donation from the first dose of study drug until 
90 days after the last dose of study drug. 
4.2 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from participation in the study: 
1. Has a known history of alcohol abuse or daily heavy alcohol consumption (females: more than 
14 units of alcohol per week; males: more than 21 units of alcohol per week [1 unit of alcohol 
is equivalent to a half pint of beer {285 mL}, 1 measure of spirits {25 mL}, or 1 glass of wine 
{125 mL}]). Alcohol abuse will be defined as having an Alcohol Use Disorders Identification 
Test-Concise (AUDIT-C) score of 3 points for men and women AND a full Alcohol Use 
Disorders Identification Test (AUDIT) score of 8 points at screening.  
Note: Only patients with AUDIT-C scores 3 points at screening will receive the full AUDIT 
and will be excluded if they score 8 points on the full AUDIT. Patients with AUDIT-C scores 
<3 points will not receive the full AUDIT. 
2. Has had bariatric surgery within the past 5 years or has bariatric surgery planned to occur 
during the study. 
3. Has significant systemic or major illnesses other than liver disease, including pulmonary 
disease, renal failure, organ transplantation, serious psychiatric disease, or malignancy that, in 
the opinion of the Investigator, would preclude treatment with NST-4016 or confound the 
study results. This would include any malignancy under evaluation, or diagnosed and/or treated 
within the past 2 years except for squamous or non-invasive basal skin cell or cervical 
carcinoma in-situ. 
4. Has a recent (within 6 months) history of cardiac dysrhythmias and/or cardiovascular disease, 
including congestive heart failure (class C and D of the American Heart Association [AHA]), 
unstable coronary artery disease, cerebrovascular disease, or myocardial infarction. 
5. Has uncontrolled arterial hypertension. 
6. Has hepatitis B surface antigen >0, HCV antibody and HCV polymerase chain reaction 
(PCR) >0 (HCV PCR only required for patients who test positive for HCV antibody; patients 
with a confirmed history of HCV infection can be included if HCV PCR has been negative for 
at least the last 2 years), or human immunodeficiency virus (HIV) infection. 
7. Has type 1 diabetes mellitus. 
8. Has diabetic ketoacidosis. 


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9. Has a history of liver decompensation, such as ascites, esophageal varices, and hepatic 
encephalopathy. 
10. Has any of the following exclusionary laboratory results upon entry into the study: 
a. Hemoglobin 11 g/dL for females and 12 g/dL for males. 
b. White blood cell count 2.5 K/L. 
c. Neutrophil count 1.5 K/µL. 
d. Platelet count 150 K/µL. 
e. Total bilirubin 1.3 mg/dL. Patients with total bilirubin 1.3 mg/dL can be included if 
direct bilirubin is within normal ranges in the setting of Gilbert’s syndrome. 
f. Albumin <3.6 g/L. 
g. International Normalized Ratio 1.3, unless due to anti-coagulant therapy. 
h. Thyroid-stimulating hormone >1.5  ULN. 
i. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. 
j. Fasting triglyceride level >300 mg/dL. 
Note: Repeat testing may be performed in consultation with the Medical Monitor if any of the 
above laboratory parameters are outside the specified ranges. 
11. Has a hemostasis disorder. 
12. Has any contraindication to liver biopsy or MRI. 
13. Has any clinically significant ECG abnormality at screening. 
14. Has participated in any other investigational drug study within the previous 3 months or 
5 half-lives of the last dose of the investigational drug, whichever is longer. 
15. Has a known hypersensitivity to any of the ingredients or excipients of the study drug.  
16. Has used any drug known to produce hepatic steatosis, including systemic corticosteroids, 
methotrexate, tetracycline, amiodarone, tamoxifen, estrogens at doses greater than those used 
for hormone replacement, anabolic steroids, or valproic acid, for more than 2 weeks in the 
6 months prior to screening. Local corticosteroid injection for musculoskeletal disorders is 
permitted, including epidural corticosteroid administration. 
17. Is unable to comply with the following concomitant medication restrictions: 
a. Lipid-lowering therapies must be stable for 3 months at screening. Fish oil and other 
omega-3 compounds must also be stable for 3 months at screening if the dose is 1000 mg 
per day. 
b. Antidiabetic drugs, including insulin regimens, must be stable for 3 months at screening, 
with the exception of sodium-glucose cotransporter-2 (SGLT2) inhibitors, and 
glucagon-like peptide-1 (GLP-1) agonists, which must be stable for 6 months at 
screening. 


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c. No vitamin E >400 U/d, pioglitazone, obeticholic acid, or antiobesity drugs for 3 months 
prior to screening or since the liver biopsy, whichever is longer.  
18. Has any other condition that, in the opinion of the Investigator, would impede competence or 
compliance or possibly hinder completion of the study. 
19. Uses any prohibited medications (see Section 5.6) or any concomitant medications used to treat 
an exclusionary medical condition. 
4.3 
Withdrawal Criteria 
Participation of a patient in this clinical study may be discontinued for any of the following 
reasons: 
 The patient withdraws consent or requests discontinuation from the study for any reason 
 Occurrence of any medical condition or circumstance that exposes the patient to substantial 
risk and/or does not allow the patient to adhere to the requirements of the protocol 
 Any serious adverse event (SAE), clinically significant adverse event, severe laboratory 
abnormality (including meeting any of the suspected drug-induced liver injury criteria as 
described in the Drug-Induced Liver Injury Monitoring Plan in Appendix E), intercurrent 
illness, or other medical condition that is considered related to the study drug or indicates to 
the Investigator that continued participation is not in the best interest of the patient 
 Pregnancy 
 Requirement of prohibited concomitant medication after consultation with the Medical 
Monitor 
 Patient failure to comply with protocol requirements or study-related procedures 
 Termination of the study by the Sponsor or the regulatory authority 
If a patient withdraws prematurely from the study due to the above criteria or any other reason, 
study staff should make every effort to complete the full panel of assessments scheduled for the 
End of Treatment Visit (Visit 9, Week 52). The reason for patient withdrawal must be documented 
in the electronic case report form (eCRF).  
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records. A minimum of 3 attempts to contact the patient must 
be made and documented prior to declaring the patient lost to follow-up. 
Withdrawn patients will not be replaced. 


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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Approximately 264 eligible patients with NASH will be randomized into 1 of 3 parallel treatment 
groups (stratified by biopsy fibrosis score), each of which will contain approximately 88 patients, 
as outlined in Table 3. 
Table 3. 
Study Treatment Groups and Dosing Regimens 
Treatment Group 
Dosing Regimen [1] 
Group 1: 300 mg NST-4016 
1 capsule (300 mg) NST-4016 and 1 capsule matching placebo 
Group 2: 600 mg NST-4016 
2 capsules (300 mg each) NST-4016 
Group 3: placebo 
2 capsules matching placebo 
1. 
Patients will take 2 capsules in the morning with water once daily (at approximately the same time each day) for 
52 weeks. Study drug can be taken in the fed or fasted state. 
5.2 
Rationale for Dosing 
The maximum dose selected for this study (600 mg) was previously administered for 12 weeks 
daily in patients with hypertriglyceridemia or mixed dyslipidemia and demonstrated statistically 
significant and clinically meaningful reductions in triglycerides and cholesterol and was shown to 
be safe and well tolerated. Single ascending doses >600 mg (up to 2800 mg) resulted in increasing 
gastrointestinal side effects, which were mainly mild. The low dose selected for this study 
(300 mg) demonstrated significant reductions in triglycerides and cholesterol, although not as 
notable as the effects seen with 600 mg dosing. These 2 doses are expected to provide evidence of 
a dose-response relationship in patients with NASH. Once-daily dosing is consistent with the 
sustained PD effects seen on lipids in repeat-dose studies. 
5.3 
Randomization and Blinding 
This study follows a randomized, double-blind, placebo-controlled design. Patients will be 
randomized via the Interactive Response Technology (IRT) system to 1 of 3 parallel treatment 
groups at Visit 2 (Week 0) in a 1:1:1 ratio. Patients will be stratified by biopsy fibrosis score 
(2 levels: F1 versus F2 or F3). Randomization information will be concealed from the Investigators 
and the patients until the end of the study, with the exception of an emergency situation involving 
a patient that requires unblinding of the treatment assignment. 
Both NST-4016 and placebo will be provided as capsules for oral administration and will be 
identical in appearance. 
5.4 
Breaking the Blind 
Until formal conclusion of the study, patients, Investigators, and all site study personnel will 
remain blinded to treatment allocation, except in the event of a medical emergency that necessitates 
unblinding. In the event of a medical emergency where knowledge of the patient’s treatment 
assignment would influence the patient’s clinical care, the site will be able to unblind the patient 
via the IRT system. The site should consult the study Medical Monitor prior to unblinding if at all 
possible without putting the patient’s safety at risk. In the case of unblinding, the IRT system will 
send a blinded notification to study team members to let them know that a patient was unblinded. 


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5.5 
Drug Supplies 
5.5.1 
Formulation and Packaging 
The drug product is presented as red, oblong-shaped, soft gelatin capsules. The formulation is 
designed as 300 mg icosabutate (drug substance) in Self-Emulsifying Drug Delivery System 
(SEDDS). In general, a SEDDS formulation is a mixture of oils and surfactants, which emulsify 
in aqueous media under conditions of gentle agitation and digestive motility that would be 
encountered in the stomach and gastrointestinal tract. The use of a self-emulsifying formulation is 
proposed to increase the bioavailability of drugs with poor water solubility. The formulation 
contains 300 mg icosabutate formulated in polysorbate 20 and triglycerides medium-chain, with 
3-tert-butyl-4-hydroxyanisole added in order to prevent oxidation of the drug substance. 
The production of the capsules is carried out under nitrogen. The capsules are packaged as bulk in 
double polyethylene bags inside a cardboard box. The soft gelatin capsules are packed for patients 
in high-density polyethylene bottles with a tamper-proof polypropylene screw cap. 
5.5.2 
Study Drug Preparation and Dispensing 
Study drug will be dispensed as 300 mg capsules for oral administration at Visits 2 to 8 by blinded 
site personnel. Patients will receive enough study drug to last until the next study visit. 
This study protocol includes contingency measures to manage disruptions due to COVID-19 
control measures, including modifications to study drug dispensation specific to situations where 
COVID-19 is impacting study conduct. See Appendix G for details of COVID-19 contingency 
measures. In the absence of a COVID-19 impact, it is expected that Investigators and patients 
follow the protocol requirements as set forth. 
5.5.3 
Study Drug Administration 
All patients will take 2 capsules of study drug (either 300 mg NST-4016 and/or matching placebo) 
orally in the morning with water once daily for 52 weeks. In the event that the Visit 9 biopsy is 
delayed, patients will continue to administer study drug daily until the biopsy occurs, for up to 
30 days after the originally projected Visit 9 date. 
Patients should take study drug at approximately the same time each day. Study drug can be taken 
in the fed or fasted state. 
On study visit days, patients should take their daily dose of study drug at the clinical site to 
accommodate predose trough PK sampling. 
5.5.4 
Treatment Compliance 
The quantity of study drug dispensed to and returned by the patient will be counted by site 
personnel and verified by the Clinical Research Associate (CRA) monitoring the study. All 
discrepancies in drug accountability should be explained and documented (missed dose, lost 
capsule, overdose, etc). If the patient is not compliant with study drug intake, the Investigator 
should discuss this with the patient. 
If study drug compliance drops below 80% or surpasses 100% at any given time during the 
treatment period, the Investigator or designee should discuss compliance with the patient and 
counsel the patient appropriately. Noncompliance includes missed doses in addition to taking the 


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wrong dose. The Investigator must continually encourage compliance with the study drug and with 
the study procedures. 
5.5.5 
Storage and Accountability 
The study drug should be stored refrigerated at 2°C to 8°C for up to 18 months and protected from 
light. The study drug may be kept at room temperature (not exceeding 25°C) by the patients 
between study visits for a maximum of 3 months. In case of longer excursions at 15°C to 25°C, 
the study drug should not be used but returned to site for replacement with new study drug. The 
study drug must not be frozen.  
At the completion of the study, all used and unused supplies should be accounted for, and any 
unused study drug should be returned to the clinical site for destruction or for return to the 
distribution site (or designee) for destruction. 
5.6 
Prior and Concomitant Medications and/or Procedures 
Unless medically warranted, all concomitant medications should remain stable from screening 
through the Safety Follow-up Visit (Visit 10). Throughout the duration of the study, patients 
should not introduce changes to their usual diet (including dietary supplements) or lifestyle. 
5.6.1 
Excluded Medications and/or Procedures 
Excluded medications and procedures include the following: 
 Any drug known to produce hepatic steatosis, including systemic corticosteroids, 
methotrexate, tetracycline, amiodarone, tamoxifen, estrogens at doses greater than those used 
for hormone replacement, anabolic steroids, or valproic acid, for more than 2 weeks in the 
6 months prior to screening. Local corticosteroid injection for musculoskeletal disorders is 
permitted, including epidural corticosteroid administration. 
 Vitamin E >400 U/d, pioglitazone, obeticholic acid, or antiobesity drugs within 3 months prior 
to screening or since the historical liver biopsy (if applicable), whichever is longer. 
 CYP3A or CYP2C19 substrates that have a narrow therapeutic index, as exposure may be 
reduced. 
 Strong inhibitors of CYP2C8, CYP2C9, or CYP2C19. 
 Bariatric surgery within the past 5 years or bariatric surgery planned to occur during the study. 
 Participation in any other investigational drug study within the previous 3 months or 
5 half-lives of the last dose of the investigational drug, whichever is longer. 
5.6.2 
Restricted Medications and/or Procedures 
Patients receiving lipid-lowering treatments need to be on stable therapy for at least 3 months prior 
to screening and must agree to remain on a stable regimen for their entire participation in the study 
unless the patient is unable to achieve adequate control with current therapy. Patients may switch 
drugs within a class prior to screening if the lipids remain controlled (as assessed 30 days after the 
switch), the drug is well tolerated, and there is no exclusionary drug interaction.  


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Fish oil and other omega-3 compounds must also be stable for 3 months at screening if the dose 
is 1000 mg per day. 
Throughout study treatment, laboratory alerts will be in place to notify the Investigator of 
low-density lipoprotein-cholesterol (LDL-C) values. If LDL-C increases from baseline by 
10 mg/dL and is >ULN on 2 consecutive visits, additional treatment (eg, initiation of statin therapy 
or an increase in the statin dose for patients who are already on treatment) may be introduced 
according to the 2018 AHA/American College of Cardiology (ACC) Guideline on the 
Management of Blood Cholesterol,2 after discussion with the Sponsor’s Medical Monitor. 
Throughout the study, it is recommended that a patient’s LDL-C is managed in accordance with 
the 2018 AHA/ACC Guideline on the Management of Blood Cholesterol. The 2018 AHA/ACC 
Guideline on the Management of Blood Cholesterol recommends personalized risk assessments 
and new cholesterol-lowering drug options for people at the highest risk for cardiovascular disease. 
The guideline provides treatment algorithms for Primary Atherosclerotic Cardiovascular Disease 
(ASCVD) prevention and Secondary ASCVD prevention. See Appendix F for links to the full and 
abbreviated versions of the 2018 AHA/ACC Guideline on the Management of Blood Cholesterol.  
In this study, it is recommended that a patient’s LDL-C is managed with a statin, when necessary, 
in accordance with the treatment algorithm outlined in the 2018 AHA/ACC Guideline on the 
Management of Blood Cholesterol. In addition, Investigators should identify patients who are at 
“Very High Risk of Future ASCVD Events” who may benefit from additional LDL-C lowering 
therapy. Patients with “Very High Risk of Future ASCVD Events” include those with multiple 
major ASCVD events in the past or 1 major ASCVD event and multiple high-risk conditions as 
defined below: 
 Major ASCVD events include the following: 
o Recent acute coronary syndrome (within the past 12 months)  
o History of myocardial infarction (other than recent acute coronary syndrome event listed 
above)  
o History of ischemic stroke  
o Symptomatic peripheral arterial disease (history of claudication with ankle brachial index) 
 High-risk conditions include the following: 
o Age 65 years  
o Heterozygous familial hypercholesterolemia  
o History of prior coronary artery bypass surgery or percutaneous coronary intervention 
outside of the major ASCVD event(s)  
o Diabetes mellitus  
o Hypertension  
o Chronic kidney disease (eGFR 15 to 59 mL/min/1.73 m2)  
o Current smoking  


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o Persistently elevated LDL-C (LDL-C 100 mg/dL [2.6 mmol/L]) despite maximally 
tolerated statin therapy and ezetimibe  
o History of congestive heart failure 
In certain circumstances as outlined in AHA/ACC treatment algorithm, Investigators should 
consider other cholesterol-lowering medications along with statins. For example, patients with a 
history of myocardial infarction or ischemic stroke, who have high-risk conditions as outlined 
above. A stepwise approach should be used. If a patient is already on a maximal dose statin 
(eg, rosuvastatin 40 mg) and has LDL-C 70 mg/dL (1.8 mmol/L), adding ezetimibe is a 
reasonable step. If that combination is not successful, then the addition of a proprotein convertase 
subtilisin kexin 9 (PCSK9) inhibitor should be considered. However, if a patient is unable able to 
tolerate a maximal dose of statin, then ezetimibe can be added. In addition, for patients who are 
unable to take statins (eg, due to poor tolerability or adverse effects), then adding ezetimibe or a 
PCSK9 inhibitor such as evolocumab or alirocumab would be a reasonable approach. 
Lipid parameters will be monitored throughout the follow-up period and any lipid-lowering 
treatment started during the study should be reviewed during the follow-up period and adjusted or 
discontinued in accordance with the 2018 AHA/ACC Guideline on the Management of Blood 
Cholesterol. 
Patients with T2DM should be on a stable dose of antidiabetic medication, including insulin 
regimens, for at least 3 months prior to screening (with the exception of SGLT2 inhibitors and 
GLP-1 agonists, which must be stable for 6 months at screening). Patients may switch drugs 
within a class prior to screening if the fasting plasma glucose (FPG) and HbA1c remain controlled 
(as assessed 30 days after the switch), the drug is well tolerated, and there is no exclusionary drug 
interaction. Patients must agree to remain on a stable regimen for their entire participation in the 
study unless at the Investigator’s discretion and according to the following rules: 
 In case of confirmed FPG/HbA1c above the threshold value, defined as FPG >270 mg/dL 
(15.0 mmol/L) and HbA1c >9% (for patients with baseline HbA1c <8%) and HbA1c increase 
of more than 1% from baseline (for patients with baseline HbA1c 8% and 9.5%), the 
Investigator should ensure that no reasonable explanation exists for insufficient glucose control 
and that: 
o Plasma glucose was measured in the fasting condition. 
o Absence of intercurrent disease that may jeopardize glycemic control. In case of an 
emergency (eg, surgery, infection), the Investigator can take appropriate measures for 
glycemic control. 
o Compliance to treatment is appropriate. 
o Compliance to diet and lifestyle is appropriate. 


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If any of the above can reasonably explain the insufficient glycemic control, the Investigator 
should consider the following: 
 Investigation and treatment of intercurrent disease (to be reported in adverse event/concomitant 
medication forms on of the eCRF). 
 Stress to the patient the need to be compliant to treatment. 
 Stress to the patient the need to be compliant to diet and lifestyle recommendations. 
An FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken. 
If none from the above-mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, additional medication may be introduced at the 
Investigator’s discretion and according to local guidelines after discussion with the Sponsor’s 
Medical Monitor. 
5.6.3 
Documentation of Prior and Concomitant Medication Use 
All prior and concomitant medications will be documented in the eCRF. Prior medications include 
any medication taken within 6 months prior to screening. Concomitant medications include any 
medication taken on or after the date the patient signs informed consent. Any changes to 
concomitant medication dosing during the study will be captured in the eCRF and closely 
monitored. 


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6 
STUDY PROCEDURES 
A 7-day window is acceptable for all visits during the treatment period, except for Visit 3 
and Visit 10 (Week 4 and Week 54, respectively), when the window is 5 days. 
This study protocol includes contingency measures to manage disruptions due to COVID-19 
control measures, including modifications to visit schedules and procedures specific to situations 
where COVID-19 is impacting study conduct. See Appendix G for details of COVID-19 
contingency measures. In the absence of a COVID-19 impact, it is expected that Investigators and 
patients follow the protocol requirements as set forth. 
6.1 
Informed Consent 
Written informed consent for the study will be obtained from all patients before any protocol 
specific procedures are performed. For a subset of patients (approximately 8 patients per group) at 
pre-identified sites, additional consent will be required for those patients who consent to also 
undergo intensive PK sampling. 
6.2 
Screening Visit (Visit 1, Week -8 to Week -1) 
For patients without a historical biopsy (ie, if the patient does not have evaluable histology slides 
from a liver biopsy performed in the previous 6 months available for review by the central 
pathology reader), FibroScan, MRI-PDFF, and liver biopsy procedures should be conducted in the 
following order: 1) FibroScan assessment (if the patient does not have a historical FibroScan with 
eligible VCTE and CAP values within 90 days of screening); 2) MRI-PDFF (if FibroScan values 
[VCTE and CAP] are within eligibility range); and 3) liver biopsy (if MRI-PDFF is within 
eligibility range). 
The following procedures will be performed at the Screening Visit (Visit 1); more than 1 visit may 
be necessary to complete all required procedures. Patients who screen fail may be rescreened once.  
 Obtain informed consent. 
 Evaluate inclusion/exclusion criteria. 
 Obtain demographics and medical history. 
 Record prior medications (any medication taken within 6 months prior to screening) and 
concomitant medications. 
 Measure height and body weight and calculate BMI. 
 Perform complete physical examination. 
 Collect vital signs (blood pressure [3 readings], pulse rate, and body temperature) with the 
patient in the sitting position after 5 minutes of rest and before any blood draws.  
 Administer the AUDIT-C test. Patients with AUDIT-C scores 3 points at screening will 
receive the full AUDIT at screening and will be excluded if they score 8 points on the full 
AUDIT. Patients with AUDIT-C scores <3 points will not receive the full AUDIT. 


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 Collect fasting blood sample for the following:  
o Viral serology (hepatitis B virus, HCV, and HIV). 
o Hematology, biochemistry, coagulation, and lipid panels. If a patient has a qualifying 
historical biopsy, the required AST levels (AST 20 U/L in men and 17 U/L in women 
by central laboratory or AST 30 U/L by a local laboratory within 60 days of screening; 
see Inclusion Criterion 7) will not be applied. 
o Serum pregnancy test (only for women of childbearing potential).  
o FSH test (only for women 55 years of age, to confirm postmenopausal state). 
 Collect urine sample for urinalysis.  
 Perform 12-lead ECG after the patient has been resting in the supine position for at least 
10 minutes. 
 Perform FibroScan (if the patient does not have a historical FibroScan with eligible VCTE and 
CAP values within 90 days of screening) for patients without historical biopsy.  
 Perform MRI-PDFF if FibroScan values (VCTE and CAP) are within eligibility range (only 
for patients without historical biopsy) or the patient is eligible based on the historical biopsy. 
If the patient is eligible based on a historical biopsy, the MRI-PDFF procedure should be 
performed but the eligibility criterion of liver fat content 8% will not be applied (see Inclusion 
Criterion 6). 
 Perform liver biopsy (only for patients without historical biopsy) if the FibroScan and 
MRI-PDFF values are within eligibility range. 
 Assess adverse events. 
6.3 
Treatment Period – Visit 2 to Visit 9 (Week 0 to Week 52)  
All visits in the treatment period have a visit window of 7 days, with the exception of Visit 3, 
which has a visit window of 5 days.  
6.3.1 
Visit 2 (Week 0) 
The following procedures will be performed at Visit 2 (Week 0): 
 Reassess inclusion/exclusion criteria prior to dosing to ensure no changes in eligibility have 
occurred since screening. 
 Obtain medical history. 
 Record concomitant medications. 
 Measure body weight and calculate BMI (using height at screening). 
 Calculate iron-corrected T1 values using screening MRI. 
 Perform complete physical examination. 
 Collect vital signs (blood pressure [3 readings], pulse rate, and body temperature) with the 
patient in the sitting position after 5 minutes of rest and before any blood draws.  


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 Collect fasting blood sample for the following:  
o Hematology, biochemistry, coagulation, and lipid panels. 
o Lipoprotein particle size. 
o Serum pregnancy test (only for women of childbearing potential).  
o Biomarkers (HOMA-IR, hsCRP, Pro-C3, and ELF panel). 
o Lipidomic analyses (in a subgroup of patients, even if using existing samples). 
 Collect urine sample for urinalysis.  
 Perform 12-lead ECG after the patient has been resting in the supine position for at least 
10 minutes. 
 Randomize eligible patients prior to dosing. 
 Assess adverse events. 
 Collect a predose PK blood sample. 
Note: For those patients participating in the intensive PK subset, collect PK blood samples in 
relation to the first dose of study drug at the following timepoints: predose (within 1 hour prior 
to the first dose), followed by 1, 2, 3, 4, 6, and 8 hours postdose (10 minutes) at Visit 2 (Day 0) 
and 24 hours postdose (1 hour, but prior to the second dose of study drug on Day 1). 
 Administer first dose of study drug on site. 
 Dispense study drug and provide dosing instructions for off-site dosing until next study visit. 
6.3.2 
Visit 3 (Week 4) 
The following procedures will be performed at Visit 3 (Week 4): 
 Record concomitant medications. 
 Measure body weight. 
 Perform abbreviated physical examination. 
 Collect vital signs (blood pressure [3 readings], pulse rate, and body temperature) with the 
patient in the sitting position after 5 minutes of rest and before any blood draws.  
 Collect fasting blood sample for hematology, biochemistry, coagulation, and lipid panels. 
 Collect urine sample for the following: 
o Urinalysis.  
o Urine pregnancy test (only for women of childbearing potential).  
 Assess adverse events. 
 Collect a predose PK blood sample.  
 Collect returned and used/unused study drug and assess compliance.  


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 Administer study drug on site. 
 Dispense new study drug for dosing until the next study visit. 
6.3.3 
Visit 4 (Week 10) 
The following procedures will be performed at Visit 4 (Week 10): 
 Record concomitant medications. 
 Measure body weight. 
 Perform abbreviated physical examination. 
 Collect vital signs (blood pressure [3 readings], pulse rate, and body temperature) with the 
patient in the sitting position after 5 minutes of rest and before any blood draws.  
 Collect fasting blood sample for hematology, biochemistry, coagulation, and lipid panels. 
 Collect urine sample for the following: 
o Urinalysis.  
o Urine pregnancy test (only for women of childbearing potential).  
 Assess adverse events. 
 Collect a predose PK blood sample.  
 Collect returned and used/unused study drug and assess compliance.  
 Administer study drug on site. 
 Dispense new study drug for dosing until the next study visit. 
6.3.4 
Visit 5 (Week 16) 
The following procedures will be performed at Visit 5 (Week 16): 
 Record concomitant medications. 
 Measure body weight. 
 Perform abbreviated physical examination. 
 Collect vital signs (blood pressure [3 readings], pulse rate, and body temperature) with the 
patient in the sitting position after 5 minutes of rest and before any blood draws.  
 Collect fasting blood sample for the following: 
o Hematology, biochemistry, coagulation, and lipid panels. 
o Lipoprotein particle size. 
o Biomarkers (HOMA-IR, hsCRP, Pro-C3, and ELF panel). 
 Collect urine sample for the following: 
o Urinalysis.  
o Urine pregnancy test (only for women of childbearing potential). 


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 Perform 12-lead ECG after the patient has been resting in the supine position for at least 
10 minutes. 
 Perform MRI-PDFF and cT1 imaging. 
 Assess adverse events. 
 Collect a predose PK blood sample.  
 Collect returned and used/unused study drug and assess compliance.  
 Administer study drug on site. 
 Dispense new study drug for dosing until the next study visit. 
6.3.5 
Visit 6 (Week 24) 
The following procedures will be performed at Visit 6 (Week 24): 
 Record concomitant medications. 
 Measure body weight. 
 Perform abbreviated physical examination. 
 Collect vital signs (blood pressure [3 readings], pulse rate, and body temperature) with the 
patient in the sitting position after 5 minutes of rest and before any blood draws.  
 Collect fasting blood sample for hematology, biochemistry, coagulation, and lipid panels. 
 Collect urine sample for the following: 
o Urinalysis.  
o Urine pregnancy test (only for women of childbearing potential).  
 Assess adverse events. 
 Collect a predose PK blood sample.  
 Collect returned and used/unused study drug and assess compliance.  
 Administer study drug on site. 
 Dispense new study drug for dosing until the next study visit. 
6.3.6 
Visit 7 (Week 32) 
The following procedures will be performed at Visit 7 (Week 32): 
 Record concomitant medications. 
 Measure body weight. 
 Perform abbreviated physical examination. 
 Collect vital signs (blood pressure [3 readings], pulse rate, and body temperature) with the 
patient in the sitting position after 5 minutes of rest and before any blood draws.  
 Collect fasting blood sample for hematology, biochemistry, coagulation, and lipid panels. 


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 Collect urine sample for the following: 
o Urinalysis.  
o Urine pregnancy test (only for women of childbearing potential). 
 Perform 12-lead ECG after the patient has been resting in the supine position for at least 
10 minutes. 
 Assess adverse events. 
 Collect a predose PK blood sample.  
 Collect returned and used/unused study drug and assess compliance.  
 Administer study drug on site. 
 Dispense new study drug for dosing until the next study visit. 
6.3.7 
Visit 8 (Week 40) 
The following procedures will be performed at Visit 8 (Week 40): 
 Record concomitant medications. 
 Measure body weight. 
 Perform abbreviated physical examination. 
 Collect vital signs (blood pressure [3 readings], pulse rate, and body temperature) with the 
patient in the sitting position after 5 minutes of rest and before any blood draws.  
 Collect fasting blood sample for hematology, biochemistry, coagulation, and lipid panels. 
 Collect urine sample for the following: 
o Urinalysis.  
o Urine pregnancy test (only for women of childbearing potential). 
 Assess adverse events. 
 Collect a predose PK blood sample.  
 Collect returned and used/unused study drug and assess compliance.  
 Administer study drug on site. 
 Dispense new study drug for dosing until the next study visit. 
6.3.8 
Visit 9 (Week 52) 
The following procedures will be performed at Visit 9 (Week 52): 
 Record concomitant medications. 
 Measure body weight. 
 Perform complete physical examination. 


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 Collect vital signs (blood pressure [3 readings], pulse rate, and body temperature) with the 
patient in the sitting position after 5 minutes of rest and before any blood draws.  
 Collect fasting blood sample for the following:  
o Hematology, biochemistry, coagulation, and lipid panels. 
o Lipoprotein particle size. 
o Biomarkers (HOMA-IR, hsCRP, Pro-C3, and ELF panel). 
o Lipidomic analyses (in a subgroup of patients). 
 Collect urine sample for the following: 
o Urinalysis.  
o Urine pregnancy test (only for women of childbearing potential). 
 Perform 12-lead ECG after the patient has been resting in the supine position for at least 
10 minutes. 
 Perform MRI-PDFF and cT1 imaging. 
 Perform liver biopsy for analyses (including lipidomics in a subset of patients). 
 Assess adverse events. 
 Collect a PK blood sample.  
 Collect returned and used/unused study drug and assess compliance. 
6.4 
Safety Follow-up Visit (Visit 10, Week 54) 
The Safety Follow-up Visit has a visit window of 5 days. The following procedures will be 
performed at the Safety Follow-up Visit (Visit 10, Week 54): 
 Record concomitant medications. 
 Measure body weight. 
 Perform complete physical examination. 
 Collect vital signs (blood pressure [3 readings], pulse rate, and body temperature) with the 
patient in the sitting position after 5 minutes of rest and before any blood draws.  
 Collect fasting blood sample for the following:  
o Hematology, biochemistry, coagulation, and lipid panels.  
o Serum pregnancy test (only for women of childbearing potential). 
 Collect urine sample for urinalysis.  
 Perform 12-lead ECG after the patient has been resting in the supine position for at least 
10 minutes. 
 Assess adverse events. 


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6.5 
Early Termination Visit and Withdrawal Procedures 
The end of treatment for patients completing the study is Visit 9 (Week 52). For patients who are 
withdrawn from the study prior to completion, all Visit 9 procedures will be performed at an 
ET Visit. Liver biopsy at ET will only be performed for patients who have been on study drug for 
at least 6 months. 
Patients who discontinue early from the study for any reason prior to completion of the treatment 
period will be requested to return to the clinic for an ET Visit as soon as possible after their last 
intake of study drug.  
If a patient discontinues early from the study for any reason after completion of the treatment 
period but before the Safety Follow-up Visit, sites should make every attempt to bring the patient 
into the site for the Safety Follow-up Visit. 
The following procedures will be performed at the ET Visit: 
 Record concomitant medications. 
 Measure body weight. 
 Perform complete physical examination. 
 Collect vital signs (blood pressure [3 readings], pulse rate, and body temperature) with the 
patient in the sitting position after 5 minutes of rest and before any blood draws.  
 Collect fasting blood sample for the following:  
o Hematology, biochemistry, coagulation, and lipid panels. 
o Lipoprotein particle size. 
o Biomarkers (HOMA-IR, hsCRP, Pro-C3, and ELF panel).  
o Serum pregnancy test (only for women of childbearing potential). 
o Lipidomic analyses (in a subgroup of patients). 
 Collect urine sample for urinalysis.  
 Perform 12-lead ECG after the patient has been resting in the supine position for at least 
10 minutes. 
 Perform MRI-PDFF and cT1 imaging. 
 Perform liver biopsy (if patient has been on study drug for at least 6 months) for analyses 
(including lipidomics in a subset of patients). 
 Assess adverse events. 
 Collect a PK blood sample.  
 Collect returned and used/unused study drug and assess compliance. 


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7 
EFFICACY ASSESSMENTS 
7.1 
Efficacy Variables 
7.1.1 
Primary Efficacy Variable 
The primary efficacy parameter is the percentage of patients with resolution of NASH, defined as 
disappearance of ballooning (score = 0) with lobular inflammation score 0 or 1, with no worsening 
of fibrosis. 
7.1.2 
Secondary Efficacy Variables 
The secondary efficacy parameters include the following: 
 Change from baseline in NAS 
 Changes in individual histological scores for steatosis, ballooning, inflammation, and fibrosis 
 Changes in the liver enzymes AST, ALT, GGT, and bilirubin 
 Changes in the imaging parameters MRI-PDFF and cT1 
 Changes in the inflammation marker hsCRP 
 Changes in the fibrosis activity markers Pro-C3 and ELF panel 
 Changes in HOMA-IR, a measure of insulin resistance and metabolic status 
7.1.3 
Exploratory Biomarker Analysis 
The exploratory parameters include the following (in a subgroup of patients): 
 Profile and characterization of lipid species on End of Treatment Visit liver biopsy 
 Profile and characterization of lipid species on baseline and End of Treatment serum samples 


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8 
SAFETY ASSESSMENTS 
8.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the investigational medicinal 
product. All adverse events, including observed or volunteered problems, complaints, or 
symptoms, are to be recorded on the appropriate eCRF. 
Adverse events, which include clinical laboratory test variables, will be monitored and 
documented from the time the patient signs the informed consent form (ICF) until Visit 10 
(Week 54) or the ET Visit (if applicable). Patients should be instructed to report any adverse event 
that they experience to the Investigator, whether or not they think the event is due to study 
treatment. Investigators should make an assessment for adverse events at each visit and record the 
event on the appropriate adverse event eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (eg, surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure itself.  
Any medical condition already present at screening should be recorded as medical history and not 
be reported as an adverse event unless the medical condition or signs or symptoms present at 
screening changes in severity, frequency, or seriousness at any time during the study. In this case, 
it should be reported as an adverse event. 
Clinically significant abnormal laboratory or other examination (eg, ECG) findings that are 
detected during the study or are present at screening and significantly worsen during the study 
should be reported as adverse events, as described below. The Investigator will exercise his or her 
medical and scientific judgment in deciding whether an abnormal laboratory finding or other 
abnormal assessment is clinically significant. Clinically significant abnormal laboratory values 
occurring during the clinical study will be followed until repeat tests return to normal, stabilize, or 
are no longer clinically significant. Abnormal test results that are determined to be an error should 
not be reported as an adverse event. Laboratory abnormalities or other abnormal clinical findings 
(eg, ECG abnormalities) should be reported as an adverse event if any of the following are 
applicable: 
 If an intervention is required as a result of the abnormality 
 If action taken with the study drug is required as a result of the abnormality 
 Based on the clinical judgment of the Investigator 


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8.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable possibility, 
ie, the relationship cannot be ruled out. 
8.1.2 
Unexpected Adverse Drug Reaction 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. 
8.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each adverse event and will also categorize 
each adverse event as to its potential relationship to study drug. 
The Investigator will assess all adverse events using the Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 grading system. 
Assessment of severity 
The severity of all adverse events should be graded according to the CTCAE. For those adverse 
event terms not listed in the CTCAE, the following grading system should be used: 
 CTCAE Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
 CTCAE Grade 2: Moderate; minimal local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
 CTCAE Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living 
 CTCAE Grade 4: Life-threatening consequences; urgent intervention indicated 
 CTCAE Grade 5: Death related to the adverse event 
Causality assessment 
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 
No (unrelated, not related, unlikely to be related) – The time course between the administration of 
study drug and the occurrence or worsening of the adverse event rules out a causal relationship 
and another cause (concomitant drugs, therapies, complications, etc) is suspected. 
Yes (possibly, probably, or definitely related) – The time course between the administration of 
study drug and the occurrence or worsening of the adverse event is consistent with a causal 
relationship and no other cause (concomitant drugs, therapies, complications, etc) can be 
identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 


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The following factors should also be considered: 
 The temporal sequence from study drug administration- 
The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
 Underlying, concomitant, intercurrent diseases- 
Each report should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the patient may have. 
 Concomitant drug- 
The other drugs the patient is taking or the treatment the patient receives should be examined 
to determine whether any of them might be recognized to cause the event in question. 
 Known response pattern for this class of study drug- 
Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
 Exposure to physical and/or mental stresses- 
The exposure to stress might induce adverse changes in the recipient and provide a logical and 
better explanation for the event. 
 The pharmacology and PK of the study drug- 
The known pharmacologic properties (absorption, distribution, metabolism, and excretion) of 
the study drug should be considered. 
8.1.4 
Adverse Events of Special Interest 
The Investigator will monitor each patient for clinical and laboratory evidence of predefined 
adverse events of special interest (AESIs) throughout the patient’s participation in this study.  
Events of suspected drug-induced liver injury will be monitored as AESIs during this study. During 
the course of the study, additional AESIs may be identified by the Sponsor.  
The Investigator will assess and record in detail any additional information on AESIs on an SAE 
form (whether or not the event meets seriousness criteria in Section 8.2), to be submitted within 
24 hours of awareness of the event. Adverse events of special interest must be recorded on the 
eCRF. 
8.2 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
 Death. 
 A life-threatening adverse event. 
Note: An adverse event or adverse reaction is considered “life-threatening” if, in view of either 
the Investigator or Sponsor, its occurrence places the patient at immediate risk of death. It does 
not include an event that, had it occurred in a more severe form, might have caused death. 


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 Requires hospitalization or prolongation of existing hospitalizations. 
Note: Any hospital admission with at least 1 overnight stay will be considered an inpatient 
hospitalization. An emergency room or urgent care visit without hospital admission will not 
be recorded as an SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing the ICF, or elective treatment of a preexisting condition that did not 
worsen from baseline. However, unexpected complications and/or prolongation of 
hospitalization that occur during elective surgery should be recorded as adverse events and 
assessed for seriousness. Admission to the hospital for social or situational reasons (ie, no place 
to stay, live too far away to come for hospital visits, respite care) will not be considered 
inpatient hospitalizations. 
 A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions. 
 A congenital anomaly/birth defect. 
 An important medical event. 
Note: Important medical events that do not meet any of the above criteria may be considered 
an SAE when, based upon appropriate medical judgment, they may jeopardize the patient and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalizations, or the development of drug dependency. 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial reports 
All SAEs occurring from the time of informed consent until 30 days following the last dose of 
study drug must be reported to Medpace Clinical Safety within 24 hours of the knowledge of the 
occurrence. After the 30-day reporting window, any SAE that the Investigator considers related to 
study drug must be reported to the Medpace Clinical Safety or Sponsor designee. 
To report the SAE, complete the SAE form electronically in the Electronic Data Capture (EDC) 
system for the study. When the form is completed, Medpace Safety personnel will be notified 
electronically by the EDC system and will retrieve the form. If the event meets serious 
criteria and it is not possible to access the EDC system, send an email to Medpace Safety at 
Medpace-safetynotification@medpace.com or call the Medpace SAE reporting line (phone 
number listed below), and fax/email the completed paper SAE form to Medpace (contact 
information listed in Section 8.6) within 24 hours of awareness. When the EDC system becomes 
available, the SAE information must be entered within 24 hours of the system becoming available. 
Follow-up reports 
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Clinical Safety via fax/email. If it 


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is not possible to access the EDC system, refer to the procedures outlined above for initial reporting 
of SAEs. 
8.4 
Pregnancy Reporting 
If a patient becomes pregnant during the study or within the safety follow-up period (ie, prior to 
the Safety Follow-up Visit), the Investigator is to stop dosing with study drug(s) immediately, and 
the patient should be withdrawn from the study. Early termination procedures should be 
implemented at that time. 
A pregnancy is not considered to be an adverse event or SAE; however, it must be reported to 
Medpace Clinical Safety within 24 hours of knowledge of the event. Medpace Clinical Safety will 
then provide the Investigator/site the Exposure In Utero (EIU) form for completion. The 
Investigator/site must complete the EIU form and fax/email it back to Medpace Clinical Safety.  
If the female partner of a male patient becomes pregnant while the patient is receiving study drug 
or within the safety follow-up period, the Investigator should notify Medpace Clinical Safety as 
described above. 
The pregnancy should be followed until the outcome of the pregnancy, whenever possible. Once 
the outcome of the pregnancy is known, the EIU form should be completed and faxed/emailed to 
Medpace Clinical Safety. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (ie, postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
8.5 
Expedited Reporting 
The Sponsor/designee will report all relevant information about Suspected Unexpected Serious 
Adverse Reactions (SUSARs) that are fatal or life-threatening as soon as possible to the Food and 
Drug Administration, and in any case no later than 7 days after knowledge by the Sponsor/designee 
of such a case. Relevant follow-up information will subsequently be communicated within an 
additional 8 days. 
All other SUSARs will be reported to the Food and Drug Administration as soon as possible but 
within a maximum of 15 days of first knowledge by the Sponsor/designee.  
The Sponsor/designee will also report any additional expedited safety reports required in 
accordance with the timelines outlined in country-specific legislation.  
The Sponsor/designee will also inform all Investigators as required per local regulation. 
The requirements above refer to the requirements relating to investigational medicinal products. 


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8.6 
Special Situation Reports 
Special situation reports include reports of overdose, misuse, abuse, medication error, and reports 
of adverse reactions associated with product complaints. 
 Overdose: Refers to the administration of a quantity of a medicinal product given per 
administration or cumulatively (accidentally or intentionally), which is above the maximum 
recommended dose according to the protocol. Clinical judgment should always be applied. In 
cases of a discrepancy in the study drug accountability, overdose will be established only when 
it is clear that the patient has taken additional dose(s) or the Investigator has reason to suspect 
that the patient has taken additional dose(s). 
 Misuse: Refers to situations where a medicinal product is intentionally and inappropriately 
used in a way that is not in accordance with the protocol instructions or local prescribing 
information and may be accompanied by harmful physical and/or psychological effects.  
 Abuse: Is defined as persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
 Medication error: Is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product by a healthcare professional, patient, or consumer, respectively. The 
administration or consumption of the unassigned treatment and administration of an expired 
product are always reportable as medication errors. Cases of patients missing doses of 
investigational product are not considered reportable as medication errors. 
All special situation events as described above must be reported on the Special Situations Report 
form and faxed/emailed to Medpace Clinical Safety (contact information listed below) within 
24 hours of knowledge of the event. All adverse events associated with these Special Situation 
Report forms should be reported as adverse events or SAEs, as well as recorded on the adverse 
event eCRF and/or the SAE report form. Details of the symptoms and signs, clinical management, 
and outcome should be provided, when available. 
Safety Contact Information: Medpace Clinical Safety 
Medpace SAE reporting line – USA: 
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax: +1-866-336-5320 or +1-513-570-5196 
Email: medpace-safetynotification@medpace.com 
8.7 
Clinical Laboratory Evaluations 
Clinical safety laboratory parameters will be measured or calculated at all study visits (see 
Appendix A). Fasting hematology, biochemistry, coagulation, and lipid panels and urinalysis 
parameters will be evaluated at all study visits. Further analysis of urine sediment or urine 
microscopy will be performed if there are any abnormalities on any of the following 3 dipstick 
results: leukocyte esterase, blood, or nitrite. Although lipid parameters will be evaluated at every 
visit, lipoprotein particle size will be assessed only at baseline, Week 16, and at the end of 
treatment (Week 52/ET). Lipid parameters will be monitored throughout the follow-up period and 
any lipid-lowering treatment started during the study should be reviewed during the follow-up 
period and adjusted or discontinued in accordance with the 2018 AHA/ACC Guideline on the 
Management of Blood Cholesterol.2 See Appendix F for links to the full and abbreviated versions 


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of the 2018 AHA/ACC Guideline on the Management of Blood Cholesterol. See Appendix B for 
a complete list of laboratory analytes. 
For women of childbearing potential, a serum hCG test will be performed at screening, Week 0, 
and at study exit (whether at the Safety Follow-up or ET Visit). Urine hCG testing will be 
performed at all other visits. If a urine hCG test is positive, pregnancy will be confirmed by a 
serum hCG test. Follicle-stimulating hormone level will be measured at screening to confirm 
postmenopausal state in women 55 years of age. 
Samples will be collected for viral serology at screening to confirm patients are negative for 
hepatitis B virus, HCV (patients with a confirmed history of HCV infection can be included if 
HCV PCR is negative for at least the last 2 years), and HIV infection. 
Blood sampling procedures, including information on blood volume, collection tubes, sample 
processing, storage, and shipping are provided in the Laboratory Manual. Where necessary, local 
laboratory testing will be acceptable to monitor events of suspected drug-induced liver injury. 
Technical details on laboratory parameters (methods and commercial kit[s]) will be specified in 
the Laboratory Manual. 
8.8 
Vital Signs 
Vital signs will be collected at every study visit and will include blood pressure, pulse rate, and 
body temperature, and will be performed with the patient in the sitting position after 5 minutes of 
rest and before any blood draws. Three replicate blood pressure readings will be taken at each visit. 
8.9 
Electrocardiograms 
Single 12-lead ECGs will be performed at screening; Visits 2, 5, 7, and 9; and at study exit 
(whether at the Safety Follow-up or ET Visit). Single 12-lead ECGs will be performed after the 
patient has been resting in the supine position for at least 10 minutes. In case of evident bad quality 
of the tracing (eg, muscle tremor), the ECG will be repeated. QTcF will be measured. 
8.10 
Physical Examinations 
Full physical examinations (including general appearance; eyes, ears, nose, and throat; head and 
neck; chest and lungs; cardiovascular; abdomen; musculoskeletal; lymphatic; dermatological; 
neurological systems; mental status; and extremities) will be performed at screening; Visits 2 
and 9; and at study exit (whether at the Safety Follow-up or ET Visit). Abbreviated physical 
examinations will be performed at all other visits. Abbreviated physical examinations should be 
targeted based on Investigator discretion and interval history. 
8.11 
Imaging Assessments 
Hepatic imaging by MRI will be performed using a standardized central imaging protocol provided 
to each site and validated by the central imaging reader.  


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Images will be provided to the central imaging reader in order to assess the following parameters: 
 MRI-PDFF: a chemical shift-based method to assess for water-fat separation. This has been 
shown to correspond to histological measures of steatosis. 
 cT1: a measure of free-water content in tissue. This has been shown to increase in inflammation 
and fibrosis, when corrected for hepatic iron. 
Hepatic imaging will be performed at screening, Visit 5, and Visit 9 (or the ET Visit, if applicable). 
The MRI performed during screening will provide the baseline data for MRI-PDFF and cT1; 
however, baseline cT1 will be calculated at Visit 2, only after the patient is randomized. 
8.12 
Liver Biopsies 
Liver biopsies will be performed at screening and Visit 9 (or the ET Visit, if applicable and the 
patient has been on study drug for at least 6 months). Assessment of the tissue collected will be 
performed by a blinded central pathology reader. In addition, in a subgroup of patients, the tissue 
collected at the End of Treatment Visit (Visit 9) will be analyzed by a central laboratory (OWL) 
for lipidomic analyses. Further details on biopsy collection, processing, storage, and shipping and 
the central review process are provided in the laboratory manual and biopsy review charter. 
8.12.1 
Nonalcoholic Fatty Liver Disease Activity Score 
The NAS was developed as a tool to measure clinical disease changes by scoring the features of 
NASH during therapeutic trials. 
The total NAS represents the sum of scores for steatosis, lobular inflammation, and ballooning, 
and ranges from 0 to 8. 
The NAS will be calculated and provided by the central pathology reader at screening and Visit 9 
(or the ET Visit, if applicable), for comparison with screening scores. 
8.12.2 
Re-Reading of Central Pathologist Assessment of Eligible Patients Based on a 
Qualifying Historical Biopsy 
The site may request a re-read of the central pathologist assessment if the prior results of the 
patient’s historical biopsy met the enrollment criteria. Both fibrosis and NAS criteria must have 
been met and the report provided to the Sponsor Study Director for approval. Further details of 
this process are outlined in the Pathology Manual and other related documents. 
8.13 
Pharmacodynamic Assessments 
Evaluation of liver inflammation and fibrosis biomarkers (HOMA-IR, hsCRP, Pro-C3, and ELF 
panel) will be performed at Visits 2, 5, and 9 (or the ET Visit, if applicable). 
8.14 
Pharmacokinetic Assessments 
For all patients, blood samples for evaluation of trough plasma PK concentrations of NST-4016 
will be collected predose at Visits 2 to 9 (or the ET Visit, if applicable). 
For those patients participating in the intensive PK subset, PK blood samples will be collected in 
relation to the first dose of study drug at Visit 2. Samples will be taken at the following timepoints: 
predose (within 1 hour prior to the first dose), followed by 1, 2, 3, 4, 6, and 8 hours postdose 


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(10 minutes) at Visit 2 (Day 0) and 24 hours postdose (1 hour, but prior to the second dose of 
study drug on Day 1). 
For the intensive PK subset of patients, the following PK parameters will be calculated in order to 
further characterize the PK of NST-4016 after the first dose: 
 AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last 
observed concentration 
 AUC0-inf: area under the plasma concentration-time curve from time 0 extrapolated to infinity 
 CL/F: apparent plasma clearance  
 Cmax: maximum observed plasma concentration 
 Tmax: time to reach the maximum observed plasma concentration 
 Vz/F: apparent volume of distribution 
Additional PK parameters may be determined, if deemed appropriate. 
Details of the parameters and handling procedures will be described in the Statistical Analysis 
Plan. 


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9 
STATISTICS 
9.1 
Analysis Populations 
The Randomized Population will include all patients who are randomized to the study. 
The Intent-to-Treat (ITT) Population will include all patients who are randomized and receive at 
least 1 dose of study drug. 
The Modified ITT (mITT) Population will include all patients from the ITT Population who have 
valid baseline and Week 52 (or ET, if applicable) liver biopsy measurements. 
The Per-Protocol (PP) Population will include all patients from the mITT Population who complete 
the 52-week treatment period without any major protocol violations. 
The Trough PK Population will include all patients who received at least 1 dose of NST-4016 and 
have at least 1 measurable trough PK concentration. 
The Intensive PK Population will include all patients who received at least 1 dose of NST-4016 
and have at least 1 measurable non-trough intensive PK sample. 
The Safety Population will include all patients who receive at least 1 dose of study drug. 
9.2 
Statistical Methods 
Full details of the analyses will be provided in the Statistical Analysis Plan, which will be finalized 
prior to database lock and unblinding. 
9.2.1 
Analysis of Efficacy 
The efficacy analysis will be performed on the ITT Population; missing values for continuous 
endpoints will be imputed using multiple imputation methods. 
Baseline will be defined as the value at the Screening Visit for measurements from the liver biopsy 
and imaging data and as the predose value at Visit 2 (Week 0) for the biomarker data. For other 
efficacy endpoints, baseline will be defined as the predose value at Visit 2 (Week 0); if this value 
is missing, then the latest predose value will be used. 
9.2.1.1 
Primary efficacy analysis 
The primary endpoint (ie, the percentage of patients with resolution of NASH without worsening 
fibrosis) will be analyzed using the ITT Population. Patients without a Week 52 (or ET, if 
applicable) liver biopsy will be imputed as nonresponders. The number and percentage of patients 
meeting the criteria for the primary endpoint will be summarized by treatment group. 
The primary analysis will be conducted using the data from the 600 mg NST-4016 and placebo 
groups using the Cochran-Mantel-Haenszel test, stratified by biopsy fibrosis score (2 levels: F1 
versus F2 or F3). The primary analysis will be based on the use of a 2-sided test at the 
alpha=0.05 level of significance. 
9.2.1.2 
Key secondary analysis of the primary endpoint 
If the primary analysis is statistically significant (p<0.05), the key secondary analysis of the 
primary endpoint will be conducted using the data from the 300 mg NST-4016 and placebo 
groups, again using the Cochran-Mantel-Haenszel test, stratified by biopsy fibrosis score 


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(2 levels: F1 versus F2 or F3). Due to the use of this fixed-sequence testing procedure, the key 
secondary analysis will be based on the use of a 2-sided test at the alpha=0.05 level of significance. 
However, if the primary analysis is not statistically significant, the comparison between the 
300 mg NST-4016 and placebo groups will be exploratory rather than confirmatory. 
9.2.1.3 
Sensitivity analysis of the primary endpoint 
A sensitivity analysis for the primary endpoint will be carried out using a logistic regression model 
with treatment group (300 mg NST-4016, 600 mg NST-4016, or placebo) and biopsy fibrosis score 
(2 levels: F1 versus F2 or F3) as factors. Pairwise treatment comparisons will be estimated in this 
model as odds ratios (NST-4016 versus placebo) along with their 95% confidence intervals and 
p-values. 
The primary, key secondary, and sensitivity analyses of the primary endpoint will be repeated on 
the mITT and PP Populations. 
9.2.1.4 
Secondary efficacy analysis 
Continuous efficacy variables will be summarized using descriptive statistics for the observed data 
and change and/or percent change from baseline by treatment group and visit as appropriate. 
Change from baseline to Week 52 in NAS and individual histological scores will be analyzed in 
an analysis of covariance model, adjusting for treatment (300 mg NST-4016, 600 mg NST-4016, 
or placebo), biopsy fibrosis score (2 levels: F1 versus F2 or F3), and respective baseline score. 
Pairwise treatment comparisons between each NST-4016 dose and placebo will be estimated in 
this model using least square (LS) means, standard errors, 95% confidence intervals, and p-values. 
A similar analysis will be carried out for the imaging parameters at Week 16 and Week 52. 
Efficacy variables measured at multiple timepoints will be analyzed with Mixed Model Repeated 
Measures methods, with change (or percent change) from baseline as the dependent variable, 
adjusting for treatment (300 mg NST-4016, 600 mg NST-4016, or placebo), biopsy fibrosis score 
(2 levels: F1 versus F2 or F3), and baseline score. Pairwise treatment comparisons between each 
NST-4016 dose and placebo at Week 52 will be estimated using LS means, standard errors, 
95% confidence intervals, and p-values. 
9.2.1.5 
Exploratory biomarker analysis 
The analysis of exploratory endpoints will be further described in the Statistical Analysis Plan. 
9.2.1.6 
Pharmacokinetic analysis 
Trough plasma PK concentrations at Visits 3 to 9 will be summarized descriptively by visit for the 
Trough PK Population.  
For the subset of patients with intensive PK sampling data, additional PK parameters will be 
summarized by treatment using descriptive statistics for the Intensive PK Population. No formal 
statistical analysis of PK parameters will be performed. 
9.2.2 
Analysis of Safety 
Safety variables will be tabulated and presented for the Safety Population. 
Baseline will be defined as the predose value at Visit 2 (Week 0); if this value is missing, then the 
latest predose value will be used. 


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A TEAE is defined as a new or worsening adverse event after the first dose of study drug. The 
number and percentage of patients with at least 1 TEAE will be summarized by treatment group 
by system organ class and preferred term. Similar summaries will be presented for study 
drug-related TEAEs and SAEs. 
Safety laboratory parameters, vital signs, and ECGs will be summarized by treatment group by 
visit. Change from baseline values by visit will also be presented for the continuous parameters. 
The number (and percentage) of patients with abnormalities based on predefined normal ranges 
will be tabulated by treatment group. 
9.2.3 
Interim Analysis 
An interim analysis was planned for this study after 90 patients had completed 16 weeks of 
treatment. This analysis was reviewed by the DSMC according to the DSMC Charter. The interim 
analysis included a comprehensive review of the following data: ALT, AST, HOMA-IR, Pro-C3, 
ELF panel, MRI-PDFF, cT1, and lipid parameters. The conclusions and recommendations of the 
DSMC were shared blindly with the Sponsor and clinical sites. A separate interim analysis plan 
was finalized prior to conducting the interim analysis. 
9.2.4 
Data Safety Monitoring Committee 
An external, independent DSMC will review all available unblinded preliminary safety and 
biomarker results, as described in the DSMC Charter. The DSMC Charter will describe the overall 
guidelines, composition and roles, and responsibilities of the independent DSMC for the NST-02 
study, including the selection of DSMC members, timing of meetings, methods of providing 
information to and from the DSMC, frequency and format of meetings, data analysis 
recommendations, and DSMC relationships with other parties participating in the conduct of this 
study. Patient accrual will continue throughout the period of the DSMC review. The DSMC will 
advise on the accrual of the remaining patients per protocol or any amendments that are necessary 
for safety reasons.  
9.2.5 
Sample Size Determination 
A sample size of 88 patients per treatment group provides 80% power to detect a 40% responder 
rate for active versus placebo, assuming a placebo response rate of 18% and a dropout rate of 25%. 


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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the CRA during monitoring visits. The 
CRAs will verify data recorded in the EDC system with source documents. All corrections or 
changes made to any study data must be appropriately tracked in an audit trail in the EDC system. 
An eCRF will be considered complete when all missing, incorrect, and/or inconsistent data has 
been accounted for. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure username and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
10.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
 Medical Dictionary for Regulatory Activities (latest) for medical history and adverse events 
 WHO Drug Dictionary for prior and concomitant medications 
10.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
10.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  


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10.3 
End of Study 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment for the last patient in the study. 
 


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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
11.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human patients. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study patients 
are protected, consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible. 
11.2 
Institutional Review Board 
The Institutional Review Board (IRB) will review all appropriate study documentation in order to 
safeguard the rights, safety, and well-being of patients. The study will only be conducted at sites 
where IRB approval has been obtained. The protocol, Investigator’s Brochure, ICF, advertisements 
(if applicable), written information given to the patients, safety updates, annual progress reports, 
and any revisions to these documents will be provided to the IRB by the Investigator. 
Federal regulations and International Council for Harmonisation (ICH) Guidelines require that 
approval be obtained from an IRB prior to participation of patients in research studies. Prior to 
study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to a patient or 
patient’s legal guardian must be approved by the IRB. 
No drug will be released to the site for dosing until written IRB authorization has been received 
by the Sponsor. 
11.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements. 
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation, and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator will obtain written informed 
consent from each patient before any study-specific activity is performed and should document in 
the source documentation that consent was obtained prior to enrollment in the study. The original 
signed copy of the ICF must be maintained by the Investigator and is subject to inspection by a 
representative of the Sponsor, their representatives, auditors, the IRB and/or regulatory agencies. 
A copy of the signed ICF will be given to the patient. 
11.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP, and applicable regulatory requirements, and that 
valid data are entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized and easily retrievable data. Before 
the enrollment of any patient in this study, the Sponsor or their designee will review with the 
Investigator and site personnel the following documents: protocol, Investigator’s Brochure, eCRFs 


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and procedures for their completion, informed consent process, and the procedure for reporting 
SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the site, the CRA will review the data for safety information, completeness, accuracy, and 
logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
11.5 
Disclosure of Data 
Data generated by this study must be available for inspection by the Food and Drug 
Administration, the Sponsor or their designee, applicable foreign health authorities, and the IRB 
as appropriate. Patients or their legal representatives may request their medical information be 
given to their personal physician or other appropriate medical personnel responsible for their 
welfare. 
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
11.6 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating patients (sufficient information to link 
records, eg, eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, 
source documents, and detailed records of treatment disposition. The records should be retained 
by the Investigator according to specifications in the ICH guidelines, local regulations, or as 
specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor.  
11.7 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 


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11.8 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. 


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12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by Medpace or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB, unless immediate implementation of the change is necessary for patient safety. In this case, 
the situation must be documented and reported to the IRB within 5 working days. 


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13 
REFERENCES 
 
1. 
NorthSea Therapeutics BV. Investigator’s Brochure NST-4016 (Icosabutate). Version 7, 
24 January 2018. 
2. 
Grundy SM, Stone NJ, Bailey AL, et al. 
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA 
Guideline on the Management of Blood Cholesterol: A Report of the American College 
of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 
J Am Coll of Cardiol. 2018. Nov 8. pii: S0735-1097(18)39034-X. 
doi: 10.1016/j.jacc.2018.11.003. [Epub ahead of print]. 


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APPENDIX A: SCHEDULE OF PROCEDURES 
 
Screeninga 
Treatment Period 
Safety 
Follow-upb 
ET 
Visitb 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
                       Study Week 
-8 to -1 
0 
4 
10 
16 
24 
32 
40 
52 
54 
Study Day 
-56 to -1 
0 
28 
70 
112 
168 
224 
280 
364 
378 
 
    Visit Window 
 
0 days 
5 days 
7 days 
7 days 
7 days 
7 days 
7 days 
7 days 
5 days 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 Xc 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
X 
 
 
 
 
 
 
 
 
 
Prior/concomitant medicationsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and body weighte 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BMI calculation 
X 
X 
 
 
 
 
 
 
 
 
 
Physical examinationf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AUDIT-Ch 
X 
 
 
 
 
 
 
 
 
 
 
Viral serologyi 
X 
 
 
 
 
 
 
 
 
 
 
Fasting hematology, 
biochemistry, coagulation, and 
lipid panelsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipoprotein particle size 
 
X 
 
 
X 
 
 
 
X 
 
X 
Urinalysisk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGm 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
FibroScan 
Xn 
 
 
 
 
 
 
 
 
 
 
MRI-PDFF and cT1 imagingo 
X 
Xp 
 
 
X 
 
 
 
X 
 
X 
Liver biopsy 
Xq 
 
 
 
 
 
 
 
Xr,s 
 
Xb 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Adverse event monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker samplingt 
 
X 
 
 
X 
 
 
 
X 
 
X 
PK samplingu 
 
Xv 
X 
X 
X 
X 
X 
X 
X 
 
X 


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Lipidomic analyses samplingw 
 
X 
 
 
 
 
 
 
X 
 
X 
Study drug administration/ 
dispensingr,x 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Study drug accountabilityy 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
COVID-19 contingency measures: This study protocol includes contingency measures to manage disruptions due to COVID-19 control measures, including modifications to 
visit schedules and procedures specific to situations where COVID-19 is impacting study conduct. See Appendix G for details of COVID-19 contingency measures. In the 
absence of a COVID-19 impact, it is expected that Investigators and patients follow the protocol requirements as set forth. 
a. 
The screening period of up to 8 weeks may include more than 1 visit. Patients who screen fail may be rescreened once.  
b. 
Patients who discontinue early from the study for any reason prior to completion of the treatment period will be requested to return to the clinic for an ET Visit as soon as 
possible after their last intake of study drug. Liver biopsy at ET will be only performed for patients who have been on study drug for at least 6 months. If a patient 
discontinues early from the study for any reason after completion of the treatment period but before the Safety Follow-up Visit, sites should make every attempt to bring 
the patient into the site for the Safety Follow-up Visit. 
c. 
Eligibility criteria will be reassessed prior to dosing with study drug to ensure no changes in eligibility have occurred since screening.  
d. 
All prior and concomitant medications will be documented in the eCRF. Prior medications include any medication taken within 6 months prior to screening. Concomitant 
medications include any medication taken on or after the date the patient signs informed consent. Unless medically warranted, all concomitant medications should remain 
stable from screening through the Safety Follow-up Visit (Visit 10). Throughout the duration of the study, patients should not introduce changes to their usual diet 
(including dietary supplements) or lifestyle. Any changes to concomitant medication dosing during the study will be captured in the eCRF and closely monitored. 
e. 
Height will be measured at screening only. Body weight will be measured at every visit.  
f. 
Full physical examinations (including general appearance; eyes, ears, nose, and throat; head and neck; chest and lungs; cardiovascular; abdomen; musculoskeletal; 
lymphatic; dermatological; neurological systems; mental status; and extremities) will be performed at screening; Visits 2 and 9; and at study exit (whether at the Safety 
Follow-up or ET Visit). Abbreviated physical examinations will be performed at all other visits. 
g. 
Vital signs will include blood pressure, pulse rate, and body temperature, and will be performed with the patient in the sitting position after 5 minutes of rest and before 
any blood draws. Three replicate blood pressure readings will be taken at each visit.  
h. 
Only patients with AUDIT-C scores 3 points at screening will receive the full AUDIT at screening and will be excluded if they score 8 points on the full AUDIT. 
Patients with AUDIT-C scores <3 points will not receive the full AUDIT. 
i. 
Patients must test negative for hepatitis B virus, HCV (patients with a confirmed history of HCV infection can be included if HCV PCR is negative for at least the last 
2 years), and HIV infection to be eligible for the study. 
j. 
If a patient has a qualifying historical biopsy, the required AST levels (AST 20 U/L in men and 17 U/L in women by central laboratory or AST 30 U/L by a local 
laboratory within 60 days of screening) will not apply. 
k. 
Further analysis of urine sediment or urine microscopy will be performed if there are any abnormalities on any of the following 3 dipstick results: leukocyte esterase, 
blood, or nitrite. 
l. 
For women of childbearing potential, a serum hCG pregnancy test will be performed at screening, Week 0, and at study exit (whether at the Safety Follow-up or ET Visit). 
Urine hCG testing will be performed at all other visits. If a urine hCG test is positive, pregnancy will be confirmed by a serum hCG test. Follicle-stimulating hormone 
level will be measured at screening to confirm postmenopausal state in women 55 years of age. 
m. Single 12-lead ECGs will be performed after the patient has been resting in the supine position for at least 10 minutes. In case of evident bad quality of the tracing 
(eg, muscle tremor), the ECG will be repeated. QTcF will be measured. 
n. 
Patients without a historical biopsy must have a FibroScan VCTE measurement 8.5 kPa and a CAP for steatosis with cut-off values 300 dB/m at screening or a 
historical FibroScan (with eligible VCTE and CAP values) within 90 days of screening. FibroScan is not required for patients who have evaluable histology slides from a 
liver biopsy performed in the previous 6 months available for review by the central pathology reader. 
o. 
At screening, perform MRI-PDFF if FibroScan values (VCTE and CAP) are within eligibility range (for patients without historical biopsy) or if the patient has a qualifying 
historical biopsy. If the patient is eligible based on a historical biopsy, the MRI-PDFF procedure should be performed but the eligibility criterion of liver fat content 8% 
will not be applied. Magnetic resonance imaging-PDFF will be performed using a standardized central imaging protocol and will be validated by the central imaging 
reader at screening (as the baseline value), Visit 5 (Week 16), and Visit 9 (Week 52) or the ET Visit. Iron-corrected T1 will be calculated for all randomized patients at 
Visit 2 (Week 0) (using the screening MRI), Visit 5 (Week 16), and Visit 9 (Week 52) or the ET Visit. 


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p. 
At Visit 2, cT1 will be calculated from the screening MRI only if the patient is randomized. No MRI will be performed at Visit 2. 
q. 
Historical liver biopsy within 6 months of screening may be used for eligibility if evaluable histology slides are available for review by the central pathology reader. 
Patients must not have received nonalcoholic steatohepatitis therapy since the historical biopsy was obtained. Historical liver biopsies obtained during the course of a prior 
investigational drug study must not be utilized if obtained within 3 months or 5 half-lives of the last dose of the prior investigational drug, whichever is longer. 
r. 
In the event that the Visit 9 biopsy is delayed, patients will continue to administer study drug daily until the biopsy occurs for up to 30 days after the originally projected 
Visit 9 date. 
s. 
In a subgroup of patients, biopsy tissue collected at the End of Treatment/Visit 9 will be used to perform lipidomic analyses. 
t. 
Biomarkers to be assessed include: HOMA-IR, hsCRP, Pro-C3, and ELF panel. 
u. 
Pharmacokinetic sampling will occur at Visits 2 to 9 at time 0 (predose, ie, within 1 hour prior to the first dose). 
v. 
For those patients participating in the intensive PK subset, PK blood samples will be collected in relation to the first dose of study drug at Visit 2. Samples will be taken at 
the following timepoints: predose (within 1 hour prior to the first dose), followed by 1, 2, 3, 4, 6, and 8 hours postdose (10 minutes) at Visit 2 (Day 0) and 24 hours 
postdose (1 hour, but prior to the second dose of study drug on Day 1). 
w. In a subgroup of patients, fasting serum samples will be collected to perform lipidomic analyses. 
x. 
On Visits 2 to 8, study drug will be administered to the patient on site to accommodate trough PK sampling prior to dosing. Sufficient study drug will be dispensed to the 
patient for dosing until the next study visit.  
y. 
Returned and used/unused study drug will be collected to assess compliance. 
AUDIT = Alcohol Use Disorders Identification Test; AUDIT-C = Alcohol Use Disorders Identification Test-Concise; BMI = body mass index; CAP = controlled attenuation 
parameter; COVID-19 = Coronavirus Disease 2019; cT1 = iron-corrected T1; ECG = electrocardiogram; eCRF = electronic case report form; ELF = enhanced liver fibrosis; 
ET = Early Termination; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HOMA-IR = Homeostatic Model Assessment 
for Insulin Resistance; hsCRP = high-sensitivity C-reactive protein; MRI-PDFF = magnetic resonance imaging-proton density-fat fraction; PCR = polymerase chain reaction; 
PK = pharmacokinetics; VCTE = vibration-controlled transient elastography. 


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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Biochemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine kinase 
Creatinine 
Estimated glomerular filtration rate 
Gamma glutamyl transferase 
Glucose 
Inorganic phosphorus 
Lactate dehydrogenase 
Lipase 
Potassium 
Sodium 
Total bilirubin [1] 
Total protein 
Uric acid 
1. 
If total bilirubin is above the upper limit of normal, add conjugated (direct) bilirubin. 
 
Hematology 
Hematocrit 
Hemoglobin 
Neutrophils 
Platelets 
Red blood cell count 
White blood cell count and differential [1] 
1. 
Manual microscopic review is performed only if white blood cell count and/or differential values are out of reference 
range. 
 
Lipid and Metabolic Profile 
Apolipoprotein B 
Apolipoprotein C3 
Hemoglobin A1c 
High-density lipoprotein-cholesterol  
Lipoprotein(a) 
Lipoprotein particle size [1] 
Low-density lipoprotein-cholesterol 
Remnant cholesterol  
Serum cholesterol 
Triglycerides 
1. 
Lipoprotein particle size will be assessed only at baseline, Week 16, and at the end of treatment (Week 52/Early 
Termination). 
 
Plasma/Serum and Liver Lipidomics 
Acyl carnitines 
 
Acyl-ether-phospholipids 
Amino acids 
Bile acids 
Cholesteryl esters 
Diacyl-phospholipids 
Fatty acids 
Glycerolipids 
Icosabutate and icosabutate metabolites 
Lyso-phospholipids 
N-acyl ethanolamines 
Oxidized fatty acids 
Primary fatty acid amides 
Sphingolipids 
 
 


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Coagulation 
Activated partial thromboplastin time 
 
Fibrinogen 
International normalized ratio 
Prothrombin time 
 
Liver Inflammation and Fibrosis Biomarkers 
Enhanced liver fibrosis panel 
High-sensitivity C-reactive protein 
Homeostatic Model Assessment for Insulin 
Pro-C3 
Resistance 
 
 
Endocrinology 
Human chorionic gonadotropin (hCG) [1] 
Follicle-stimulating hormone (FSH) [2] 
Thyroid-stimulating hormone (TSH) [3] 
 
1. 
For women of childbearing potential, a serum hCG pregnancy test will be performed at screening, Week 0, and at study 
exit (whether at the Safety Follow-up Visit or Early Termination Visit). Urine hCG testing will be performed at all other 
visits. If a urine hCG test is positive, pregnancy will be confirmed by a serum hCG test. 
2. 
FSH level will be measured at screening to confirm postmenopausal state in women 55 years of age. 
3. 
Free triiodothyronine and free thyroxine will be measured if TSH is abnormal. 
 
Urinalysis [1] 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Microscopy 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
1. 
Dipstick urine qualitatively. Further analysis of urine sediment or urine microscopy will be performed if there are any 
abnormalities on any of the following 3 dipstick results: leukocyte esterase, blood, or nitrite. 
 
Serology 
Hepatitis B surface antigen 
Hepatitis C virus antibody (and polymerase 
chain reaction ribonucleic acid for positive 
antibody samples) 
Human immunodeficiency virus 
 


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APPENDIX C: ALCOHOL USE DISORDERS IDENTIFICATION 
TEST-CONCISE 
The Alcohol Use Disorders Identification Test-Concise (AUDIT-C) has 3 questions and is scored 
on a scale of 0 to 12. Read the questions as written and circle the letter that corresponds to the 
answer. Each AUDIT-C question has 5 answer choices valued from 0 to 4 points. In men, a score 
of 4 or more is considered positive, optimal for identifying hazardous drinking or active alcohol 
use disorders. In women, a score of 3 or more is considered positive. Generally, the higher the 
score, the more likely it is that a person’s drinking is affecting his or her safety. 
 
See answer module on the next page. 


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Answer Module 
Question 1: How often do you have a drink containing alcohol? 
 
Question 2: How many standard drinks containing alcohol do you have on a typical day? 
 
Question 3: How often do you have six or more drinks on one occasion? 
 
 


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APPENDIX D: ALCOHOL USE DISORDERS IDENTIFICATION TEST: 
INTERVIEW VERSION 
Read questions as written. Read answers carefully. Begin the AUDIT by saying “Now I am going 
to ask you some questions about your use of alcoholic beverages during this past year.” Explain 
what is meant by “alcoholic beverages” by using local examples of beer, wine, vodka, etc. Code 
answers in terms of “standard drinks.” Place the correct answer number in the box at the right. 
Total scores of 8 are recommended as indicators of hazardous and harmful alcohol use. 
 


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APPENDIX E: DRUG-INDUCED LIVER INJURY MONITORING PLAN 
Throughout the study, all treatment-emergent adverse events, clinical assessments, and clinical 
laboratory parameters will be closely monitored against the criteria for suspected drug-induced 
liver injury as detailed in this Monitoring Plan. 
Patients with normal liver transaminases and bilirubin at baseline 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized ratio; TBL = total bilirubin; 
ULN = upper limit of normal. 


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Suspected drug-induced liver injury monitoring in patients with normal liver transaminases and 
bilirubin at baseline should be performed throughout the study according to the procedures 
summarized below.  
 If patients with normal baseline liver indices develop elevations of aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) >2  upper limit of normal (ULN) or total bilirubin 
(TBL) >1.5  ULN values during the study, repeat testing should be performed within 
48 hours. 
o If there are persistent elevations (ALT or AST >2  ULN or TBL >1.5  ULN) upon repeat 
testing, close observation (testing and physical examination 2 to 3 times per week) should 
be implemented. An important purpose of the close observation is to gather additional 
clinical information to seek other possible causes of the observed liver test abnormalities, 
such as one of the following: acute viral hepatitis, alcoholic and autoimmune hepatitis, 
hepatobiliary disorders, cardiovascular causes, or concomitant treatments. Discontinuation 
of study drug should be considered. 
 Study drug should be discontinued, and the patient should be followed until resolution of signs 
or symptoms, in the following situations:  
o ALT or AST >8  ULN. 
o ALT or AST >5  ULN for more than 2 weeks. 
o ALT or AST >3  ULN and (TBL >2  ULN or international normalized ratio [INR] >1.5). 
o ALT or AST >3  ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
For any patients who present with a constellation of syndromes indicative of liver disease as per 
the Investigator’s overall assessment (ie, fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia [>5%]), perform liver function tests to determine if 
liver disease is worsening and discontinue the study drug if worsening is confirmed. 
Reinitiation of study drug may be considered after consultation with the Medical Monitor. 


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Patients with elevations in liver transaminases or bilirubin at baseline 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized ratio; TBL = total bilirubin; 
ULN = upper limit of normal. 
Suspected drug-induced liver injury monitoring in patients with elevations in liver transaminases 
or bilirubin at baseline should be performed throughout the study according to the procedures 
summarized below. 


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 If patients with abnormal baseline liver indices develop elevations of AST or ALT 
>2  baseline average or TBL >1.5  baseline average values during the study, repeat testing 
should be performed within 48 hours. 
o If there are persistent elevations (ALT or AST >2  baseline average or TBL 
>1.5  baseline average values) upon repeat testing, then close observation (testing and 
physical examination 2 to 3 times per week) should be implemented and discontinuation 
of study drug should be considered. 
 Discontinue the study drug if any of the following occur:  
o Baseline average measurements were <2  ULN and ALT or AST increases to 
>5  baseline measurements. 
o Baseline average measurements were 2  ULN (but <5  ULN as per eligibility 
requirements) and ALT or AST increases to >3  baseline measurements. 
o Baseline average measurements were 5  ULN and ALT or AST increases to 
>2  baseline measurements. 
o ALT or AST increase >2  baseline average measurements AND the increase is 
accompanied by a concomitant increase in TBL to >2  baseline average measurements or 
the INR concomitantly increases by >0.2. 
For any patients who present with a constellation of syndromes indicative of liver disease as per 
the Investigator’s overall assessment (ie, fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia [>5%]), perform liver function tests to determine if 
liver disease is worsening and discontinue the study drug if worsening is confirmed. 
Reinitiation of study drug may be considered after consultation with the Medical Monitor. 
For all patients, close observation for suspected drug-induced liver injury includes the following: 
 Repeating liver enzyme (ALT, AST, and alkaline phosphatase) and serum bilirubin tests 2 or 
3 times weekly (if a patient lives in a remote area, he or she can be tested locally and the results 
promptly communicated to the study site). 
 The frequency of repeat testing can decrease to once a week or less if abnormalities stabilize 
or the study drug has been discontinued and the patient is asymptomatic. 
 Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
 Obtaining a history of concomitant drug use (including nonprescription medications and herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets. 
 Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; 
hypoxic/ischemic hepatopathy; and biliary tract disease. 
 Obtaining a history of exposure to environmental chemical agents. 
 Obtaining additional tests to evaluate liver function, as appropriate (eg, INR, direct bilirubin). 
 Considering gastroenterology or hepatology consultations. 


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APPENDIX F: 2018 AMERICAN HEART ASSOCIATION/AMERICAN 
COLLEGE OF CARDIOLOGY GUIDELINE ON THE MANAGEMENT OF 
BLOOD CHOLESTEROL 
The manuscript (to appear in the Journal of the American College of Cardiology [ACC]) of the 
2018 American Heart Association (AHA)/ACC Guideline on the Management of Blood 
Cholesterol1 can be accessed at the following link: 
https://www.ahajournals.org/doi/10.1161/cir.0000000000000625 
The “Guidelines Made Simple” version of the 2018 AHA/ACC Guideline on the Management of 
Blood Cholesterol, which contains excerpts from the full guideline, can be accessed at the 
following link: 
https://www.acc.org/~/media/Non-Clinical/Files-PDFs-Excel-MS-Word-
etc/Guidelines/2018/old_Guidelines-Made-Simple-Tool-2018-Cholesterol.pdf 
 
1 Grundy SM, Stone NJ, Bailey AL, et al. 
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the 
Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association 
Task Force on Clinical Practice Guidelines. J Am Coll of Cardiol. 2018. Nov 8. pii: S0735-1097(18)39034-X. 
doi: 10.1016/j.jacc.2018.11.003. [Epub ahead of print]. 


NorthSea Therapeutics B.V. 
Clinical Study Protocol NST-02 
Confidential & Proprietary 
 
Version 8.0, 21 July 2022 
84 
APPENDIX G: CORONAVIRUS DISEASE 2019 CONTINGENCY 
MEASURES 
The following contingency measures have been established to mitigate the potential impact that 
Coronavirus Disease 2019 (COVID-19) has on study conduct, patient safety, and data integrity. It 
is important to note that these mitigations are specific to situations where COVID-19 is impacting 
study conduct. In the absence of a COVID-19 impact, it is expected that Investigators and patients 
follow the protocol requirements as set forth.  
Visit schedule and procedures 
 Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, Visit 8, Visit 9, and Visit 10 windows extended to 
±14 days as long as study drug supply is sufficient. If the extended window is used, any 
accompanying study drug interruption should not exceed 14 days. 
 The screening period may be extended to a total of 12 weeks to account for potential delays in 
scheduling screening assessments. If the extended screening window is used, Investigators 
must ensure that the screening magnetic resonance imaging-proton density-fat fraction 
assessment is conducted within 8 weeks of randomization. 
 If on-site visits cannot occur, assessments and safety follow-up may occur via telehealth, local 
community laboratories, and in-home visits by qualified nurses. The following visits may be 
replaced by telehealth or in-home visits: Visit 3, Visit 4, Visit 6, Visit 7, Visit 8, Visit 9, and 
Visit 10. 
 Every effort should be made to utilize the central laboratory for study-specific laboratory 
assessments. If the patient must report to a local community laboratory for safety follow-up 
purposes, the following samples should be ordered from the local laboratory: biochemistry 
panel, 
hematology 
panel, 
coagulation, 
hemoglobin 
A1c, 
and 
low-density 
lipoprotein-cholesterol. Refer to Appendix B of the protocol to ensure all required analytes in 
a given laboratory panel are being collected by the local laboratory.  
Study drug dispensation 
 Patients may be supplied with additional study drug during a visit if there is a concern that the 
patient may not be able to report to the site as scheduled for the next required visit. This will 
ensure that patients have enough study drug to accommodate extended visit windows or 
telehealth visits.  
 In some circumstances, it may be necessary to ship study drug directly to the patient. Shipping 
will be performed by a qualified professional courier who is contracted by the Sponsor or 
Contract Research Organization. The courier will be responsible for providing packing 
materials and cold chain monitoring to complete the shipment. Patients must consent to 
providing personal data to the courier to complete the shipment. Refer to the Pharmacy Manual 
for additional details. 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
Protocol Title:
A Multicenter, Randomized, Double-Blind, Placebo Controlled, 
Parallel-Group Study of NST-4016 in Patients With 
Nonalcoholic Steatohepatitis (NASH) 
 
Protocol Number: 
NST-02 
Protocol Version/Date: 
Version 8.0 / 21 July 2022 
Investigational Product:
NST-4016 Icosabutate
 
 
Sponsor: 
NorthSea Therapeutics B.V. 
Gooimeer 2-35  
1411 DC Naarden  
The Netherlands
 
SAP Version/Date: 
Version 1.0 / 14 February 2023 
 
 
 
 
 
CONFIDENTIAL 
The information in this document is confidential and is not to be disclosed without the written 
consent of NorthSea Therapeutics B.V. (hereinafter NorthSea) except to the extent that 
disclosure would be required by law and for the purpose of evaluating and/or conducting a 
clinical study for NorthSea. Persons to whom the information is disclosed must be informed that 
the information is confidential and proprietary to NorthSea and that it may not be further 
disclosed to third parties.  
 


NorthSea Therapeutics B.V. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol NST-02 
 
Version 1.0, 14 February 2023 
 
Page 2 of 28 
 
 
Protocol Title:
A Multicenter, Randomized, Double-Blind, Placebo Controlled, 
Parallel-Group Study of NST-4016 in Patients With Nonalcoholic 
Steatohepatitis (NASH) 
 
Protocol Number:
NST-02 
SAP Version/Date: 
Version 1.0 / 14 February, 2023
We, the undersigned, have reviewed and approved this Statistical Analysis Plan: 
  
Signature
 Date
 
  
Suzanne Lloyd 
Manager, Statistical Programming 
Medpace, Inc. 
  
 
  
 
  
Ping Xu 
Director, Biostatistics 
Medpace, Inc. 
  
 
  
 
  
Xinyan Qu,PhD 
Clinical Pharmacologist 
Medpace, Inc 
  
 
  
 
  
Holly Schachner, MD 
Head of Clinical Development 
NorthSea Therapeutics B.V. 
  
 
  
 
  
Stephen Harrison, MD 
Chief Medical Officer 
NorthSea Therapeutics B.V. 
  
Suzanne Lloyd
Electronically signed by: Suzanne Lloyd
Reason: Approved
Date: Feb 14, 2023 16:37 GMT
14-Feb-2023
Electronically signed by: Stephen Harrison
Reason: Approved
Date: Feb 14, 2023 10:50 CST
14-Feb-2023
Xinyan Qu
Electronically signed by: Xinyan Qu
Reason: Approved
Date: Feb 14, 2023 11:51 EST
14-Feb-2023
Holly Schachner, MD
Electronically signed by: Holly Schachner,
MD
Reason: Approved
Date: Feb 14, 2023 12:31 EST
14-Feb-2023
Ping Xu
Electronically signed by: Ping Xu
Reason: Approved
Date: Feb 14, 2023 12:59 EST
14-Feb-2023


NorthSea Therapeutics B.V. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol NST-02 
 
Version 1.0, 14 February 2023 
 
Page 3 of 28 
 
 
 
  
 
  
David Fraser 
Chief Scientific Officer 
NorthSea Therapeutics B.V. 
  
 
 
David Fraser
Electronically signed by: David Fraser
Reason: Approved
Date: Feb 15, 2023 17:53 GMT+1
15-Feb-2023


NorthSea Therapeutics B.V. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol NST-02 
 
Version 1.0, 14 February 2023 
 
Page 4 of 28 
 
 
 
Version
Version Date
Description
1.0  
14 February 2023 
First version 
 
 


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Statistical Analysis Plan 
Protocol NST-02 
 
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1 
Introduction ......................................................................................................................... 9 
2 
Study Overview ................................................................................................................... 9 
2.1 
Study Objectives .......................................................................................................... 9 
2.1.1 
Primary Objective ................................................................................................. 9 
2.1.2 
Secondary Objective ............................................................................................. 9 
2.2 
Study Design ............................................................................................................... 9 
2.2.1 
Overview ............................................................................................................... 9 
2.2.2 
Sample Size Determination ..................................................................................10 
2.3 
Study Endpoints/Parameters ......................................................................................10 
2.3.1 
Primary Efficacy Endpoint ....................................................................................10 
2.3.2 
Key Secondary Efficacy Endpoints ......................................................................11 
2.3.3 
Other Secondary Efficacy Endpoints ....................................................................11 
2.3.4 
Exploratory Parameters .......................................................................................11 
2.3.5 
Pharmacokinetic Parameters ...............................................................................12 
2.3.6 
Safety Parameters ...............................................................................................12 
3 
Statistical Methodology ......................................................................................................13 
3.1 
General Considerations ..............................................................................................13 
3.1.1 
Analysis Day ........................................................................................................13 
3.1.2 
Analysis Visits ......................................................................................................13 
3.1.3 
Definition of Baseline ...........................................................................................13 
3.1.4 
Summary Statistics ..............................................................................................13 
3.1.5 
Hypothesis Testing ..............................................................................................14 
3.1.6 
Handling of Dropouts and Missing Data ...............................................................14 
3.2 
Analysis Populations ...................................................................................................14 
3.2.1 
Randomized Population .......................................................................................14 
3.2.2 
Intent-to-Treat (ITT) Population ............................................................................14 
3.2.3 
Modified Intent-to-Treat (mITT) Population ..........................................................14 
3.2.4 
Per-Protocol (PP) Population ...............................................................................15 
3.2.5 
Trough Pharmacokinetics (PK) Population ...........................................................15 
3.2.6 
The Intensive Pharmacokinetics (PK) Population .................................................15 
3.2.7 
Safety Population .................................................................................................15 
3.3 
Patient Data and Study Conduct .................................................................................15 
3.3.1 
Patient Disposition ...............................................................................................15 
3.3.2 
Protocol Deviations ..............................................................................................15 
3.3.3 
Analysis Populations ............................................................................................16 
3.3.4 
Demographic and Baseline Characteristics ..........................................................16 
3.3.5 
Medical History ....................................................................................................16 


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3.3.6 
Prior and Concomitant Medications .....................................................................17 
3.3.7 
Study Drug Exposure and Compliance ................................................................17 
3.4 
Efficacy Assessment ...................................................................................................18 
3.4.1 
Primary Efficacy Endpoint ....................................................................................18 
3.4.2 
Secondary Efficacy Endpoints .............................................................................19 
3.4.3 
Exploratory Biomarker Analysis ...........................................................................21 
3.5 
Pharmacokinetic Assessment .....................................................................................21 
3.5.1 
Sample Collections for Pharmacokinetic Analysis ........................................................21 
3.5.2 
Handling Missing or Below the Lower Limit of Quantification Data ................................22 
3.5.3 
Pharmacokinetic Concentration ...........................................................................22 
3.5.4 
Pharmacokinetic Parameters....................................................................................22 
3.6 
Safety Assessment .....................................................................................................24 
3.6.1 
Adverse Events (AEs) ..........................................................................................24 
3.6.2 
Clinical Laboratory Tests .....................................................................................25 
3.6.3 
Vital Signs ............................................................................................................25 
3.6.4 
Anthropometric measures ....................................................................................25 
3.6.5 
Electrocardiograms ..............................................................................................26 
3.6.6 
Physical Examinations .........................................................................................26 
4 
Data Safety Monitoring committee .....................................................................................26 
5 
Analysis Timing ..................................................................................................................27 
5.1 
Interim Analysis ..........................................................................................................27 
5.2 
Pre-Final Analysis .......................................................................................................27 
5.3 
Final Analysis ..............................................................................................................27 
6 
Changes from Protocol-Specified Statistical Analyses .......................................................27 
7 
Programming Specifications ..............................................................................................28 
 
 


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Abbreviation
Definition
ATC 
Anatomical Therapeutic Chemical 
ADaM 
Analysis Data Model 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
AST  
Aspartate aminotransferase 
AUC 
Area under the concentration time curve 
AUC0-t 
Area under the plasma concentration-time curve from time 0 to the 
time of the last observed concentration 
AUC0-inf 
Are under the plasma concentration-time curve from time 0 
extrapolated to infinity 
BMI 
Body Mass Index 
CDISC 
Clinical Data Interchange Standards Consortium 
CL/F 
Apparent plasma clearance 
Cmax 
Maximum observed plasma concentration 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case report form 
CSR 
Clinical Study Report 
cT1 
Iron-corrected T1 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form  
ELF 
Enhanced liver fibrosis 
ET 
Early Termination 
GGT 
Gamma glutamyl transferase 
HOMA-IR 
Homeostatic Model Assessment for Insulin Resistance 
hsCRP 
High-sensitivity C-reactive protein 
ITT 
Intent-to-Treat 
LS 
Least square 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed-Model Repeated Measures 
MNAR
Missing not a random
MRI 
Magnetic resonance imaging 
MRI-PDFF
Magnetic resonance imaging-proton density-fat fraction
NAS 
Nonalcoholic Fatty Liver Disease Activity Score 
NASH
Nonalcoholic steatohepatitis
PK 
Pharmacokinetic(s) 
PP
Per-Protocol
Pro-C3 
N-terminal type 3 collagen propeptide 


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Abbreviation
Definition
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
STDM 
Standard Data Tabulation Model 
TEAE 
Treatment-emergent adverse event 
TEAESI 
Treatment-emergent adverse event of special interest 
TESAE 
Treatment-emergent serious adverse event 
TFL 
Tables, Figures and Listings 
Tmax
Time to reach the maximum observed plasma concentration 
WHO 
World Health Organization 
Vz/F 
Apparent volume of distribution 
 
 


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Protocol NST-02 
 
Version 1.0, 14 February 2023 
 
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The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical 
methods to be implemented for the analysis of data from the study with protocol number NST-02.  
The SAP will be finalized prior to database lock.  Any deviations from the SAP after database lock 
will be documented in the final Clinical Study Report (CSR). 
 
 
2.1.1 Primary Objective 
The primary objective is to evaluate the efficacy of different doses of NST-4016 on the 
resolution of nonalcoholic steatohepatitis (NASH) without worsening of fibrosis in patients with 
NASH without histological or clinical evidence of cirrhosis. 
2.1.2 Secondary Objective  
The secondary objectives of the study are: 
 
To determine the safety and tolerability of NST-4016 in patients with NASH  
 
To characterize the pharmacokinetics (PK) of NST-4016 
 
2.2.1 Overview 
This was a 52-week (62 week, including screening and follow-up), multicenter, randomized, 
double-blind, placebo-controlled, parallel-group study in male and female patients with a 
histological diagnosis of NASH.  Approximately 264 patients were to be randomized into 1 of 3 
parallel treatment groups (300 mg NST-4016, 600 mg NST-4016 or Placebo); randomization was 
stratified by baseline biopsy fibrosis score (2 levels: F1 or F2 /F3).   
The study included a screening period, double-blind treatment period, and post-treatment follow-
up.  The Screening Visit could occur up to 8 weeks prior to randomization at Visit 2 (Week 0).  
The double-blind treatment period entailed 52 weeks of dosing with study drug and was to be 
followed by a Safety Follow-up Visit 2 weeks after the last dose of study drug.  The study design 
is depicted in Figure 1 – Study Design. 
Study drug dosing was to begin at Visit 2 (Week 0) and continue daily for 52 weeks. All patients 
were instructed to take 2 capsules of study drug (either 300 mg NST-4016 and/or matching 
placebo) orally in the morning with water once daily for 52 weeks. In the event that the Visit 9 
biopsy was delayed, patients continued to administer study drug daily until the biopsy occurred, 
for up to 30 days after the originally projected Visit 9 date.  
During the 52-week treatment period, patients were to return to the clinic for study visits every 1 
to 3 months.   
An external, independent Data Safety Monitoring Committee (DSMC) reviewed all available 
unblinded preliminary safety and biomarker results per the DSMC Charter. 


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Figure 1 – Study Design 
 
 
In addition, the following data was reviewed during an interim analysis, which was performed after 
90 patients completed 16 weeks of treatment: alanine aminotransferase (ALT), aspartate 
aminotransferase (AST) and AST/ALT ratio, Homeostatic Model Assessment for Insulin (HOMA-
IR), Pro-C3, Enhanced Liver Fibrosis (ELF) panel, magnetic resonance imaging-proton density-
fat fraction (MRI-PDFF), Iron-corrected T1 (cT1) and lipid parameters. The DSMC reviewed 
summary statistics and made recommendations which were shared blindly with the sponsor and 
clinical sites. 
2.2.2 Sample Size Determination 
A sample size of 88 patients per treatment group provides 80% power to detect a treatment effect 
of 22% (40% responder rate for active versus 18% placebo), assuming  a dropout rate of 25%. 
 
2.3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the percentage of patients with resolution of NASH, defined as 
disappearance of ballooning (score = 0) with lobular inflammation score 0 or 1, and with no 
worsening of fibrosis. 
 
 


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2.3.2 Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are: 
Percentage of patients with 
• 
fibrosis improvement, defined as greater than or equal to one stage of fibrosis 
improvement and no worsening of steatohepatitis (inflammation/ballooning)  
• 
resolution of NASH (defined as disappearance of ballooning (score = 0) with lobular 
inflammation score 0 or 1  AND fibrosis improvement (defined as greater than or equal to 
one stage of fibrosis improvement) 
2.3.3 Other Secondary Efficacy Endpoints 
Percentage of patients with: 
• 
fibrosis improvement, defined as greater than or equal to one stage of fibrosis 
improvement 
• 
2-stage fibrosis improvement, defined as greater than or equal to two stages of fibrosis 
improvement 
Change from baseline in: 
 
Liver enzymes - AST, ALT, alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), 
and bilirubin 
 
Inflammation marker – high-sensitivity C-reactive protein (hsCRP) 
 
Fibrosis activity markers – N-terminal type 3 collagen propeptide (Pro-C3) and ELF panel 
 
HOMA-IR, a measure of insulin resistance and metabolic status. 
 
Composite Disease Activity Score – composite NASH score of inflammation, ballooning, 
fibrosis 
 
Nonalcoholic Fatty Liver Disease Activity Score (NAS) 
 
Individual histological scores for steatosis, ballooning, inflammation, and fibrosis 
 
Imaging parameters - MRI-PDFF  
 
2.3.4 Exploratory Parameters 
Exploratory biomarkers and endpoints of serum and tissue lipidomics and AI Histology from Path 
AI and/or HistoIndex and cT1 will be reported in a supplemental CSR if and when available. 
 
 
 


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Version 1.0, 14 February 2023 
 
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2.3.5 Pharmacokinetic Parameters 
The following PK parameters will be summarized: 
 
NST-4016 concentrations (all patients) 
In addition, for the Intensive PK subset: 
 
AUC0-t 
 
AUC0-inf 
 
CL/F 
 
Cmax 
 
Tmax 
 
Vz/F 
2.3.6 Safety Parameters 
The safety endpoints include: 
 
Adverse events (AEs) 
 
Serious AEs (SAEs) 
 
Adverse events of special interest (AESI) – suspected drug induced liver injury. 
 
Vital signs 
 
Physical examinations 
 
Electrocardiograms (ECGs) 
 
Clinical laboratory parameters 
 


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3.1.1 Analysis Day 
Analysis day will be calculated from the date of first dose of study drug.  The day of the first dose 
of study drug will be Day 1, and the day immediately before Day 1 will be Day -1.  There will be 
no Day 0. 
3.1.2 Analysis Visits 
Scheduled visits will be assigned to analysis visits as recorded on the electronic case report form 
(eCRF). Unscheduled and early termination visits will be assigned to analysis visits according to 
the visit windows described in the following table: 
Analysis Visit 
Target Analysis 
Day 
Low Analysis 
Day 
High Analysis 
Day 
Visit 2 (Week 0) 
1 
NA 
NA 
Visit 3 (Week 4) 
28 
2 
49 
Visit 4 (Week 10) 
70 
50 
91 
Visit 5 (Week 16) 
112 
92 
140 
Visit 6 (Week 24) 
168 
141 
196 
Visit 7 (Week 32) 
224 
197 
252 
Visit 8 (Week 40) 
280 
253 
322 
Visit 9 (Week 52) 
364 
323 
371 
Visit 10 (Week 54) Safety FUP 
378 
372 
 
If there is more than one assessment within a visit window, then the analysis visit will be assigned 
by the following priorities: 
1. Use the assessment from the visit with the matching visit label. 
2. Use the visit closest to the target visit day; in the case of ties, use the earlier visit. 
Further details of analysis visit assignment will be provided in the Analysis Data Model (ADaM) 
Specifications 
3.1.3 Definition of Baseline  
Baseline is defined as the value at the Screening Visit for the liver biopsy and imaging data and 
as the predose value at Visit 2 (Week 0) for the biomarker data.  For all other efficacy and safety 
endpoints, baseline is defined as the predose value at Visit 2 (Week 0); if this value is missing, 
then the latest predose value is used. 
3.1.4 Summary Statistics  
Categorical data will generally be summarized with counts and percentages of patients.  The 
denominator used for the percentage calculation will be clearly defined.  Continuous data will 
generally be summarized with descriptive statistics including n (number of non-missing values), 
mean, standard deviation, median, Q1, Q3, minimum, and maximum. 


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3.1.5 Hypothesis Testing 
Given the primary and key secondary endpoints along with 2 active doses, hypothesis testing will 
be performed in a hierarchical order to preserve the overall Type 1 error. 
The 600mg dose will be tested first vs placebo. The primary and the 2 key secondary endpoints 
will be tested in the order as presented in section 2.3.2. Testing of these 3 endpoints will next 
move to the 300mg dose arm vs placebo. If during the sequential testing of these 6 hypotheses, 
a p-value is non-significant (at alpha = 0.05), the remaining (from that point onwards) p-values 
will be considered nominal and significance cannot be claimed. 
No multiplicity adjustments will be applied for other secondary endpoints and exploratory 
parameters analysis.  Since the testing of the other secondary endpoints will not involve any 
control of Type 1 error, all associated p-values are deemed to be nominal. 
3.1.6 Handling of Dropouts and Missing Data 
Date Values 
In cases of incomplete dates (e.g., AE, concomitant medication, and medical history start and/or 
stop dates), the missing component(s) will be assumed as the most conservative value possible. 
For example, if the start date is incomplete, the first day of the month will be imputed for the 
missing day and January will be imputed for the missing month. If a stop date is incomplete, the 
last day of the month will be imputed for the missing day and December will be imputed for the 
missing month. Incomplete start and stop dates will be listed as collected without imputation. 
Date imputation will only be used for computational purposes such as treatment-emergent status. 
Actual date values, as they appear in the original case report forms (CRFs), will be presented 
within the data listings. 
Non-Date Values 
Missing values for the primary endpoint, Week 52 (or at the early termination (ET) visit, if 
applicable) liver biopsy will be imputed as nonresponders.  
All other efficacy and safety data will be used according to availability, with no imputation for 
missing data. 
 
3.2.1 Randomized Population 
The Randomized population will include all patients who were randomized to the study. 
3.2.2 Intent-to-Treat (ITT) Population 
The ITT Population will include all patients who were randomized and received at least 1 dose of 
study drug. 
3.2.3 Modified Intent-to-Treat (mITT) Population 
The mITT Population will include all patients from the ITT Population who have valid baseline and 
Week 52 (or ET, if applicable) liver biopsy measurements; a valid Week 52/ET liver biopsy is 


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defined as a liver biopsy that has occurred within 90 days of last dose/Week 52 visit. This will be 
the primary population for efficacy analysis.  
3.2.4 Per-Protocol (PP) Population 
The PP Population will include all patients from the mITT Population who complete the 52-week 
treatment period without any protocol violations that could impact on the primary efficacy 
endpoint. Patients who have a valid week 52/EOT biopsy within 30 days of last dose will be 
included in the PP population. The PP Population, along with the reason for exclusion, will be 
finalized prior to study unblinding. 
3.2.5 Trough Pharmacokinetics (PK) Population 
The Trough PK Population will include all patients who received at least 1 dose of NST-4016 and 
have at least 1 measurable trough PK concentration. 
3.2.6 The Intensive Pharmacokinetics (PK) Population 
The Intensive PK Population will include all patients who received at least 1 dose of NST-4016 
and have at least 1 measurable non-trough intensive PK sample. 
3.2.7 Safety Population 
The Safety Population will include all patients who received at least 1 dose of study drug. 
 
3.3.1 Patient Disposition 
Counts and percentages of patients who were screened (signed informed consent), screen failed, 
and randomized will be summarized overall based on all screened patients. Reasons for screen 
failure will also be summarized. 
Counts and percentages of patients who were randomized, withdrew early from the study, 
including primary reason for withdrawal, and those that completed the study will be summarized 
by treatment group and overall based on the Randomized Population.  
For each scheduled visit, counts and percentages of patients who do not complete the visit, 
partially complete the visit in-person, or complete the visit virtually will be summarized by 
treatment group and overall. The denominator for calculating percentages will be based on the 
ITT Population. 
Data listings for patient disposition and exclusion and inclusion criteria violations will be provided. 
3.3.2 Protocol Deviations 
Protocol deviations will be identified based on the clinical data as defined in the Protocol Deviation 
Plan.  The Protocol Deviation Plan will define all protocol deviations as either CSR reportable or 
non-CSR reportable. Counts and percentages of patients with CSR reportable protocol deviations 
by deviation category will be summarized by treatment group and overall, for the Randomized 
Population. A similar summary will be provided for Coronavirus Disease 2019 (COVID-19) related 
CSR reportable protocol deviations.  A listing of CSR reportable deviations will also be generated. 


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3.3.3 Analysis Populations 
Counts and percentages of patients in each analysis population will be summarized by treatment 
group and overall based on the Randomized Population.  Reasons for exclusion from PP 
Population will also be summarized. 
A listing of patients included in each of the study populations will be provided. 
3.3.4 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized with descriptive statistics or counts 
and percentage of patients as appropriate by treatment group and overall, for the ITT population. 
If they differ from the ITT Population, summaries will also be provided for the mITT Population, 
the and the PP Population.   
Demographic characteristics include age, gender, ethnicity and race.  
Baseline characteristics include: 
 
Body Mass Index (BMI) 
 
Alcohol use (current/former/never) 
Baseline histology includes: 
 
Biopsy fibrosis score (F1, F2 or F3) 
 
Biopsy fibrosis score for stratification (2 levels: F1 or F2/F3) 
 
NAS Score and individual scores for steatosis, ballooning, inflammation and fibrosis 
 
Composite Disease Activity Score – composite NASH score of inflammation, ballooning 
and fibrosis. 
Baseline chemistry includes: 
 
Liver enzymes (AST, ALT, ALP, GGT and bilirubin [Total, Direct and Indirect]) 
 
Imaging parameters (MRI-PDFF and cT1) 
 
Biomarkers (HOMA-IR, hsCRP, Pro-C3 [COBAS] and ELF test) 
 
All demographic,  baseline characteristic, histology and chemistry data will be provided in by 
patient listings. 
3.3.5 Medical History 
Medical history will be coded to system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 22.0.  Counts and percentages of patients 
with medical history by system organ class and preferred term will be summarized by treatment 
group and overall for the Randomized Population. 
A listing of all medical history data will be provided. 
 
 


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3.3.6 Prior and Concomitant Medications 
Prior and concomitant medications will be coded to World Health Organization (WHO) Drug 
Dictionary Global B3, March 2019. Prior medications include any medication taken within 6 
months prior to screening. Concomitant medications include any medication taken on or after the 
date the patient signs informed consent.  
Counts and percentages of patients taking prior and concomitant medications by Anatomical 
Therapeutic Chemical (ATC) class and preferred term will be summarized by treatment group and 
overall for the Safety Population.   
All medications will be listed and flagged as either prior or concomitant (or both). 
3.3.7 Study Drug Exposure and Compliance 
Patients’ exposure to study drug will be summarized with descriptive statistics for the Safety 
Population.  Weeks of exposure to study drug will be calculated as: 
(date of last dose of study drug – date of first dose of study drug + 1) / 7. 
Note that the exposure duration calculation is intended to describe the length of time a patient 
was exposed to study drug and therefore does not take study drug interruptions into account.  
Exposure to study drug will be summarized by treatment group for the Safety Population using 
descriptive statistics. Furthermore, exposure will be summarized in the following categories: 
 
≤4 weeks (≤28 days) 
 
>4 to ≤10 weeks (29 - 70 days) 
 
>10 to ≤16 weeks (71 - 112 days) 
 
>16 to ≤ 24 weeks (113 - 168 days) 
 
>24 to ≤ 32 weeks (169 – 224 days) 
 
>32 to ≤ 40 weeks (225 -280 days) 
 
>40 to ≤ 52 weeks (281 – 364 days) 
 
> 52 weeks 
Summary statistics will be presented for overall compliance to study drug by treatment group.  
Percent compliance will be calculated as: 
𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑎𝑐𝑡𝑢𝑎𝑙 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑡𝑎𝑘𝑒𝑛
𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑡𝑎𝑘𝑒𝑛× 100 
The number of actual capsules taken will be calculated as number of capsules dispensed – 
number of capsules returned.  If study drug is not returned, the number of capsules returned will 
be considered 0 for the compliance calculation.  The number of  expected capsules will be derived 
from the dates of randomization and the earliest of the Visit 9 (Week 52) and ET dates, assuming 
2 capsules are taken each day. Descriptive statistics will be used to summarize the compliance 
to the study drug by treatment group for the Safety Population. Additionally, the number and 


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percentages of patients in each treatment group will be provided with compliance in the following 
categories: 
 
<75% 
 
 75-125%  
 
>125% 
Listings of drug accountability and derived exposure and compliance will be provided for the 
Safety Analysis Set. 
 
All efficacy analyses will be performed using the mITT Population and repeated in for the ITT 
Population.  Analyses of the primary and all secondary endpoints will also be repeated for PP 
Population.  All efficacy data will be listed. 
3.4.1 Primary Efficacy Endpoint 
Primary Analysis 
The primary efficacy endpoint is the percentage of patients with resolution of NASH without 
worsening of fibrosis. Patients without a valid Week 52 (or ET, if applicable) liver biopsy will be 
imputed as non-responders. The number and percentage of patients meeting the criteria for the 
primary endpoint will be summarized by treatment group. 
The analysis of the primary endpoint will be performed using the data from the 600 mg NST-4016 
and placebo groups using the Cochran-Mantel-Haenszel test, stratified by baseline biopsy fibrosis 
score (2 levels: F1 or F2/F3). The Cochran-Mantel-Haenszel test p-values will be reported, along 
with Odds Ratio and 95% confidence interval. Sample SAS code is below. 
/****************************************************************  
TREATMENT: 0=Placebo, 1=NST-4016 600 mg  
STATIFICATION_VARIABLE: liver fibrosis score(F1 versus F2 or F3)  
OUTCOME: 1-resolution of NASH without worsening fibrosis; 0 – resolution of 
NASH with worsening fibrosis or non-responders 
COUNT: percentage of patients  
****************************************************************/  
 
proc freq;  
     table STRATIFICATION_VARIABLE*TREATMENT*OUTCOME / cmh;  
     weight COUNT;  
run; 
 
Secondary Analyses  
The key secondary analysis of the primary endpoint will be conducted using data for the 300 mg 
NST-4016 and placebo groups, again using the Cochran-Mantel-Haenszel test, stratified by 
baseline biopsy fibrosis score (2 levels: F1 or F2/F3).  
 
 


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Sensitivity Analyses 
A sensitivity analysis for the primary endpoint will be carried out using a logistic regression model 
with treatment group (300 mg NST-4016, 600mg NST-4016, or placebo) and baseline biopsy 
fibrosis score (2 levels: F1 or F2/F3) as factors. Pairwise treatment comparisons will be estimated 
in this model as odds ratios (NST-4016 versus placebo) along with their 95% confidence intervals 
and p-values. Sample SAS code is below. 
/****************************************************************************  
TREATMENT: 0=Placebo, 1=NST-4016 600 mg, 2=NST-4016 300mg  
STRATIFICATION_VARIABLE: liver fibrosis score (F1 versus F2 or F3)  
OUTCOME: 1-resolution of NASH without worsening fibrosis;  
         0 – resolution of NASH with worsening fibrosis or non-responders 
****************************************************************************/  
 
ods output ParameterEstimates=pa 
           OddsRatios=or; 
 
proc logistic;  
     class TREATMENT (ref=’0’) STRATIFICATION_VARIABLE/ param=ref;  
     model OUTCOME (event=’1’) = TREATMENT STRATIFICATION_VARIABLE;  
run; 
 
Additional sensitivity analyses of the analyses described above, CMH and logistic regression, 
will be conducted for the primary endpoint replacing the stratification factor of baseline biopsy 
score with the baseline ballooning score (1 or 2). 
 
3.4.2 Secondary Efficacy Endpoints 
Continuous efficacy variables will be summarized using descriptive statistics for the observed 
data and change and/or percent change from baseline by treatment group and visit as 
appropriate.  
3.4.2.1 Responder analysis 
The key secondary efficacy endpoints will be summarized and analyzed as described above for 
the primary efficacy endpoint.  
The analysis of key secondary endpoints will also be tested in a hierarchical order as described 
in Section 3.1.5.  
3.4.2.2 Nonalcoholic fatty liver disease activity score (NAS) 
The NAS measures disease changes by scoring features of NASH during therapeutic trials.  The 
total NAS represents the sum of scores for steatosis, lobular inflammation, and ballooning, and 
ranges from 0 to 8. 
The change from baseline to Week 52/ET in NAS and individual histological scores (steatosis, 
ballooning, inflammation, and fibrosis) and a composite Disease Activity Score of inflammation, 
ballooning and fibrosis will be analyzed using an analysis of covariance model (ANCOVA). The 
model will be adjusted for treatment (300 mg NST-4016, 600 mg NST-4016, or placebo), biopsy 


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fibrosis score (2 levels: F1 or F2/F3), and respective baseline score. Pairwise treatment 
comparisons between each NST-4016 dose and placebo will be estimated using least square 
(LS) means, standard errors, 95% confidence intervals, and p-values. Sample SAS code is below. 
 
/**********************************************************************  
TREATMENT: 0=Placebo, 1=NST-4016 600 mg, 2=NST-4016 300mg  
STRATIFICATION_VARIABLE: liver fibrosis score (F1 versus F2 or F3)  
BASE: NAS baseline value  
CHANGE: change from baseline to Week 52/ET in NAS 
**********************************************************************/  
 
 
proc glm data=mydata;  
     class TREATMENT STRATIFICATION_VARIABLE;  
     model CHANGE= TREATMENT STRATIFICATION_VARIABLE BASE;  
     lsmeans TREATMENT/pdiff cl;  
run; 
 
A sensitivity analysis will also be conducted for the NAS and individual histological scores withi 
an ANCOVA model replacing the stratification factor of baseline biopsy score with the baseline 
ballooning score (1 or 2). 
 
3.4.2.3 Liver Enzymes 
Liver enzymes are assessed at Screening, Visit 2 (Week 0), Visit 3 (Week 4), Visit 4 (Week 10), 
Visit 5 (Week 16), Visit 6 (Week 24), Visit 7 (Week 32), Visit 8 (Week 40), Visit 9 (Week 52), Visit 
10 (Week 54) and at the ET Visit.   
The change and percent change from baseline in AST, ALT, ALP, GGT and total bilirubin at each 
scheduled visit will be analyzed using a Mixed Model Repeated Measures (MMRM) model, with 
change (or percent change) from baseline as the dependent variable, adjusting for treatment (300 
mg NST-4016, 600 mg NST-4016, or placebo), visit, treatment-by-visit interaction, biopsy fibrosis 
score (2 levels: F1 or F2/F3); and baseline score. The Restricted Maximum Likelihood (REML) 
estimation approach will be used with an unstructured covariance matrix.  The LS means, 
standard errors, 95% confidence intervals, and p-values for the pairwise treatment comparisons 
between each NST-4016 dose and placebo will be estimated for each visit.  
At visits where the fasted status of the patient is recorded (Visit 2 (Week 0 ), Visit 5 (Week 16) 
and Visit 9 (Week 52)), only samples taken in a fasted state will be included.  All results from other 
visits will be included.  An additional analysis will be carried out to include patients who we fasted 
at all three visits where fasted status is recorded. 
3.4.2.4 Inflammation Marker: hsCRP 
High sensitivity C-reactive protein (hsCRP) is measured at Visit 2 (Week 0), Visit 5 (Week 16) 
and Visit 9 (Week 52)/ET. 


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To be included in the analysis, the patient must have been in a fasted state at the time of the 
assessment. 
The change and percent change from baseline in hsCRP and the log-transformation will be 
analyzed using a similar MMRM model as described for the Liver Enzymes.  
3.4.2.5 Fibrosis activity markers: Pro-C3 and ELF Test 
Pro-C3 (COBAS) and ELF test are measured at Visit 2 (Week 0), Visit 5 (Week 16) and Visit 9 
(Week 52)/ET. 
To be included in the analysis, the patient must have been in a fasted state at the time of the 
assessment. 
The change and percent change from baseline in Pro-C3 (COBAS) and ELF will be analyzed 
using a similar MMRM model as described for the Liver Enzymes.  
3.4.2.6 Measure of insulin resistance and metabolic status: HOMA-IR 
HOMA-IR is measured at Visit 2 (Week 0), Visit 5 (Week 16) and Visit 9 (Week 52)/ET. 
To be included in the analysis, the patient must have been in a fasted state at the time of the 
assessment. 
The change and percent change from baseline in HOMA-IR will be analyzed using a similar 
MMRM model as described for the Liver Enzymes.  
3.4.2.7 MRI-PDFF  
Hepatic imaging by MRI will be performed at Screening, Visit 5 (Week 16) and Visit 9 (Week 
52)/ET.  Images will be assessed centrally for MRI-PDFF. 
The change from the baseline to Week 16 and Week 52/ET in MRI-PDFF  will be performed using 
similar ANCOVA models as described above.  The change from baseline to Week 16 and Week 
52/ET will be analyzed in separate models. 
3.4.3 Exploratory Biomarker Analysis 
As part of the exploratory analysis, cT1 will be analyzed as described for MRI-PDFF above.  
Lipodomics data will be available for a sub-set of the patients; data will be analyzed using similar 
ANCOVA or MMRM models as described for the secondary endponts. 
The AI Histology data will be compared with the liver biopsy results from the manual reads. 
 
3.5.1 Sample Collections for Pharmacokinetic Analysis 
For the Trough PK Population, PK blood samples of NST-4016 will be collected pre-dose at Visit 
2 through to Visit 9 (or the ET Visit, if applicable). 
For the Intensive PK Population, PK blood samples of NST-4016 will be collected at the following 
timepoints, in relation to the first dose of study drug on Visit 2: pre-dose (within 1 hour prior to first 


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dose), followed by 1, 2, 3, 4, 6, and 8 hours (+/- 10 minutes) post-dose (Day 0) and at 24hours 
post-dose (+/- 1 hour, but prior to the second dose of study drug on Day 1). 
3.5.2 Handling Missing or Below the Lower Limit of Quantification Data 
For PK concentration data, if the actual sampling time is missing, but a valid concentration value 
has been measured, the concentration value will be flagged, and the scheduled time point may 
be used for the calculation of PK parameters. 
In cases of missing pre-dose concentrations for Visit 2 the missing components may be assumed 
as zero. For all other cases, the missing data will not be imputed. 
At Visit 2, PK blood concentration values that are below the lower limit of quantification will be 
presented as “BLQ” in the concentration data listing. 
For the individual concentration and PK parameter calculation, the following rules will be applied: 
 
If one or more BLQ values occur before the first measurable concentration, they will be 
assigned a value of zero.  
 
If BLQ values occur between measurable concentrations in a profile, the BLQ should be 
omitted (set to missing).  
 
If BLQ values occur after the last measurable concentration in a profile, the BLQ should 
be omitted (set to missing). 
 
For the concentration summary and mean plot preparation, the following rules will be 
applied: Mean concentration at any individual time point will only be calculated if at least 
half of the subjects have valid values (i.e. quantifiable and not missing) at this time point 
 
In cases where a mean value is not calculated due to the above criterion not being met, 
the value will be set to missing 
 
BLQ values will be set to zero 
3.5.3 Pharmacokinetic Concentration 
For the Trough PK Population, trough plasma PK concentrations, defined as the plasma PK 
concentration taken prior to the administration of study drug, at Visits 3 to 9 will be listed and 
summarized descriptively by visit and treatment. Mean (+/- SD) trough plasma PK concentrations 
will be plotted by visit and treatment group on a linear and semi-logarithmic scale against nominal 
sampling time points. Individual trough plasma PK concentrations will be plotted on linear and 
semi-logarithmic scales against actual sampling time points relative to dosing time. 
For the Intensive PK Population, Individual plasma PK concentrations will be listed and 
summarized by treatment group at each nominal time point descriptively. Mean (+/- SD) plasma 
PK concentrations will be plotted by treatment group on linear and semi-logarithmic scales against 
nominal time. Individual plasma PK concentrations will be plotted on linear and semi-logarithmic 
scales by treatment group against actual sampling time points relative to dosing time. 
For all plots, LLOQ will be plotted as a reference line. 
3.5.4 Pharmacokinetic Parameters 
For the Intensive PK Population at Visit 2, the following plasma PK parameters of NST-4016 will 
be determined using non-compartmental methods as appropriate: 


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Parameter 
Description 
Cmax 
Maximum observed plasma concentration; determined directly from the 
concentration time profile; if the maximum plasma concentration occurs at 
more than one time point, Cmax is defined as the first maximum value 
Tmax 
Time to Cmax; If the maximum value occurs at more than one time point, 
Tmax is defined as the first time point with this value. 
λz 
Apparent first-order terminal elimination rate constant calculated from a 
semi-log plot of the plasma concentration versus time curve. The 
parameter will be calculated by linear least-squares regression analysis 
using points in the terminal log-linear phase. 
t1/2 
Apparent first-order terminal elimination half-life; calculated as ln(2)/λz 
AUC0-t 
Area under the plasma concentration-time curve from time 0 to the time of 
the last observed concentration 
AUC0-inf 
Area under the plasma concentration-time curve from time 0 extrapolated 
to infinity; calculated as (AUC0-last+ Clast/λz) 
AUC%extrap 
Percent of AUC0-infextrapolated, represented as (1 -AUC0-t/AUC0-
inf)*100 
CL/F 
Apparent total plasma clearance after oral administration; calculated as 
Dose/AUC0-inf 
Vz/F 
Apparent volume of distribution during terminal elimination phase after oral 
administration; calculated as Dose/[λz*AUC0-inf] 
Actual collection times will be used for the calculation of PK parameters. AUCs will be calculated 
using linear up log down method. 
λz will not be presented for subjects who do not exhibit a terminal elimination phase in their 
concentration-time profiles. In order to estimate λz, linear regression of concentration in logarithm 
scale versus time will be performed using at least 3 data points. Uniform weighting will be selected 
to perform the regression analysis. 
The constant λz will not be assigned if one of the following occurs:  
1. The terminal elimination phase is not linear (as it appears on a semi-logarithmic 
scale).  
2. The terminal elimination rate constant indicates a positive slope (λz > 0).  
3. Tmax is one of the three last data points.  
 
 
 


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The constant λz and its derived parameters will be listed but excluded from statistical analysis if 
one of the following occurs:  
1. The adjusted regression coefficient (R2) is less than 0.8.  
2. The AUC%extrap exceeds 20%.  
If λz is not assigned, the values of any associated PK parameters (e.g. AUC0-inf, AUC%extrap, t1/2, 
CL/F, or Vz/F) will not be calculated. 
No PK parameters will be calculated for subjects with 2 or fewer detectable concentrations in their 
PK profile.  
Plasma PK parameters will be summarized by treatment using descriptive statistics for the 
Intensive PK Population. 
 
Safety data include AEs, vital signs, physical examinations, ECGs and clinical laboratory 
parameters and will be summarized by actual treatment received based on the Safety Population.  
3.6.1 Adverse Events (AEs) 
An adverse event is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the investigational medicinal 
product. A treatment emergent AE (TEAE) is defined as a new or worsening adverse event after 
the first dose of study drug.  
All AEs will be coded to system organ class and preferred term using MedDRA version 22.0.   
An overview of AEs will be provided including counts and percentages of patients and number 
of events by treatment group and overall for Safety Population (and event counts) with the 
following: 
 
Any Adverse Event 
 
Any TEAEs  
 
Maximum severity of TEAEs  
 
Study drug related TEAEs 
 
Maximum severity of study drug related TEAEs 
 
TEAEs leading to discontinuation of study drug 
 
Any TEAEs of special interest (TEAESI) 
 
Any serious TEAEs (TESAEs) 
 
Study drug related TESAEs 
 
TESAE/TEAESIs leading to discontinuation of study  


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 
TESAEs leading to death 
 
TESAEs related to COVID leading to death 
The TEAEs described above will be summarized separately by System Organ Class and 
Preferred Term (and by maximum severity). 
Listings will be presented specifically for all TEAEs, TEAESI, TESAEs, TEAEs Leading to 
Discontinuation of Study Drug, TEAEs Leading to Discontinuation of Study and TESAEs Leading 
to Death. 
3.6.2 Clinical Laboratory Tests 
Fasting Hematology, biochemistry, coagulation and lipid panels and urinalysis will be collected at 
all study visits. A list of laboratory tests to be performed is included in Protocol Appendix B. 
Descriptive statistics of each clinical laboratory parameter will be presented for baseline values 
and for values and the change and percent change from the baseline at each post-baseline visit 
by treatment group and overall. 
Values outside the normal range will be categorized as High (i.e., above the normal range) or Low 
(i.e., below the normal range) based on the central laboratory’s normal reference range. The 
number and percentage of patients with values outside the normal range will be summarized by 
parameter for baseline and for each post-baseline visit. 
Shift tables will also be presented for baseline versus maximum-baseline values and baseline 
versus minimum post-baseline values. 
All safety laboratory data will be presented in patient listings. 
3.6.3 Vital Signs 
Vital signs will be measured at all study visits. Vital signs parameters include blood pressure, 
heart rate and body temperature. Three replicate blood pressure readings will be taken at each 
visit and the average of these measurements will be used in the analysis.   
Vital signs parameters will be summarized by visit, treatment group and overall. Change and 
percent change from baseline at each post-baseline visit will be presented for each parameter. 
All vital sign data will be presented in patient listings. 
3.6.4 Anthropometric measures 
Height is measured at the Screening Visit only.  Weight will be measured at each study visit.  BMI 
will be derived for each study visit using the weight measured at that visit and the height measured 
at the screening visit. Anthropometric data will be summarized by visit, treatment and overall.  
Change from baseline at each post-baseline visit will be presented for weight and BMI. 
All anthropometric data will be presented in patient listings. 


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3.6.5 Electrocardiograms 
Single 12-lead ECGs will be performed at Screening, Visit 2 (Week 0), Visit 5 (Week 16), Visit 7 
(Week 32), Visit 9 (Week 52), and at the Safety Follow-up or ET Visit. ECG parameters include  
Heart Rate, PR Interval, QRS Duration, QT Interval, QTcF Interval and RR Interval. 
ECG parameters will be summarized by visit, treatment group and overall. Change and percent 
change from baseline at each post-baseline visit will be presented for each parameter.   
Additionally, the number and percentages of patients in each treatment group will be provided 
with QTcF in the following categories: 
 
Absolute values: 
o QTcF Interval > 450 msec 
o QTcF Interval > 480 msec 
o QTcF Interval > 500 msec 
 
Change from baseline: 
o QTcF increase from baseline > 30 msec 
o QTcF increase from baseline > 60 msec 
Overall interpretation will also be summarized by visit. 
All ECG data will be presented in patient listings. 
3.6.6 Physical Examinations 
Full physical examinations (including general appearance; eyes, ears, nose, and throat; head and 
neck; chest and lungs; cardiovascular; abdomen; musculoskeletal; lymphatic; dermatological; 
neurological systems; mental status; and extremities) will be performed at Screening; Visit 2 
(Week 0), Visit 9 (Week 52) and at the Safety Follow-up or ET Visit.  Abbreviated physical 
examinations will be performed at all other study visits. 
All physical examination data will be listed.  
 
An external, independent Data Safety Monitoring Committee (DSMC) was to review all available 
unblinded preliminary safety and biomarker results, as described in the DSMC Charter. The 
DSMC Charter describes the overall guidelines, composition and roles, and responsibilities of the 
independent DSMC, timing of meetings, methods of providing information to and from the DSMC, 
frequency and format of meetings, data analysis recommendations, and DSMC relationships with 
other parties participating in the conduct of this study. Patient accrual continued throughout the 
period of the DSMC review. The DSMC was to advise on the accrual of the remaining patients 
per protocol or any amendments that are necessary for safety reasons. 
Patients, investigators, site staff and in general all personnel directly involved in the conduct of 
the study were to remain blinded to the patients’ treatment assignment until the completion of the 
study. 


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An interim analysis was planned for this study after 90 patients had completed 16 weeks of 
treatment.  This analysis was reviewed by the DSMC according to the DSMC Charter.  The 
conclusions and recommendations of the DSMC were shared blindly with the Sponsor and clinical 
sites.  A separate interim analysis plan was finalized prior to conducting the interim analysis. 
 
After the database is locked and exclusions from analysis populations have been finalized, the 
randomized treatment assignments will be unblinded and the pre-final analysis will be generated.  
Pre-final tables, figures and listings (TFLs) will be provided approximately 3 weeks after database 
lock.   
 
After all comments on the pre-final analysis have been resolved and the study database is 
declared final, the final analysis will be generated.  Final TFLs will be provided approximately 1 
week after the study database is declared final.  If there were no changes to the pre-final analysis 
or the study database, the pre-final TFLs may be considered final. In addition to TFLs, SDTM data 
and ADaM data along with associated files will be provided.  Associated files may include:  
annotated CRFs, Standard Data Tabulation Model (SDTM) specifications, SDTM programs, 
ADaM specifications, ADaM programs, TFL programs, and Clinical Data Interchange Standards 
Consortium (CDISC) Define packages for both SDTM and ADaM data.   
 
The planned changes to the protocol-specified statistical analyses, as detailed in this SAP are: 
 
Key secondary efficacy endpoints added for different definitions of response – fibrosis 
improvement and resolution of NASH with fibrosis improvement. 
 
cT1 demoted to exploratory endpoint (from secondary) as there is uncertainty over clinical 
significance. 
 
The primary population for all efficacy analysis updated to mITT Population, with all analyses 
to be repeated for the ITT Population. 
 
No imputation to be performed for the continuous secondary endpoints. 
 
ALP added to list of liver enzymes to be analyzed as secondary endpoints. 
 


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Analyses will be performed using SAS® version 9.4 or higher.  All available data will be presented 
in patient data listings which will be sorted by patient and visit date as applicable.   
Phoenix WinNonlin version 8.3 or higher will be used to calculate PK parameter estimates. PK 
parameter estimates will also be calculated via SAS and verified with the Phoenix WinNonlin 
results.  
Detailed Programming Specifications will be provided in a separate document(s).