Clinical trial NCT02784444
Conditions: Non-alcoholic Fatty Liver Disease Non-alcoholic Steatohepatitis NASH - Nonalcoholic Steatohepatitis
Keywords: NASH
Sponsor: Cirius Therapeutics, Inc.
Start date: 2016-09-14; Completion date: 2019-06-01
Enrollment: 392 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blinded study of three doses of MSDC-0602K or placebo given orally once daily to subjects with biopsy proven NASH with fibrosis and no cirrhosis.

Detailed description:
This is a randomized, double-blinded study of three doses of MSDC-0602K or placebo given orally once daily to subjects with biopsy proven NASH with fibrosis and no cirrhosis. Visits to the clinic will be at baseline, 1, 2, 3, 6, 9, and 12 months, with one 2- week follow-up visit.

Safety will be assessed by monitoring of vital signs, 12 lead electrocardiogram (ECG), physical examinations, safety labs, and adverse events (AEs).

Arms: arm 1: MSDC-0602K Dose 1 capsule taken once daily for 360 days arm 2: MSDC-0602K Dose 2 capsules taken once daily for 360 days arm 3: MSDC-0602K Dose 3 capsules taken once daily for 360 days arm 4: Matching Placebo capsule taken once daily for 360 days
Interventions: intervention 1: MSDC-0602K intervention 2: Placebo
Intervention descriptions: intervention 1: MSDC-0602K capsules intervention 2: Placebo capsules

Protocol documents:
Prot_000.pdf: 
 
 
Confidential 
Clinical Trial Protocol:  MSDC-0602K-C009NASH 
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 12-
Month, Multiple-Dose Study to Evaluate the Safety, Tolerability 
and Efficacy of Three Dose Levels of MSDC-0602K in Patients 
with NASH (EMMINENCE™) 
Study Number 
MSDC-0602K-C009NASH 
Study Phase: 
Phase 2 
Product Name: 
MSDC-0602K Tablets 
Indication: 
Non-alcoholic steatohepatitis (NASH) 
Sponsor: 
Cirius Therapeutics, Inc. 
Medical Monitor: 
Bill Welder, MD 
Chiltern International Inc. 
Phone:  +1 (423) 990-0471 
 
Chief Medical Officer 
and After Hours 
Medical Monitor: 
Howard C. Dittrich, MD 
Cirius Therapeutics, Inc. 
Phone:  +1 (858) 333-6274, ext. 508 
 
 
 
Date 
Original Protocol: 
Amendment 1 
Amendment 2 
Amendment 3 
Amendment 4 
 
04 March 2016 
22 May 2016 
23 June 2016 
11 October 2016 
31 July 2017 
Confidentiality Statement 
This protocol contains confidential information belonging to Cirius Therapeutics, Inc.  Except as may be 
otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold such information in 
confidence and not to disclose it to others (except where required by applicable law) nor use it for unauthorized 
purposes.  In the event of actual or suspected breach of this obligation, Cirius Therapeutics, Inc. should be 
notified promptly. 
 
 


Cirius Therapeutics, Inc. 
Clinical Protocol MSDC-0602K-C009NASH, Amendment 4 
MSDC-0602K 
31-July-2017
 
 
 
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SPONSOR SIGNATURE 
 
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-
Controlled, 12-Month, Multiple-Dose Study to Evaluate 
the Safety, Tolerability and Efficacy of Three Dose 
Levels of MSDC-0602K in Patients with NASH 
(EMMINENCE™) 
Study Number: 
MSDC-0602K-C009NASH 
Amendment Number: 
Amendment 4 
Amendment Date: 
31 July 2017 
 
This clinical study protocol was subject to critical review and has been approved by the sponsor.  
 
 
 
 
 
Signed: 
 
 
Date:  
 
Howard Dittrich, MD 
Chief Medical Officer 
Cirius Therapeutics, Inc. 
 
 


Cirius Therapeutics, Inc. 
Clinical Protocol MSDC-0602K-C009NASH, Amendment 4 
MSDC-0602K 
31-July-2017
 
 
 
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INVESTIGATOR’S SIGNATURE 
 
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-
Controlled, 12-Month, Multiple-Dose Study to Evaluate 
the Safety, Tolerability and Efficacy of Three Dose 
Levels of MSDC-0602K in Patients with NASH 
(EMMINENCE™) 
Study Number: 
MSDC-0602K-C009NASH 
Amendment Number: 
Amendment 4 
Amendment Date: 
31 July 2017 
 
I agree to conduct this clinical study in accordance with the design and specific provisions of this 
protocol; deviations from the protocol are acceptable only with a mutually agreed upon protocol 
amendment.  I agree to conduct the study in accordance with Good Clinical Practice guidelines.  I 
also agree to report all information or data in accordance with the protocol and, in particular, I 
agree to report any serious adverse experiences as defined in this protocol.  I also agree to handle 
all clinical supplies provided by the sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used and 
disclosed as described in the protocol, and that such information may be transferred to countries 
that do not have laws protecting such information. 
It is obligatory that the Investigator become familiar with all the sections of the MSDC-0602K 
Investigator’s Brochure prior to initiation of the study. 
 
 
Signed: 
 
 
Date:  
 
Principal Investigator Signature 
 
 
 
 
 
 
 
Principal Investigator Name (print) 
 
 


Cirius Therapeutics, Inc. 
Clinical Protocol MSDC-0602K-C009NASH, Amendment 4 
MSDC-0602K 
31-July-2017
 
 
 
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SYNOPSIS 
Sponsor: 
Cirius Therapeutics, Inc. 
Name of Finished 
Product 
MSDC-0602K Tablets 
Name of Active 
Ingredient 
MSDC-0602K 
Study Title 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 12-
Month, Multiple-Dose Study to Evaluate the Safety, Tolerability and 
Efficacy of Three Dose Levels of MSDC-0602K in Patients with 
NASH (EMMINENCE™) 
Study Number 
MSDC-0602K-C009NASH 
Study Phase 
Phase 2 
Study Design 
This is a randomized, double-blinded study of three doses of MSDC-
0602K (62.5, 125 and 250 mg) or placebo given orally once daily to 
subjects with biopsy proven NASH with fibrosis and no 
cirrhosis.  Subjects will be stratified by presence of T2DM (Yes/No), 
use of Vitamin E ≥ 400 IU (Yes/No) and fibrosis score (F1 or ≥ F2) 
to ensure equal representation across all groups.  The primary 
efficacy endpoint will be assessed at 12 months. Visits to the clinic 
will be at baseline, 1, 2, 3, 6, 9, and 12 months, with one 2-week 
follow-up visit. 
Subject Population 
Subjects with biopsy proven NASH (NAS ≥ 4; at least one point in 
each category) with F1 to F3 fibrosis score.  Subjects with 
demonstrated cirrhosis, or evidence of other chronic liver diseases to 
include active hepatitis, excess alcohol consumption, documented 
hemochromatosis or other metabolic liver diseases, or autoimmune 
hepatitis will be excluded from the trial.  Females should be 
postmenopausal or surgically sterilized.  Subjects must have signed 
an informed consent. 
Planned Number of 
Subjects 
Approximately 380 subjects will be randomized with the intent to 
have 340 subjects complete the 12-month assessment (4 groups; 
approximately 85 subjects/group) at approximately 50 to 75 sites in 
the US.  Sites in other regions may be added.  Subjects who do not 
complete the study will not be replaced. 


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Clinical Protocol MSDC-0602K-C009NASH, Amendment 4 
MSDC-0602K 
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Test Product, Dose, and 
Mode of 
Administration 
Size #00 opaque gelatin capsules will be prepared using MSDC-
0602K tablets or matching placebo capsules containing micro-
crystalline cellulose.  All doses will be taken orally with about 
8 ounces (one glassful) of room temperature water at least 30 
minutes before each morning meal  Dose levels for MSDC-0602K 
will be 62.5, 125, and 250 mg.  Each subject will self-administer one 
capsule per day.  
Duration of Treatment 
This study will be comprised of a maximum 42-day Screening 
period, a treatment period of 360 days and a 14-day follow-up 
period.  The total duration of the study for each subject will be up to 
416 days, including follow-up. 
Pharmacokinetic 
Variables 
Blood samples for trough PK analysis of MSDC-0602 and 
MSDC-0597 (the hydroxymetabolite) will be taken at Study Visits 
2, 4, 5, 6 and 7 (Days 30, 90, 180, 270 and 360). 
Efficacy Variables 
Primary Efficacy 
Endpoint 
Hepatic histological improvement in NAS defined as a decrease of 
at least 2 points with no worsening of fibrosis stage at 12 months.  
The reduction in NAS must include at least a 1 point reduction in 
either ballooning or inflammation.  No worsening of fibrosis is 
defined as no increase in CRN fibrosis score.  
Secondary Efficacy 
Endpoints 
1. Proportion of subjects with resolution of NASH with no 
worsening of fibrosis at 12 months.  Resolution of NASH is 
defined as a ballooning score of 0 and an inflammation score 
of 0-1.  No worsening of fibrosis is defined as no increase in 
CRN fibrosis score.  
2. Proportion of subjects with improvement of fibrosis (CRN 
staging score) by at least 1 stage with no worsening of 
NASH at 12 months. 
3. Mean change from baseline in NAFLD activity score (NAS) 
and each one of its components (steatosis, inflammation and 
ballooning) at 12 months. 
4. Mean change from baseline in fibrosis score at 12 months. 


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Exploratory Efficacy 
Endpoints  
1. Mean change in liver stiffness as measured by transient 
elastography (FibroScan) (change from baseline relative to 
placebo at 12 months). 
2. Change from baseline relative to placebo for liver function 
tests (ALT, AST, ALP, GGT, bilirubin, albumin, PT and 
INR) at 6 and 12 months, and biomarkers and indirect 
measures of apoptosis and liver fibrosis (CK-18 [M30 and 
M65], Fibrosure, APRI, FIB-4 index, Pro C3-C3 and ELF 
score and its individual components (HA, PIIINP, TIMP-1) 
at 12 months. 
3. Changes from baseline relative to placebo in circulating 
inflammatory markers (HMW adiponectin and hsCRP) and 
markers of bone metabolism (osteocalcin and serum CTX) at 
6 and 12 months. 
4. Changes from baseline relative to placebo in FFA, serum 
triglycerides and fasting cholesterol (total, HDL, LDL, 
VLDL) at 6 and 12 months and changes from baseline of 
NMR analysis of lipoprotein particle size at 12 months. 
5. Changes from baseline relative to placebo in markers of 
insulin sensitivity: HOMA-IR, HbA1c, fasting plasma 
glucose, and fasting insulin at 6 and 12 months.  
6. Changes from baseline relative to placebo in blood pressure 
(systolic and diastolic), heart rate, weight, and abdominal 
girth at 6 and 12 months. 
7. Changes from baseline relative to placebo at the 12 month 
endpoint in the pathologist’s general impression as to the 
three categories of diagnosis: 1) NASH, 2) Simple/isolated 
steatosis with no steatohepatitis (NASH), or 3) No fatty liver 
disease (no NAFLD). 
8. Changes from baseline relative to placebo in subjects with 
PNPLA3 variants and other genotypes. 
Eligibility Criteria 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be 
eligible for enrollment into the study: 
1. 
Adult subjects at least 18 years of age. 
2. 
Histological evidence of NASH, based on biopsy, with a 
NAS (NASH CRN scoring) ≥ 4 with a score of at least 1 in 
each component of NAS 
3. 
Histological evidence of liver fibrosis defined as NASH 
CRN System fibrosis score of F1 to F3  


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4. 
Qualifying liver biopsy must be within 9 months prior to or 
during Screening. If no usable liver biopsy is available 
within 9 months prior to Screening, a liver biopsy must be 
performed during Screening after the following criteria are 
confirmed: 
a. AST ≥ 20 U/L  
b. FibroScan with CAP score ≥ 270 db/m and kPa ≥ 8.5 
5. 
Subjects with type 2 diabetes mellitus (DM) must be under 
stable and reasonable control, defined as under a healthcare 
provider’s care for DM with glycosylated hemoglobin 
[HbA1c] ≤ 9.5%.  Subjects taking permitted anti-diabetic 
therapies (metformin, GLP-1 agonists, SGLT2 inhibitors, 
sulfonylureas or DPP4 inhibitors) must be on stable doses for 
a period of at least 3 months prior to randomization.  Refer to 
Section 6.4 for additional clarification about the use of 
antidiabetics.   
6. 
Subjects taking Vitamin E must be on a stable dose (if ≥ 400 
IU) for a period of at least 3 months prior to randomization.  
7. 
Females must be either postmenopausal (at least 12 months 
since last menses) or surgically sterilized (bilateral tubal 
ligation, bilateral oopherectomy and/or hysterectomy) 
verified by a follicle-stimulating hormone (FSH) test result 
≥ 40 mIU/mL.  Those with FSH <40 or with bilateral tubal 
ligation must use a barrier method of birth control.  In 
addition, all females must have a negative pregnancy test at 
Screening and Day 1 regardless of childbearing potential.  
For postmenopausal women only, if FSH levels are above 
40 mIU/mL and serum pregnancy results are indeterminant, 
the subject will be assessed as not pregnant. 
Males with female partners of child-bearing potential must 
agree to use adequate contraceptive methods (including a 
condom, plus one other form of contraception) if engaging in 
sexual intercourse. 
8. 
Body Mass Index (BMI) ≤ 50 kg/m2. 
9. 
Willing and able to sign an informed consent document 
indicating understanding of the purpose of and procedures 
required for the study and willingness to participate in the 
study. 
10. 
Willing and able to attend all study visits and undergo all 
protocol-specified procedures including liver biopsies at 
baseline and at the end of study treatment (one year). 


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MSDC-0602K 
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Subject Exclusion 
Criteria 
1. 
Known history of HIV. 
2. 
Prior liver transplantation. 
3. 
Other well-documented causes of active chronic liver 
disease, including, but not restricted to: history of positive 
hepatitis B surface antigen (HBsAg) or HCV RNA (subjects 
must be viremia free for a minimum of 2 years), suspicion of 
drug-induced liver disease, alcoholic liver disease and auto-
immune hepatitis, Wilson’s disease hemochromatosis, 
primary biliary cirrhosis, primary sclerosing cholangitis, 
genetic hemochromatosis, known or suspected HCC, history 
of planned liver transplant or current MELD score > 12.   
4. 
History of cirrhosis and/or hepatic decompensation including 
ascites, hepatic encephalopathy or variceal bleeding.  Platelet 
count < 100,000/µL of blood at Screening. 
5. 
AST or ALT > 5 times the upper limit of normal at 
Screening.  
6. 
Total bilirubin > 1.8 mg/dL unless diagnosis of Gilbert’s 
disease or serum albumin < 2.5 gms/dL at Screening.   
7. 
INR ≥ 1.5 times ULN at Screening or other evidence of 
impaired coagulation. 
8. 
History of alcohol abuse or drug abuse within 6 months of 
Screening. 
9. 
Inability to safely obtain a liver biopsy. 
10. 
Current or history of Type 1 diabetes mellitus. 
11. 
Current or history of recent (≤ 6 months) use of 
ursodeoxycholic acid. 
12. 
Current use of any diabetes medications other than 
metformin, GLP-1 agonists, SGLT2 inhibitors, sulfonylureas 
or DPP4 inhibitors three months prior to the baseline 
diagnostic liver biopsy or during the study unless as specified 
in the protocol.  Current use of insulin or PPARγ agonists 
(pioglitazone or rosiglitazone) is not allowed for the duration 
of the study. Refer to Section 6.4 for additional clarification 
about the use of antidiabetics. 
13. 
Use of concomitant medications with a known significant 
metabolism by CYP2C8 or CYP2C9 including paclitaxel, 
phenytoin, warfarin, celecoxib, tolbutamide, or replaglinide 
for the duration of the study. 


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14. 
History of diabetic ketoacidosis or hyperosmolar non-ketotic 
coma within the 6 months prior to randomization. 
15. 
History of heart failure (including CHF) or previous 
cardiovascular event (acute coronary syndrome, myocardial 
infarction, coronary by-pass surgery, or catheter based 
coronary intervention) within the 6 months prior to 
randomization. 
16. 
Serum creatinine >2 mg/dL at Screening. 
17. 
Current or recurrent disease that may affect the action, 
absorption or disposition of the study treatment, or clinical or 
laboratory assessments. 
18. 
Current or history of severe or unstable disorder (medical or 
psychiatric) requiring treatment that may make the subject 
unlikely to complete the study. 
19. 
Blood pressure greater than 160/100 mmHg.  Subjects with 
elevated BP (but < 160/100 mmHg) with or without current 
treatment are allowed at the discretion of the Investigator and 
primary care physician.  Individuals with hypertension must 
have been stabilized to the current treatment regimen for at 
least 6 weeks prior to randomization. 
20. 
Known or suspected intolerance or hypersensitivity to the 
study drugs, closely related compounds or any of their stated 
ingredients. 
21. 
Participation in an investigational study (other than a non-
treatment registry study) or received an investigational drug 
within 30 days or 5 half-lives (whichever is longer) prior to 
randomization. 
22. 
Blood donation of 1 unit or more within 56 days of 
randomization. 
23. 
Plasmapheresis or plasma donation within 30 days of 
randomization. 
24. 
Single 12-lead ECG demonstrating a screening QTc > 450 
msec in men and > 470 msec in women.  A single repeat 
ECG may be done at the Investigator’s discretion. 
25. 
Any surgical or medical condition which may significantly 
alter the absorption of the study drug including, but not 
limited to the following: history of major gastrointestinal 
tract surgery such as gastrectomy, gastroenterostomy, bowel 
resection, gastric bypass, gastric stapling, or gastric banding, 
currently active inflammatory bowel syndrome.  Subjects 


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with reversal of gastric sleeve or banding are allowed. 
26. 
Evidence of clinically relevant pathology that could interfere 
with the study results or put the patient’s safety at risk. 
27. 
Malignancy, including leukemia and lymphoma (excluding 
basal cell and squamous cell skin cancers and localized 
prostate cancer) not treated within the last 2 years. 
Safety Assessments 
Safety will be assessed by periodic measurement of vital signs, 
12-lead electrocardiogram (ECG), physical examinations and the 
occurrence of adverse events (AEs).  Fasting blood samples for 
central lab analyses of clinical chemistries and hematology will be 
collected at each study visit (Screening and Study Visits 1-8).  
Samples for urinalysis will be collected at Screening and all Study 
Visits except Visits 2 and 3. 
Statistical Plan and 
Methods 
Sample Size  
Each of the three MSDC-0602K dose groups will be compared to 
the placebo group at the two-sided 0.05 significance level; 85 
subjects per arm provides approximately 80% power to detect a 
difference in response rates of 39.5% in any MSDC-0602K dose 
group versus 20% response rate in the placebo group. Assuming 
10% of subjects will not complete the 12-month assessment due to 
early discontinuation, approximately 380 subjects will be 
randomized to the study.  The randomization ratio is 1:1:1:1.  
Plan for statistical analysis  
The modified Intent-to-Treat analysis set (mITT, see Section 11.2 
for details), including treated subjects in the treatment group to 
which randomized, will be used in the analysis of the primary 
endpoint.  The other key efficacy response related endpoints will 
also use mITT for the main analysis. 
A responder with respect to the primary endpoint will be defined as 
having a 2 point reduction in NAS (NASH CRN scoring) with no 
concurrent worsening of fibrosis defined as progression of at least 
one stage (using the NASH Clinical Research Network (CRN) 
fibrosis staging system).  The reduction in NAS must include at least 
a 1 point reduction in either ballooning or inflammation. 
Comparisons between each active treatment group and the placebo 
group with respect to the primary efficacy endpoint will be 
evaluated using appropriate contrasts from a logistic regression 
model that includes adjustments for randomization stratification 
factors and baseline NAS. Model-adjusted odds ratios and their 95% 
confidence intervals (CI) will be provided. In addition, the stratum-


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31-July-2017
 
 
 
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adjusted response rate differences between each dose group and the 
placebo group and their associated 95% CIs will be provided. An 
exploratory evaluation of the homogeneity of comparisons across 
the randomization stratification factors will be provided. 
The secondary response-related, binary efficacy endpoints will also 
be analyzed using logistic regression adjusting for the randomization 
stratification factors. Model-adjusted odds ratios and their associated 
95% confidence intervals will be provided.  The mean change from 
baseline secondary endpoints will be analyzed using Analysis of 
Covariance (ANCOVA) models adjusted for the stratification factors 
and the baseline score.  
An interim analysis of exploratory and safety endpoints is planned 
after all subjects have been randomized into the study and 6-month 
data are available on a minimum of 300 randomized subjects.   
 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE ............................................................................................................... 2 
INVESTIGATOR’S SIGNATURE ................................................................................................ 3 
SYNOPSIS 
................................................................................................................................. 4 
TABLE OF CONTENTS .............................................................................................................. 12 
LIST OF TABLES ........................................................................................................................ 15 
LIST OF ABBREVIATIONS ....................................................................................................... 16 
1 
STUDY ADMINISTRATION STRUCTURE ................................................................. 19 
 
Medical Monitors .................................................................................................. 19 
 
Chief Medical Officer and After Hours Medical Monitor: ................................... 19 
 
SAE Reporting Contact Information .................................................................... 19 
2 
BACKGROUND AND RATIONALE FOR THE STUDY ............................................. 19 
 
Background ........................................................................................................... 19 
 
Summary of Preclinical Safety of MSDC-0602 ................................................... 20 
 Safety Pharmacology ................................................................................ 20 
 Toxicology ................................................................................................ 20 
 
Clinical Summary and Dose Selection ................................................................. 22 
 Early Clinical Data for MSDC-0602 ........................................................ 22 
 Rationale for Dose Selection .................................................................... 23 
3 
STUDY OBJECTIVES ..................................................................................................... 24 
4 
ENDPOINTS .................................................................................................................... 24 
 
Safety .................................................................................................................... 24 
 
Efficacy ................................................................................................................. 24 
 Primary Efficacy Endpoint ....................................................................... 24 
 Secondary Efficacy Endpoints .................................................................. 24 
 Exploratory Efficacy Endpoints ................................................................ 25 
 
Pharmacokinetics .................................................................................................. 25 
5 
SUBJECT SELECTION ................................................................................................... 25 
 
Inclusion Criteria .................................................................................................. 25 
 
Subject Exclusion Criteria .................................................................................... 26 
6 
STUDY DESIGN.............................................................................................................. 28 
 
Summary of Study Design .................................................................................... 28 


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 Schedule of Activities ............................................................................... 29 
 
Study Activities ..................................................................................................... 32 
 Method of Assigning Subjects to Treatment ............................................ 32 
 Screening Period (Days -42 to -1) ............................................................ 32 
 Study Visit 1 ............................................................................................. 33 
 Study Visit 2, Month 1 .............................................................................. 34 
 Study Visit 3, Month 2 .............................................................................. 34 
 Study Visit 4, Month 3 .............................................................................. 34 
 Study Visit 5, Month 6 .............................................................................. 35 
 Study Visit 6, Month 9 .............................................................................. 36 
 Study Visit 7, Month 12 ............................................................................ 36 
 Study Visit 8, Day 374 (Follow-Up Visit) ................................................ 37 
 Additional Follow-Up Visits..................................................................... 37 
 
Discontinuation of Study Drug and Study Termination ....................................... 37 
 
Type 2 Diabetes Mellitus ...................................................................................... 38 
 
Liver Function Tests ............................................................................................. 39 
 
PT/INR Tests ........................................................................................................ 39 
7 
STUDY PROCEDURES AND EVALUATIONS ........................................................... 40 
 
Vital Signs ............................................................................................................. 40 
 
Physical Examinations .......................................................................................... 40 
 
Electrocardiograms ............................................................................................... 41 
 
Laboratory Assessments ....................................................................................... 41 
 
Efficacy and Pharmacokinetic Assessments ......................................................... 43 
 
Transient elastography (FibroScan) measurement of liver fibrosis ...................... 43 
 
Liver Biopsies ....................................................................................................... 44 
 
Concomitant Medications and Other Therapy ...................................................... 45 
 
Alcohol, Caffeine and Tobacco ............................................................................ 45 
 
Physical Activity ................................................................................................... 45 
 
Dietary Guidance .................................................................................................. 46 
 
Meals and Fluid Intake.......................................................................................... 46 
 
Contraception ........................................................................................................ 46 
 
Premature Termination of Study/Closure of Site.................................................. 46 


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8 
STUDY DRUG ................................................................................................................. 46 
 
Investigational and Control Drugs ........................................................................ 46 
 
Treatments............................................................................................................. 47 
 
Randomization Code Creation and Storage .......................................................... 47 
 
Study Drug Blinding ............................................................................................. 47 
 
Study Drug Assignment and Dispensing Procedures ........................................... 47 
 Dispensing the Study Drug ....................................................................... 48 
 
Study Drug Interruptions ...................................................................................... 48 
 
Compliance ........................................................................................................... 49 
 
Study Drug Supply, Storage and Tracking ........................................................... 49 
 
Emergency Unblinding ......................................................................................... 49 
9 
ADVERSE EVENTS ........................................................................................................ 49 
 
Adverse Events ..................................................................................................... 49 
 Adverse Event Definitions ........................................................................ 50 
 Serious Adverse Event Definition ............................................................ 50 
 Pre-existing Condition Definition ............................................................. 51 
 Procedures ................................................................................................. 52 
 Grading of Adverse Event Severity .......................................................... 52 
 Relationship to Study Drug ....................................................................... 52 
 Reporting Serious Adverse Events ........................................................... 52 
10 
STUDY DURATION ....................................................................................................... 54 
11 
STATISTICS .................................................................................................................... 54 
 
Sample Size and Power Calculations .................................................................... 54 
 
Analysis Set .......................................................................................................... 54 
 
Planned Methods of Analysis ............................................................................... 55 
 Analysis of Key Study Endpoints ............................................................. 55 
 Demographic and Baseline Characteristics .............................................. 58 
 Study Drug Exposure, Compliance, and Concomitant Therapies ............ 58 
 Interim Analysis ........................................................................................ 59 
12 
BIOLOGICAL SPECIMENS ........................................................................................... 60 
13 
CLINICAL AND LABORATORY DATA COLLECTION ............................................ 60 
 
Case Report Forms ................................................................................................ 60 


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Laboratory Results ................................................................................................ 60 
14 
STUDY DOCUMENTATION AND RECORDS RETENTION..................................... 61 
 
Access to Records ................................................................................................. 61 
 
Source Documents ................................................................................................ 61 
 
Record Retention (Investigator’s Study File) ....................................................... 61 
15 
INSTITUTIONAL REVIEW BOARD / ETHICS COMMITTEE ................................... 61 
16 
ETHICAL CONDUCT OF THE STUDY ........................................................................ 61 
17 
INFORMED CONSENT .................................................................................................. 62 
18 
CONFIDENTIALITY....................................................................................................... 62 
 
Confidentiality of Data ......................................................................................... 62 
 
Confidentiality of Subject Records ....................................................................... 62 
19 
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT ........................................ 62 
20 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................ 63 
21 
PUBLICATIONS .............................................................................................................. 63 
22 
REFERENCES ................................................................................................................. 64 
APPENDIX 1 - ADA DIABETIC DIET GUIDELINES ............................................................. 67 
APPENDIX 2 - THE NCEP DIETARY GUIDELINES .............................................................. 68 
 
LIST OF TABLES 
Table 1. 
Schedule of Activities ............................................................................................. 30 
Table 2. 
Safety Laboratory Tests .......................................................................................... 42 
 
 


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LIST OF ABBREVIATIONS  
ADA 
American Diabetes Association 
AE(s) 
Adverse event(s) 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase (SGPT) 
ANCOVA 
Analysis of covariance 
APRI 
Aspartate aminotransferase-to-platelet ratio index 
AST 
Aspartate transaminase (SGOT) 
AUC 
Area under the concentration-time curve 
AUC0-24 
Area under the concentration-time curve calculated over 
the dosing interval 
Β-hCG 
Beta human Chorionic Gonadotropin 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CHF 
Congestive Heart Failure 
CK-18 
Cytokeratin-18 
Cmax 
Maximum plasma concentration 
CRN 
Clinical Research Network 
CPRU 
Clinical Pharmacology Research Unit, Investigational 
Site 
(e)CRF 
(electronic) Case Report Form 
CRO 
Contract Research Organization 
CTX 
C-terminal telopeptide 
DM 
Diabetes Mellitus 
DBP 
Diastolic Blood Pressure 
DPP4 
Dipeptidyl peptidase-4 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ELF 
Enhanced liver fibrosis score 
FFA 
Free fatty acids 
FIB-4 
Fibrosis 4 score 
FPG 
Fasting Plasma Glucose 
FSH 
Follicle-stimulating hormone 


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GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
GLP 
Good Laboratory Practices 
GLP-1 
Glucagon-like peptide-1 
HA 
Hyaluronic acid 
hERG 
Human ether-a-go-go 
HbA1c 
Glycosylated hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HEENT 
Head Ears Eyes Nose and Throat 
HIV 
Human Immunodeficiency Virus 
HMW 
High molecular weight 
HOMA-IR 
Homeostasis model assessment-insulin resistance 
hsCRP  
High-sensitivity C-reactive protein 
HR 
Heart Rate 
IATA 
International Air Transport Association  
IC20 
Inhibitory Concentration 20% 
ICH 
International Conference on Harmonization  
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IXRS 
Interactive Response System 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
miRNA 
Micro RNA 
MedDRA 
Medical Dictionary for Regulatory Authorities 
MELD 
Model for End-Stage Liver Disease 
MRS 
Magnetic resonance spectroscopy 
MSDC 
Metabolic Solutions Development Company 
mTOR 
Mechanistic Target of Rapamycin 
mTOT 
Mitochondrial Target Of the Thiazolidinediones 
NAFLD 
Non-alcoholic fatty liver disease 
NAS 
Non-alcoholic fatty liver disease (NAFLD) activity score  
(Sum of scores for steatosis, lobular inflammation and 


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ballooning, ranging from 0 to 8) 
NASH 
Non-alcoholic steatohepatitis 
NMR 
Nuclear magnetic resonance 
NOAEL 
No-Observable Adverse Effect Level 
OTC 
Over the counter 
PIIINP 
Amino-terminal peptide of type III collagen 
PD 
Pharmacodynamic 
PI 
Principal Investigator 
PIC 
Powder in Capsule 
PK 
Pharmacokinetic 
PNPLA3 
Patatin-like phospholipase domain-containing protein 3 
PP 
Per Protocol 
PPARγ 
Peroxisome proliferator-activated receptor gamma 
Pro-C3 
N-terminal type III collagen propeptide 
PT 
Prothrombin Time 
PTCA 
Percutaneous Transluminal Coronary Angioplasty 
QTc 
Corrected QT interval 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SGLT2 
Sodium-glucose linked transporter member 2 
T2DM 
Type 2 diabetes mellitus 
TB 
Total bilirubin 
TEAEs 
Treatment emergent adverse events 
TG 
Triglycerides 
TIMP-1 
Tissue inhibitor of metalloproteinases 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 


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1 STUDY ADMINISTRATION STRUCTURE 
 
Medical Monitors 
Bill Welder, MD 
Chiltern International Inc. 
Phone:  +1 (423) 990-0471 
 
Chief Medical Officer and After Hours Medical Monitor: 
Howard C Dittrich, MD 
Cirius Therapeutics, Inc. 
Phone:  +1 (858) 333-6274, ext. 508 
 
SAE Reporting Contact Information 
Serious adverse events (SAEs) should be reported by completing the AE eCRF in the EDC 
system and completing and submitting the SAE report form by e-mail 
(GlobalSAEInbox@chiltern.com) or by fax (1-888-726-8416) within 24 hours after the 
Investigator becomes aware of their occurrence.  Section 9.1.7 contains details regarding 
reporting of SAEs. 
2 BACKGROUND AND RATIONALE FOR THE STUDY  
 
Background 
MSDC-0602K is a novel insulin sensitizer that interacts with a newly identified mitochondrial 
target (mTOT, mitochondrial Target Of the Thiazolidinediones), while sparing direct activation 
of the PPARγ receptor believed to be associated with side effects of volume expansion and weight 
gain related to the first generation of insulin sensitizers which were marketed as PPARγ agonists 
(1-3).  As an mTOT modulating insulin sensitizer, MSDC-0602K has a favorable 
pharmacological profile to treat fatty liver disease including non-alcoholic steatohepatitis 
(NASH).  The effects of MSDC-0602K have been evaluated in two animal models of fatty liver 
disease.  In the first model, C57B1/6J mice were fed a diet providing 60% of its calories as fat for 
10 weeks (C57 DIO mice) and then administered a high fat diet containing either no drug or 
MSDC-0602K 30 mg/kg for 2 to 4 weeks.  Treatment of these mice resulted in a number of 
positive effects associated with the insulin-sensitizing pharmacology, including a complete 
clearance of fat from the liver once the high fat diet was removed.  Consistent with the proposed 
mechanism of action, MSDC-0602K treatment reduced the activation of mTOR in the liver and 
resulted in changes that favored lipid oxidation over lipid storage (4).  Since the C57 DIO mouse 
model does not develop liver lesions that are representative of NASH, similar studies were 
repeated in C57 mice fed a diet containing a high content of trans fat (40% of calories, mainly 
trans-oleic and trans-linoleic acids) together with cholesterol (2%) and fructose (22%).  This diet 
produces scarring of the liver and a liver pathology with ballooning that is characteristic of 
NASH.  Treatment of these mice with MSDC-0602K after 4 weeks of this diet through 16 weeks 
of age produced a significant reduction in the portal tract pathology even though the mice were 
retained on the diet throughout the 16 week period.  These data suggest that MSDC-0602K should 
be effective in the treatment of NASH. 


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Summary of Preclinical Safety of MSDC-0602 
 Safety Pharmacology 
MSDC-0602 did not induce adverse neurofunctional (5) or pulmonary effects (6) in rats at doses 
up to the limit dose of 2000 mg/kg/day.  In vitro, MSDC-0602 inhibited the hERG-mediated 
potassium current with an IC20 (unbound drug concentration) of 20.2 μM (7490 ng/mL). 
However, the hydroxymetabolite MSDC-0597 inhibited the hERG-mediated potassium current by 
only 7.62% at 33 µM (12,300 ng/mL), the highest concentration that could be tested based on 
solubility (7).  Given the high degree of binding of MSDC-0602 and MSDC-0597 to plasma 
proteins in humans (>98%) (8), free concentrations associated with hERG inhibition in vitro are 
unlikely to be achieved in vivo.  In the cardiovascular safety study in monkeys given up to the 
limit dose of 1000 mg/kg/day, no effects on heart rate, blood pressure, or ECG parameters 
including QT interval were noted (9). 
 Toxicology 
The nonclinical safety profile of non-micronized MSDC-0602 was evaluated in rats and monkeys 
given once daily oral doses for up to 28 days (10,11).  Pharmacokinetic studies of the micronized 
MSDC-0602 in the vehicle used in toxicology studies indicated that systemic exposures to both 
MSDC-0602 and MSDC-0597 were approximately 2.5-fold higher in rats and approximately 
6-fold higher in monkeys than after administration of non-micronized compound. Consequently, 
the nonclinical safety profile of micronized MSDC-0602 was also evaluated in mice, rats and 
monkeys given once daily oral doses for up to 15 days.  Subsequent pharmacokinetics studies 
demonstrated that even higher systemic exposure to both MSDC-0602 and MSDC-0597 was 
achieved following administration of MSDC-0602K (12,13).  Since MSDC-0602K was selected 
for continued development, the nonclinical safety profile of MSDC-0602K was also evaluated in 
mice, rats and monkeys in repeated dose studies up to 52 weeks.  
In 13-week studies, there were no MSDC-0602K-related deaths in mice given up to 
2000 mg/kg/day (14) or in monkeys given up to 1000 mg/kg/day for 13 weeks (15).  In the 
13-week study in rats, 2 females given 2000 mg/kg/day had drug-related deaths; the highest 
nonlethal dose was 300 mg/kg/day (16).  Decreases in red cell mass, and increases in liver and 
heart weight were observed in all 3 species; these effects were reversible.  In rodents, the organ 
weight increases were accompanied by hepatocellular and cardiac myofiber hypertrophy.  
Increased adipocytes were seen in bone marrow in all 3 species, but hematopoietic cells were 
unaffected.  Macrovesiculation of brown adipose tissue was noted in monkeys.  There was 
biochemical and ultrastructural evidence of peroxisome proliferation in rats but not in monkeys.  
The NOAEL in the primary toxicology species, rats and monkeys, were 30 and 100 mg/kg/day, 
respectively.  The mean combined-sex steady-state AUC0-24 of pharmacologically active species 
(MSDC-0602 + MSDC-0597) at the NOAEL was 1,040,000 ng·hr/mL in rats and 
549,000 ng·hr/mL in monkeys. 
The chronic toxicity of MSDC-0602K was evaluated in rats given up to 60 mg/kg/day for 
26 weeks (17) and in monkeys given up to 300 mg/kg/day for up to 52 weeks, including a 
26-week interim sacrifice group (18).  There were no MSDC-0602K-related deaths in rats treated 
for 26 weeks or in monkeys treated for up to 52 weeks.  Body weight and food consumption were 
increased in rats but not in monkeys.  Decreases in red cell mass were noted in both species.  


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Heart weights were increased in rats but there were no accompanying histopathologic or 
histomorphometric changes.  No effects on heart weight or histopathology or histomorphometry 
of the heart were observed in monkeys.  Echocardiographic examinations did not identify any 
drug-related changes in heart chamber size, systolic performance, or hemodynamics in monkeys 
after 26 or 52 weeks.  Liver weights were increased in monkeys but there were no associated 
histopathologic changes.  Increased adipocytes in bone marrow were seen in rats and monkeys but 
hematopoietic cells were unaffected in all but a few rats.  Macrovesiculation of intrascapular 
brown adipose tissue was observed in monkeys at ≥30 mg/kg/day.  Urothelial vacuolation in 
urinary bladder and/or renal pelvis was observed in monkeys at ≥30 mg/kg/day.  None of these 
changes were considered adverse.  Therefore, the NOAEL was 60 mg/kg/day in rats and 
300 mg/kg/day in monkeys.  The mean combined-sex steady-state AUC0-24 of pharmacologically 
active species (MSDC-0602 + MSDC-0597) at the NOAEL was 1,380,000 ng·hr/mL in rats and 
901,000 ng·hr/mL in monkeys. 
As described above, some findings typically observed with other insulin-sensitizing agents were 
observed in mice, rats, and monkeys given high doses of MSDC-0602 or MSDC-0602K in sub-
chronic studies.  However, in chronic studies with MSDC-0602K, findings similar to those of 
other insulin-sensitizing agents that were noted were not considered adverse based on the low 
magnitude of the changes and lack of adverse physiologic consequences.  Importantly, key effects 
such as edema, fluid volume expansion, body weight (in monkeys), pericardial/thoracic fluid 
accumulation, heart weight increase (in monkeys), fatty change in liver, adipose tissue 
proliferation, and effects in ovary and lymphoid tissue reported with other insulin-sensitizing 
agents were not observed in chronic studies in rats or monkeys at exposures 7 to 11 times those in 
humans given 250 mg doses of MSDC-0602K (free acid equivalents).  The diminished effects of 
MSDC-0602 and MSDC-0602K in toxicology studies completed to date may reflect a reduced 
ability to directly activate the nuclear transcription factor PPARγ, particularly at the lower dose 
levels evaluated, compared to typical PPARγ agonists.  This supposition is supported by recent 
evidence indicating that PPARγ activation is not necessary for insulin sensitization, but it is 
responsible for dose-limiting side effects of pioglitazone, including increased plasma volume (19, 
20). 
MSDC-0602 was not mutagenic in bacteria, was not clastogenic in human peripheral blood 
lymphocytes in vitro, and was not genotoxic in bone marrow of mice.  The hydroxymetabolite 
MSDC-0597 was also not mutagenic in bacteria. 
Two-year carcinogenicity studies in mice and rats with MSDC-0602K have been completed (21, 
22), and neoplastic findings were limited to an increased incidence of hemangiosarcoma in male 
mice at 100 mg/kg/day (only when compared to the upper range of historical control incidence) 
and an increased, albeit low incidence of transitional cell carcinoma in the urinary bladder in male 
rats at ≥10 mg/kg/day.  Published mechanistic studies with other compounds inducing similar 
tumors suggest that such tumors are not indicative of human risk (23-26). 
 
 


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Clinical Summary and Dose Selection 
 Early Clinical Data for MSDC-0602 
Three Phase 1 clinical studies in healthy volunteers have been completed (27-29).  Study MSDC-
0602-C001 evaluated the safety and pharmacokinetics of single and multiple doses of non-
micronized and micronized unformulated bulk drug given as powder in capsule (PIC).  Study 
MSDC-0602-C003 was a pharmacokinetics and relative bioavailability study of 100 mg and 
250 mg tablets made with micronized bulk drug that were administered at doses of 100 mg, 
250 mg, and 500 mg (2 x 250 mg tablets) in hard gelatin capsules.  The bioavailability was 
determined relative to micronized MSDC-0602 bulk drug powder in a gelatin capsule similar to 
what was dosed in Study MSDC-0602-C001.  Study MSDC-0602K-C004 was a 
pharmacokinetics and relative bioavailability study of 125 mg, 250 mg and 500 mg (2 x 250 mg 
tablets) (free acid equivalents) of MSDC-0602K tablets in hard gelatin capsules.  The 
bioavailability was determined relative to micronized MSDC-0602 free acid tablets (250 mg) in a 
gelatin capsule similar to what was dosed in Study MSDC-0602-C002. 
Two Phase 2 clinical studies in subjects with type 2 diabetes mellitus have been conducted (30, 
31).  MSDC-0602-C002, a completed Phase 2a study, was conducted to assess the efficacy and 
safety of once daily oral doses of micronized MSDC-0602 free acid compressed tablets at 100, 
250 and 500 mg in subjects with type 2 diabetes.  Daily treatment with MSDC-0602 250 mg and 
MSDC-0602 500 mg for 4 weeks resulted in clinically meaningful median reductions in fasting 
plasma glucose (FPG) from baseline that reached borderline statistical significance relative to 
placebo and were comparable in magnitude to those observed in a parallel group with 
pioglitazone 45 mg.  Treatment with MSDC-0602 500 mg resulted in a small, statistically 
significant mean reduction in HbA1c, and in statistically significant reductions in fasting plasma 
insulin and HOMA-IR when compared with placebo.  Overall male and female mean steady state 
Cmax of MSDC-0602 and MSDC-0597 for the 100, 250 and 500 mg doses were 2360, 4650 and 
7740 ng/mL, respectively, and overall male and female steady state AUC (0-24) of MSDC-0602 
and MSDC-0597 were 34,700, 80,100 and 112,000 ng∙hr/mL, respectively. 
MSDC-0602 treatment was safe and well tolerated. The incidences of treatment emergent adverse 
events (TEAEs) and drug-related TEAEs were similar among the treatment groups. There were no 
serious adverse events (SAEs) and no deaths during this study.  There were no clinically 
meaningful differences between the MSDC-0602 dose groups and placebo with respect to safety 
laboratory parameters, heart rate, physical examination results, ECG parameters, or edema. 
These data confirm that MSDC-0602 has insulin-sensitizing pharmacology similar to pioglitazone 
45 mg. The full insulin-sensitizing potential of MSDC-0602 will be further evaluated in larger 
clinical studies of longer duration. 
A pilot, three month mechanistic study is ongoing in type 2 diabetic subjects given once daily 
250 mg doses of MSDC-0602K (MSDC-0602K-C007UT).  Results from three subjects who have 
completed this study to date confirmed the ability of this treatment to increase insulin sensitivity 
in a hyperinsulinemic euglycemic glucose clamp (80 mU/m2/min Insulin) by 40% and also 
resulted in an average reduction in hemoglobin A1c of 1.4%.  There was also a 50% reduction in 
intramyocellular fat content in skeletal muscle and a similar reduction in hepatic fat. 


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 Rationale for Dose Selection  
The choice of doses that will be explored in the NASH Phase 2 dose ranging study with MSDC-
0602K have been established from an ongoing program connecting AUC to clinical results for 
MSDC-0602 (free acid, micronized acid, and eventually potassium salt), together with historical 
results using earlier generation compounds including pioglitazone and the prototype mTOT 
modulating insulin sensitizer, MSDC-0160 (also known as oxopioglitazone and Mitoglitazone). 
Clinical development in Phase 1 for MSDC-0602 began with the free acid as powder-in-capsule 
(PIC).  These studies showed that the target AUCs could not be easily achieved with free acid, but 
that adequate exposures could be reached with the micronized free acid (27-29).  A tablet 
formulation of the micronized free acid was developed for evaluation in the first Phase 2a trial.  
The Phase 2a trial then confirmed that the targeted AUCs would have anti-diabetic pharmacology 
similar to 45 mg pioglitazone with the reduced PPARγ side effects as predicted from the clinical 
comparison with the pilot compound, MSDC-0160 (20).  The micronized free acid of MSDC-
0602 was able to produce pharmacology similar to pioglitazone 45 mg in a 28 day study, again 
with less effect on body weight and adiponectin (30). 
The sodium and the potassium salts of MSDC-0602 were considered as possible replacements for 
the micronized free acid and both were compared in the cynomolgus monkey, which proved to be 
a good predictor of the kinetics in man.  The potassium (K) salt proved to be most effective (13).  
Therefore, the development program was shifted to the K salt for all long-term preclinical work 
and for subsequent clinical development.  The use of the K salt simplified the production of drug 
product, allowed much higher exposures in the preclinical models to expand the exploration of 
safety margins, and allows for lower tablet strengths for drug product.  A cross-over relative 
bioavailability study was conducted in normal volunteers to directly compare the pharmaco- 
kinetics for micronized free acid tablets that were used in the Phase 2a trial to the new 
formulation of MSDC-0602K tablets (29).  In contrast to the Phase 2a 250 mg micronized free 
acid tablet formulation that produced exposures of 101,000 ng.hr/ml and the 500 mg micronized 
free acid tablets that produced exposures from 126,000 to 151,000 ng.hr/ml, the 250 mg MSDC-
0602K tablet produced an AUC of over 130,000 ng.hr/ml.  These results suggest that 250 mg 
MSDC-0602K should be more than sufficient to produce the maximum insulin sensitizing 
pharmacology based on available data with this compound, as well as the prototype mTOT insulin 
sensitizer, MSDC-0160.  Importantly, exploring doses up to this exposure allows for a direct 
comparison to pioglitazone (45 mg), which along with its active metabolites achieves an AUC of 
60,000 ng.hr/ml.  Cusi demonstrated effective resolution of NASH with treatment of 45 mg/day 
of pioglitazone (32). 
To confirm that the 250 mg MSDC-0602K dose would produce significant insulin sensitizing 
pharmacology in man, a small, 3-month mechanistic study was conducted in 3 subjects with 
type 2 diabetes.  This dose was capable of producing a 1.4% reduction in hemoglobin A1c, a 40% 
improvement in insulin sensitivity, and a 50% reduction in intramyocellular lipids in skeletal 
muscle.  Measurement of hepatic lipid by MRS demonstrated a similar reduction in the one 
subject who has been evaluated for this parameter.  Therefore, the effects of MSDC-0602K are at 
least as large, if not larger, than what has ever been observed with 45 mg pioglitazone in such 
subjects (31,33). 


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In summary, the choice of doses that will be explored in the Phase 2 NASH dose-ranging study 
with MSDC-0602K, 62.5, 125 and 250 mg, have been established from an ongoing program 
connecting AUC to clinical results for MSDC-0602 (free acid, micronized acid, and eventually 
potassium salt) together with historical results using earlier generation compounds including 
pioglitazone and the prototype mTOT modulating insulin sensitizer, MSDC-0160.  An ongoing, 
small, 3-month mechanistic study of MSDC-0602K in 3 subjects with type 2 diabetes confirmed 
that the 250 mg MSDC-0602K dose would produce significant insulin sensitizing pharmacology 
in man.  The effects of MSDC-0602K are expected to be at least as significant as what was 
observed with 45 mg pioglitazone in such subjects.  Data available from the trial of Cusi (32) that 
evaluated the effects of 45 mg pioglitazone in subjects with NASH have been used to power this 
trial. 
All preclinical and clinical data regarding the development of MSDC-0602K are summarized in 
the MSDC-0602K Investigator’s Brochure. 
3 STUDY OBJECTIVES 
To assess the preliminary safety and efficacy of 3 doses of MSDC-0602K (62.5, 125, or 250 mg) 
as compared to placebo in subjects with non-alcoholic steatohepatitis (NASH). 
4 ENDPOINTS 
 
Safety 
Safety will be assessed by periodic measurement of vital signs, 12-lead electrocardiogram (ECG), 
physical examinations and the occurrence of adverse events (AEs).    Fasting blood samples for 
central lab analyses of clinical chemistries and hematology will be collected at each study visit 
(Screening and Study Visits 1-8).  Samples for urinalysis will be collected at Screening and all 
Study Visits except Visits 2 and 3.  
 
Efficacy 
 Primary Efficacy Endpoint  
Hepatic histological improvement in NAS defined as a decrease of at least 2 points with no  
worsening of fibrosis stage at 12 months.  The reduction in NAS must include at least a 1 point 
reduction in either ballooning or inflammation.  No worsening of fibrosis is defined as no increase 
in CRN fibrosis score.  
 Secondary Efficacy Endpoints  
1. Proportion of subjects with resolution of NASH with no worsening of fibrosis at 
12 months.  Resolution of NASH is defined as a ballooning score of 0 and an 
inflammation score of 0-1.  No worsening of fibrosis is defined as no increase in CRN 
fibrosis score.  
2. Proportion of subjects with improvement of fibrosis (CRN staging score) by at least 1 
stage with no worsening of NASH at 12 months. 
3. Mean change from baseline in NAFLD activity score (NAS) and each one of its 
components (steatosis, inflammation and ballooning) at 12 months. 


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4. Mean change from baseline in fibrosis score at 12 months. 
 Exploratory Efficacy Endpoints 
1. Mean change in liver stiffness as measured by transient elastography (FibroScan) (change 
from baseline relative to placebo at 12 months). 
2. Change from baseline relative to placebo for liver function tests (ALT, AST, ALP, GGT, 
bilirubin, albumin, PT and INR) at 6 and 12 months, and biomarkers and indirect 
measures of apoptosis and liver fibrosis (CK-18 [M30 and M65], Fibrosure, APRI, FIB-4 
index, Pro-C3 and ELF score and its individual components (HA, PIIINP, TIMP-1) at 12 
months. 
3. Changes from baseline relative to placebo in circulating inflammatory markers (HMW 
adiponectin, and hsCRP) and markers of bone metabolism (osteocalcin and serum CTX) at 
6 and 12 months.  
4. Changes from baseline relative to placebo in FFA, serum triglycerides and fasting 
cholesterol (total, HDL, LDL, VLDL) at 6 and 12 months and changes from baseline of 
NMR analysis of lipoprotein particle size at 12 months. 
5. Changes from baseline relative to placebo in markers of insulin sensitivity: HOMA-IR, 
HbA1c, fasting plasma glucose, and fasting insulin at 6 and 12 months.  
6. Changes from baseline relative to placebo on blood pressure (systolic and diastolic), heart 
rate, weight, and abdominal girth at 6 and 12 months. 
7. Changes from baseline relative to placebo at the 12 month endpoint in the pathologist’s 
general impression as to the three categories of diagnosis: 1) NASH, 2) Simple/isolated 
steatosis with no steatohepatitis (NASH), or 3) No fatty liver disease (no NAFLD). 
8. Changes from baseline relative to placebo in subjects with PNPLA3 variants and other 
genotypes. 
 
Pharmacokinetics 
Steady-state trough measurements will be made for MSDC-0602 and MSDC-0597 (a major 
metabolite) at Study Visits 2, 4, 5, 6, and 7 (Days 30, 90, 180, 270, 360). 
5 SUBJECT SELECTION 
Approximately 380 subjects will be randomized with the intent to have 340 subjects complete the 
12-month assessment (4 groups; approximately 85 subjects/group) at approximately 50 to 75 sites 
in the US.  Sites in other regions may be added.  Subjects who do not complete the study will not 
be replaced. 
 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
1. 
Adult subjects at least 18 years of age. 


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2. 
Histological evidence of NASH, based on biopsy, with a NAS (NASH CRN scoring) ≥ 4 
with a score of at least 1 in each component of NAS. 
3. 
Histological evidence of liver fibrosis defined as NASH CRN System fibrosis score of F1 
to F3.  
4. 
Qualifying liver biopsy must be within 9 months prior to or during Screening. If no usable 
liver biopsy is available within 9 months prior to Screening, a liver biopsy must be 
performed during Screening after the following criteria are confirmed: 
a. AST ≥ 20 U/L  
b. FibroScan with CAP score ≥ 270 db/m and kPa ≥ 8.5 
5. 
Subjects with type 2 diabetes mellitus (DM) must be under stable and reasonable control, 
defined as under a healthcare provider’s care for DM with glycosylated hemoglobin 
[HbA1c] ≤ 9.5%.  Subjects taking permitted anti-diabetic therapies (metformin, GLP-1 
agonists, SGLT2 inhibitors, sulfonylureas or DPP4 inhibitors) must be on stable doses for 
a period of at least 3 months prior to randomization.  Refer to Section 6.4 for additional 
clarification about the use of antidiabetics.   
6. 
Subjects taking Vitamin E must be on a stable dose (if ≥ 400 IU) for a period of at least 
3 months prior to randomization.  
7. 
Females must be either postmenopausal (at least 12 months since last menses) or 
surgically sterilized (bilateral tubal ligation, bilateral oopherectomy and/or hysterectomy) 
verified by a follicle-stimulating hormone (FSH) test result ≥40 mIU/mL.  Those with 
FSH < 40 or with bilateral tubal ligation must use a barrier method of birth control.  In 
addition, all females must have a negative pregnancy test at Screening and Day 1 
regardless of childbearing potential.  For postmenopausal women only, if FSH levels are 
above 40 mIU/mL and serum pregnancy results are indeterminant, the subject will be 
assessed as not pregnant. 
Males with female partners of child-bearing potential must agree to use adequate 
contraceptive methods (including a condom, plus one other form of contraception) if 
engaging in sexual intercourse. 
8. 
Body Mass Index (BMI) ≤ 50 kg/m2. 
9. 
Willing and able to sign an informed consent document indicating understanding of the 
purpose of and procedures required for the study and willingness to participate in the 
study. 
10. 
Willing and able to attend all study visits and undergo all protocol-specified procedures 
including liver biopsies at baseline and at the end of study treatment (one year). 
 
Subject Exclusion Criteria 
1. 
Known history of HIV. 
2. 
Prior liver transplantation. 


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3. 
Other well-documented causes of active chronic liver disease, including, but not restricted 
to: history of positive hepatitis B surface antigen (HBsAg) or HCV RNA (subjects must 
be viremia free for a minimum of 2 years), suspicion of drug-induced liver disease, 
alcoholic liver disease and auto-immune hepatitis, Wilson’s disease hemochromatosis, 
primary biliary cirrhosis, primary sclerosing cholangitis, genetic hemochromatosis, known 
or suspected HCC, history of planned liver transplant or current MELD score > 12.   
4. 
History of cirrhosis and/or hepatic decompensation including ascites, hepatic 
encephalopathy or variceal bleeding.  Platelet count < 100,000/µL of blood at Screening. 
5. 
AST or ALT >5 times the upper limit of normal at Screening.  
6. 
Total bilirubin > 1.8 mg/dL unless diagnosis of Gilbert’s disease or serum albumin 
< 2.5 gms/dL at Screening.   
7. 
INR ≥ 1.5 times ULN at Screening or other evidence of impaired coagulation. 
8. 
History of alcohol abuse or drug abuse within 6 months of Screening. 
9. 
Inability to safely obtain a liver biopsy. 
10. 
Current or history of Type 1 diabetes mellitus. 
11. 
Current or history of recent (≤ 6 months) use of ursodeoxycholic acid. 
12. 
Current use of any diabetes medications other than metformin, GLP-1 agonists, SGLT2 
inhibitors, sulfonylureas or DPP4 inhibitors three months prior to the baseline diagnostic 
liver biopsy or during the study unless as specified in the protocol.  Current use of insulin 
or PPARγ agonists (pioglitazone or rosiglitazone) is not allowed for the duration of the 
study. Refer to Section 6.4 for additional clarification about the use of antidiabetics. 
13. 
Use of concomitant medications with a known significant metabolism by CYP2C8 or 
CYP2C9 including paclitaxel, phenytoin, warfarin, celecoxib, tolbutamide, or replaglinide 
for the duration of the study. 
14. 
History of diabetic ketoacidosis or hyperosmolar non-ketotic coma within the 6 months 
prior to randomization. 
15. 
History of heart failure (including CHF) or previous cardiovascular event (acute coronary 
syndrome, myocardial infarction, coronary by-pass surgery, or catheter based coronary 
intervention) within the 6 months prior to randomization. 
16. 
Serum creatinine >2 mg/dL at Screening. 
17. 
Current or recurrent disease that may affect the action, absorption or disposition of the 
study treatment, or clinical or laboratory assessments. 
18. 
Current or history of severe or unstable disorder (medical or psychiatric) requiring 
treatment that may make the subject unlikely to complete the study. 
19. 
Blood pressure greater than 160/100 mmHg.  Subjects with elevated BP (but 
< 160/100 mmHg) with or without current treatment are allowed at the discretion of the 
Investigator and primary care physician.  Individuals with hypertension must have been 
stabilized to the current treatment regimen for at least 6 weeks prior to randomization. 


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20. 
Known or suspected intolerance or hypersensitivity to the study drugs, closely related 
compounds or any of their stated ingredients. 
21. 
Participation in an investigational study (other than a non-treatment registry study) or 
received an investigational drug within 30 days or 5 half-lives (whichever is longer) prior 
to randomization. 
22. 
Blood donation of 1 unit or more within 56 days of randomization. 
23. 
Plasmapheresis or plasma donation within 30 days of randomization. 
24. 
Single 12-lead ECG demonstrating a screening QTc > 450 msec in men and > 470 msec in 
women.  A single repeat ECG may be done at the Investigator’s discretion. 
25. 
Any surgical or medical condition which may significantly alter the absorption of the 
study drug including, but not limited to the following: history of major gastrointestinal 
tract surgery such as gastrectomy, gastroenterostomy, bowel resection, gastric bypass, 
gastric stapling, or gastric banding, currently active inflammatory bowel syndrome.  
Subjects with reversal of gastric sleeve or banding are allowed. 
26. 
Evidence of clinically relevant pathology that could interfere with the study results or put 
the patient’s safety at risk. 
27. 
Malignancy, including leukemia and lymphoma (excluding basal cell and squamous cell 
skin cancers and localized prostate cancer) not treated within the last 2 years. 
6 STUDY DESIGN 
 
Summary of Study Design 
This is a double-blind, randomized, placebo-controlled study of three oral dose levels of MSDC-
0602K.  Subjects will be screened for eligibility up to 42 days in advance of randomization 
(between Days -42 and -1).  Subjects will be randomized into 1 of 4 treatment groups based on a 
stratification criteria of presence Type 2 DM (Yes/No), use of Vitamin E ≥ 400 IU (Yes/No), and 
fibrosis score (F1 or ≥ F2) and will receive single daily doses of MSDC-0602K (62.5, 125 or 
250 mg), or placebo for one year (360 days).  Approximately 380 subjects will be randomized to 
achieve 85 completed subjects in each of the 4 treatment groups.  The number of subjects who 
have a fibrosis score of F1 will be no greater than 50% of each group in order to best inform the 
design of the Phase 3 clinical trial. 
• Male or female subjects with NASH and fibrosis should have an interpretable liver biopsy 
within 9 months prior to randomization and at the end of study treatment at Visit 7.  
Double-blind study drug will be dispensed for daily administration starting at Study 
Visit 1.  Subsequent study visits will occur on Days 30 (1 month), 60 (2 months), 90 
(3 months), 180 (6 months), 270 (9 months), 360 (12 months) and a 14-day follow-up visit 
on Day 374.  Subjects will self-administer study drug once daily throughout the treatment 
period through the Day 360 visit. Site personnel will contact subjects every month to 
inquire about safety, adverse events and serious adverse events. 
Blood samples will be collected for trough level assay of MSDC-0602 and major metabolite 
MSDC-0597 concentrations.  Fasting blood samples will also be collected for analysis of 


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biomarkers and for safety chemistry/hematology laboratory testing at all outpatient visits.  Urine 
samples will be collected for urinalysis quarterly throughout the study. 
Subjects will return to the clinic for a Follow-Up visit approximately 2 weeks after the final dose 
(Day 374, Visit 8) for blood sampling.  A complete physical examination will be performed at 
Screening and at the Follow-up visit on Day 374, and a limited physical examination will be 
performed at all other study visits. 
 Schedule of Activities 
A schedule of activities is provided in Table 1.


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Table 1. 
Schedule of Activities 
 Screen1 
Treatment 
Follow-up 
Visit Number 
 
1 
2 
3 
4 
5 
6 
7 
8 
Study Months 
 
Randomization 
1 
2 
3 
6 
9 
12 
 
Study Day -42 to -1 
1 
30 
60 
90 
180 
270 
360 
374 
Window 
 
N/A 
± 7 days 
± 3 days 
General Activities 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Complete Physical Examination2 
X 
 
 
 
 
 
 
 
X 
Limited Physical Examination2 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
X 
 
X 
X 
Pregnancy test (females only) 
X 
X 
 
 
 
 
 
 
X 
FSH (post-menopausal females only) 
X 
 
 
 
 
 
 
 
 
FibroScan4 
X 
 
 
 
 
 
 
X 
 
Liver Biopsy5 
X 
 
 
 
 
 
 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Dietary guidance and assessment of alcohol intake6 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event review  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
 
Monthly phone assessment7 
 
 
 
 
X 
X 
X 
 
 
Study drug dispensing8  
 
X 
 
 
X 
X 
X 
 
 
Central Lab Evaluations 
 
 
 
 
 
 
 
 
 
Hematology & serum chemistry 9, 10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver function tests 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
X 
 
 
X 
X 
X 
X 
X 
HMW adiponectin, hsCRP, CK-18 [M30 & M65], 
osteocalcin, and CTX 
 
X 
 
 
 
X 
 
X 
 
Fibrosure, ELF score, APRI, FIB-4 index, Pro-C3 
 
X 
 
 
 
X 
 
X 
 
Serum sample for NMR analysis 
 
X 
 
 
 
 
 
X 
 
Blood sample for genotyping analyses (optional)11 
 
X 
 
 
 
 
 
 
 
Plasma samples for future miRNA and biomarker 
testing12 
 
X 
 
 
 
X 
 
X 
 
Trough PK sample13 
 
 
X 
 
X 
X 
X 
X 
 
 
 


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1. 
ICF may be obtained before the 42-day screening window. Re-testing is allowed within the 42-day Screening period if, in the opinion of the Investigator, the subject may 
become eligible upon repeat testing  
2. 
Height and body weight are collected at Screening only; body weight, waist circumference measured midway between the lowest rib and the iliac crest, and signs of 
peripheral edema are collected at all study visits. 
3. 
Vital sign measurements including seated BP and heart rate are collected at every visit; oral temperature is collected at screening, pre-dose on Day 1 and Visit 8. 
4. 
FibroScan is required within 90 days prior to or during Screening.   
5. 
A qualifying liver biopsy is required within 9 months prior to Screening.  If a historical liver biopsy result is not available within this period, a liver biopsy must be performed 
during Screening for eligible subjects who meet all other entry criteria.  A liver biopsy is also performed at Visit 7. 
6. 
Non-diabetic subjects are provided the NCEP dietary guidance at Screening and diabetic subjects are provided the ADA dietary guidance at Screening.  Guidance regarding 
alcohol consumption is also provided to all subjects at Screening.  All subjects are assessed for compliance with dietary guidelines and alcohol consumption at each visit. 
7. 
Study staff will contact the subjects by phone every month between Visits 4-7 to inquire about adverse events and serious adverse events. 
8. 
3 bottles dispensed at Visits 1, 4, 5, and 6. 
9. 
Minimum 10-hour fasting blood sample collected pre-dose. 
10. FPG and HbA1c will also be measured at Visits 1, 5 and 7. 
11. A separate genotyping informed consent is required to enable collection of blood sample for genotyping analyses.   
12. At each timepoint, plasma samples will be split into two separate vials and stored for biomarker testing, including miRNA, to be determined at a later date. 
13. Pre-dose trough PK sample collected for analysis of MSDC-0602 and MSDC-0597. 


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Study Activities 
 Method of Assigning Subjects to Treatment 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be allocated 
centrally by an IXRS to one of the four treatment groups in a 1:1:1:1 allocation ratio, according to 
a central randomization scheme stratified by the presence of T2DM (Yes/No), use of Vitamin E ≥ 
400 IU (Yes/No), and fibrosis score (F1 or ≥ F2), each enrolled subject will be sequentially 
assigned the next available randomization number and be allotted the specified treatment 
corresponding to that randomization number. 
 Screening Period (Days -42 to -1) 
Prior to conducting any study-related procedures, written informed consent must be obtained from 
the subject.  Participation in this study is voluntary.  The nature of the study will be fully 
explained to each subject during the informed consent process and the subject will have the 
opportunity to ask questions.  An informed consent document will then be signed by the subject 
and the person performing the consent discussion, and retained by the Investigator.  A copy of the 
informed consent form will be given to the subject. Informed consent may be obtained before the 
42-day screening window.  
 
After obtaining a signed informed consent form, study site personnel will access the IXRS to 
assign a subject identification (ID) number to a potential study subject. This number will be used 
to identify the patient for the remainder of the study. Screening evaluations to determine subject 
eligibility will be conducted within 42 days prior to randomization (Day 1) in the study.  Subjects 
must fast for at least 10 hours prior to the following Screening procedures. 
• Medical history  
• Complete physical examination  
• Vital sign measurements 
• 12-lead ECG 
• Pregnancy test (serum, females only) 
• FSH (post-menopausal females only) 
• Transient elastography measure of liver fibrosis (FibroScan) within 90 days prior to or 
during Screening   
• Qualifying liver biopsy within 9 months prior to Screening.  If a usable liver biopsy is 
not available, a liver biopsy must be performed during Screening for eligible subjects 
who meet all other entry criteria after the following criteria are confirmed: 
a. AST ≥ 20 U/L 
b. FibroScan with CAP score ≥ 270 db/m and kPa ≥ 8.5 
• Documentation of any AEs 
• Assessment of alcohol use 


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• Provide and discuss the recommended standard of care diet program, the NCEP step 1 
diet for subjects who are not diabetic and the ADA diet recommended for subjects with 
diabetes (Appendix 2 and Appendix 1) 
• Clinical chemistry and hematology laboratory evaluations 
• Liver function tests  
• Urine sample for urinalysis 
• Concomitant medication review 
Re-testing is allowed within the 42-day Screening period if, in the opinion of the Investigator, the 
subject may become eligible upon repeat testing.  
Eligible subjects will be scheduled to return to the clinic for the start of the 12-month treatment 
period.  Male subjects will be advised to inform female partners of their participation in the study 
and to use adequate contraceptive methods (including a condom plus another form of 
contraception) if engaging in sexual intercourse with a woman who could become pregnant. 
 Study Visit 1  
Day 1 is the day of randomization, which is usually the day of the first dose of randomized study 
drug treatment.  
Continued eligibility based on exclusion criteria relating to safety and concomitant medications 
will be reassessed.  Eligible subjects will be instructed to report to the clinic for a study visit on 
Day 1 following a minimum 10-hour fast.  The following procedures will be performed for all 
subjects at Study Visit 1 (Day 1): 
• Limited physical examination  
• Vital sign measurements  
• Pregnancy test (dip-stick, females only) 
• Randomization 
• Assess compliance to diet (Y/N) and alcohol intake (Y/N) 
• Clinical chemistry and hematology laboratory evaluations 
• Liver function tests  
• HMW adiponectin, hsCRP, and CK-18 [M30 & M65], osteocalcin and serum CTX  
• Calculation of Fibrosure, APRI, FIB-4 index, ELF score and its indivudual components 
(TIMP-1, PIIINP and HA), and Pro-C3 
• NMR analysis of lipoprotein particle size  
• Genotyping analyses (provided subject has signed the ancillary informed consent for 
genotype testing, which is optional) 
• Future miRNA and additional biomarkers of interest testing 


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• Urine sample for urinalysis 
• Documentation of any AEs 
• Notation of any change in concomitant medication use 
• Study drug (3 bottles of 33 capsules from the assigned kit) will be dispensed  
 Study Visit 2, Month 1  
Subjects will be instructed to report to the clinic for a study visit on Day 30 following a minimum 
10-hour fast and without having taken their morning dose of study drug.  The following 
procedures will be performed for all subjects at Study Visit 2 (Day 30 ± 7 days): 
• Limited physical examination  
• Vital sign measurements  
• Assess compliance to diet (Y/N) and alcohol intake (Y/N) 
• Clinical chemistry and hematology laboratory evaluations 
• Liver function tests  
• Trough PK analysis of MSDC-0602 and MSDC-0597  
• Notation of any change in concomitant medication use 
• Documentation of any AEs 
 Study Visit 3, Month 2  
Subjects will be instructed to report to the clinic on Day 60 following a minimum 10-hour fast 
and without having taken their morning dose of study drug.  The following procedures will be 
performed for all subjects at Study Visit 3 (Day 60 ±7 days): 
• Limited physical examination 
• Vital sign measurements  
• Assess compliance to diet (Y/N) and alcohol intake (Y/N) 
• Clinical chemistry and hematology laboratory testing evaluations 
• Liver function tests  
• Documentation of any AEs 
• Notation of any change in concomitant medication use 
 Study Visit 4, Month 3  
Subjects will be instructed to report to the clinic on Day 90 following a minimum 10-hour fast 
and without having taken their morning dose of study drug.  Subjects should return the unused 
study drug.  The following procedures will be performed for all subjects at Study Visit 2 (Day 90 
±7 days): 


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• Limited physical examination  
• Vital sign measurements  
• Assess compliance to diet (Y/N) and alcohol intake (Y/N) 
• Clinical chemistry and hematology laboratory evalations 
• Liver function tests  
• Urine sample for urinalysis 
• Trough PK analysis of MSDC-0602 and MSDC-0597  
• Documentation of any AEs 
• Notation of any change in concomitant medication use 
• Monthly phone calls to inquire about adverse events and serious adverse events  
• Study drug (3 bottles of 33 capsules from the assigned kits) will be dispensed  
 Study Visit 5, Month 6  
Subjects will be instructed to report to the CPRU for an outpatient study visit on the morning of 
Day 180 following a minimum 10-hour fast and without having taken their morning dose of study 
drug.  Subjects should return the unused study drug.  The following procedures will be performed 
for all subjects at Study Visit 5 (Day 180 ±7 days): 
• Limited physical examination  
• Vital sign measurements  
• 12-lead ECG  
• Assess compliance to diet (Y/N) and alcohol intake (Y/N) 
• Clinical chemistry and hematology laboratory evaluations  
• Liver function tests  
• Urine sample for urinalysis 
• HMW adiponectin, hsCRP, and CK-18 [M30 & M65], osteocalcin and serum CTX  
• Calculation of Fibrosure, APRI, FIB-4 index, ELF score and its indivudual components 
(TIMP-1, PIIINP and HA), and Pro-C3 
• Future miRNA and additional biomarkers of interest testing  
• Trough PK analysis of MSDC-0602 and MSDC-0597  
• Notation of any change in concomitant medication use 
• Documentation of any AEs 
• Monthly phone calls to inquire about adverse events and serious adverse events  
• Study drug (3 bottles of 33 capsules from the assigned kits) will be dispensed  


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 Study Visit 6, Month 9  
Subjects will be instructed to report to the clinic on the morning of Day 270 following a minimum 
10-hour fast and without having taken their morning dose of study drug.  Subjects should return 
the unused study drug.  The following procedures will be performed for all subjects at Study 
Visit 6 (Day 270 ±7 days): 
• Limited physical examination 
• Vital sign measurements  
• Assess compliance to diet (Y/N) and alcohol intake (Y/N) 
• Blood sample for clinical chemistry and hematology laboratory testing  
• Liver function tests  
• Blood sample for trough PK analysis of MSDC-0602 and MSDC-0597  
• Urine sample for urinalysis 
• Monthly phone calls to inquire about adverse events and serious adverse events  
• Notation of any change in concomitant medication use 
• Documentation of any AEs 
• Study drug (3 bottles of 33 capsules from the assigned kits) will be dispensed  
 Study Visit 7, Month 12  
Subjects will be instructed to report to the clinic on the morning of Day 360 following a minimum 
10-hour fast before taking their morning dose of study drug.  Subjects should return the unused 
study drug.  The following procedures will be performed for all subjects at Study Visit 7 
(Day 360 ± 7 days): 
• Limited physical examination  
• Vital sign measurements  
• 12-lead ECG  
• Assess compliance to diet (Y/N) and alcohol intake (Y/N) 
• Transient elastography of liver fibrosis (FibroScan)  
• Liver biopsy   
• Clinical chemistry and hematology laboratory testing  
• Liver function tests  
• Urine sample for urinalysis 
• HMW adiponectin, hsCRP, CK-18 [M30 & M65], osteocalcin and serum CTX  


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• Calculation of Fibrosure, ELF score, and its individual components (HA, PIIINP, 
TIMP-1), APRI, FIB-4 index, and Pro-C3 
• NMR analysis of lipoprotein particle size  
• Future miRNA and additional biomarkers of interest testing 
• Trough PK analysis of MSDC-0602 and MSDC-0597 
• Notation of any change in concomitant medication use 
• Documentation of any AEs 
 Study Visit 8, Day 374 (Follow-Up Visit) 
The following procedures will be performed for all subjects at the Follow-Up Visit (Study Visit 8, 
Day 374 ±3 days): 
• Complete physical examination 
• Vital sign measurements  
• 12-lead ECG 
• Pregnancy Test (females only) 
• Clinical chemistry and hematology laboratory evaluations 
• Urine sample for urinalysis 
• Documentation of any AEs 
 Additional Follow-Up Visits 
In the event of an AE that has not resolved by the follow-up visit, additional follow-up visits may 
be scheduled until the event resolves or is deemed to be a permanently continuing event.  At the 
Investigator’s discretion, minor AEs may be followed until resolution via a telephone contact.   
 
Discontinuation of Study Drug and Study Termination 
Subjects are free to discontinue participation in the study at any time and for any reason without 
prejudice to future medical care; however, prior to randomization, it should be made clear to 
potential subjects that early withdrawal from the study including loss to follow up can be 
extremely damaging to the scientific research and may pose some risk to the subject.  If a subject 
withdraws consent to be treated with study drug prior to receiving any dose of study drug, the 
subject should be discontinued from the study.  Once a subject has been randomized, the 
investigator will make every reasonable effort to keep the subject in the study.  
 
Subjects may withdraw from study for the following reasons: 
 
• Withdrawal of informed consent:  A subject should be considered to have withdrawn 
consent when the subject no longer wishes to participate in any aspect of the study, and 


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does not want any further assessments, visits, or contact.  A subject’s refusal to participate 
in specific aspects of the study, such as a refusal to continue taking study drug or to 
provide blood samples, will NOT constitute withdrawal of consent. Investigators should 
make every effort to facilitate the subject’s continued participation in remaining aspects of 
the study.   
• Subject is lost to follow-up:  A subject will not be considered lost to follow-up until just 
prior to database lock and after all efforts to contact the subject have been exhausted. 
 
If a subject withdraws from study for any reason above, vital status as of Day 374 may be 
obtained through pubic registries as permitted by local regulations. 
 
Subjects who wish to withdraw consent from the study, to the extent possible, will undergo an 
End of Study evaluation equivalent to Visit 8 (Day 374) (see Table 1). 
The appropriate case report forms (eCRFs) should be completed, including an explanation as to 
why the subject participation in the study is being discontinued.  Subjects who do not complete 
the study will not be replaced.  
The Investigator and Cirius Therapeutics, Inc. have the right to discontinue study drug dosing 
from any subject in the event of an intercurrent illness, AE, protocol violation, or other reason 
including, but not limited to:  
• Need for any treatment not allowed by the protocol 
• Subject’s inability to comply with protocol-specified procedures 
• Sites with serious GCP or quality concerns 
• Adverse event that in the opinion of the Investigator requires discontinuation of study 
drugDevelopment of symptoms of CHF that in the opinion of the Investigator requires 
immediate treatment. 
 
Type 2 Diabetes Mellitus 
Refer to subject’s healthcare provider for diabetic care; however, note that no change in dose is 
allowed for GLP1 agonists or SGLT2 inhibitors during the study and these drugs cannot be added 
as rescue medications during the study if the subject had not been on a previous stable dose of 
either drug 3 months prior to randomization.  Use of PPARγ agonists (pioglitazone or 
rosiglitazone) or insulin are prohibited during the study. 
Subjects being treated with therapeutic agents for diabetes should be on stable dose(s) of the 
following antidiabetic medications at least 3 months prior to randomization and for the full 
duration of the trial: metformin, GLP1 agonists, SGLT2 inhibitors, sulfonylureas and DPP4 
inhibitors.   
If, during the study, a measurement of HbA1c exceeds 9.5% at two consecutive visits, the 
following suggested rescue approach may be followed: 
1. Start metformin or uptitrate metformin if the subject is already taking it 


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2. Start a DPP4 inhibitor or uptitrate the DPP4 inhibitor if the subject is already taking a 
DPP4 inhibitor 
3. Start careful titration of a sulfonylurea or titrate sulfonylurea if the subject is already 
taking it. 
If no reversible cause is identified or hyperglycemia persists despite counseling and all permitted 
co-therapies, subject should be discontinued from study drug, referred for treatment, and continue 
in the study and complete the required study visits. 
If a measurement of fasting plasma glucose (FPG) during the study is lower than 60 mg/dL, an 
alert will be sent to the investigational site and confirmatory FPG should be performed at the site 
within 7 days.  In case of a symptomatic hypoglycemic event and if the subject is on a 
sulfonylurea, the sulfonylurea dose should be reduced by 50% or discontinued.  Severe 
hypoglycemia is defined as any hypoglycemia requiring the assistance of a third party, 
hospitalization or associated with seizures or coma.  Refer to Section 9 Adverse Events for 
reporting instructions. 
 
Liver Function Tests 
If subjects demonstrate an increase in AST, ALT or total bilirubin (TB) greater than 2 times their 
baseline values (mean of Screening & Visit 1), there should be repeat tests of transaminases (AST 
and ALT), bilirubin, and physical exam performed within 48-72 hours.  If the levels then 
decrease, the subjects will be under close observation (repeat testing 2-3x weekly) until the levels 
return toward the individual's baseline values.  Should these levels continue to be elevated, the 
drug should be discontinued.   
Subjects should be discontinued for elevations of transaminases (AST or ALT) or TB above 
baseline associated with symptoms of right upper quadrant abdominal pain, fatigue, anorexia, 
nausea or vomiting, or eosinophilia.  Subjects should be discontinued for persistent (> 1 month) 
increases of AST and ALT and/or TB > 2 times baseline. 
Subjects may be rechallenged with study drug and closely monitored with repeat testing at least 
weekly.  Re-elevation of values after re-challenge necessitate permanent discontinuation of study 
drug (but continuation of study visits).   
If a new concomitant medication with known hepatotoxicity is started and liver function tests rise 
to meet the above criteria, the known hepatotoxin should be discontinued (replaced) if possible 
and liver function tests be followed in the same manner as outlined above.  If liver function tests 
remain elevated or increase further, then the study drug should be discontinued (and subjects 
should continue with the study. visits). 
 
PT/INR Tests 
If subjects demonstrate an increase in PT or INR > 2 times the baseline value (mean of Screening 
& Visit 1), repeat tests of PT or INR and eosinophil counts should be performed within 
approximately 48-72 hours.  If the PT or INR elevation is associated with changes in liver 
biochemistries, the subject should be followed closely per Investigator judgement with repeat 
testing at least weekly until levels return toward baseline values.  Subjects should be discontinued 


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from study drug (and continue with study visits) and be referred for treatment if they show signs 
of spontaneous, serious or persistent bleeding. 
7 STUDY PROCEDURES AND EVALUATIONS 
 
Vital Signs 
Vital signs will be measured at every study visit including Screening and Follow-Up visits .  Vital 
sign measurements will include blood pressure and heart rate, will be taken pre-dose. 
For all subjects, oral temperature (in degrees Celsius) will be measured at Screening and pre-dose 
on Day 1 (Study Visit 1) and at the Follow-up visit on Day 374 (Study Visit 8). 
 
Physical Examinations  
A complete physical examination will be performed at Screening and at the Follow-Up Visit 
(Day 374, Study Visit 8); a limited physical examination will be performed at all other study 
visits (Study Visits 1-7).  Information regarding body weight, waist circumference and assessment 
for the presence of edema will be collected at all study visits and height will be recorded only at 
Screening.  Subjects are to be weighed in similar attire without shoes on the same scale at each 
visit.  Measure waist circumference as follows: 
Locate the lowest rib and the iliac crest.  Place the tape measure evenly around the bare abdomen 
at the midpoint between the lowest rib and the iliac crest.  Read the tape measure and record the 
waist circumference in centimeters. 
The complete physical examination will be comprised of the following general categories of 
parameters: General Appearance, Dermatological, Head Ears Eyes Nose and Throat 
(HEENT)/Neck, Pulmonary, Cardiovascular, Gastro-Intestinal, Neurological, Extremities, 
Lymphatic, and Other.   
The limited physical examination will be comprised of at least the following categories of 
parameters: Pulmonary, Cardiovascular, and Extremities.  The presence or absence of edema will 
be recorded as “yes“ or “no“ at each complete and limited physical examination.  If “yes,“ a grade 
will be recorded for the edema.  Peripheral edema will be assessed as follows: 
Place your index finger over the participant's tibia, 10 cm above the lateral malleolus.  Exert 
pressure for 5 seconds.  Any depression that does not resume its original contour almost 
immediately is a sign of pitting edema.  Record if there is no edema observed.  The following 
scale should be used to grade any edema that is observed.   


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Grade 
Physical Characteristics 
1+ 
No visible change in shape of the extremity, pitting ≤ 2 mm, pit 
disappears rapidly 
2+ 
No marked change in the shape of the extremity, 2 mm < pitting ≤ 5 
mm, pit usually disappears in 10-15 seconds 
3+ 
Noticeably swollen extremity, 5 mm < pitting ≤ 10 mm, pit may 
persist for about a minute 
4+ 
Very swollen and distorted extremity, very deep pit > 10 mm, pit 
may persist 2 - 5 minutes 
 
Electrocardiograms 
Twelve-lead ECGs will be performed at Screening, Study Visit 5 (Day 180), Visit 7 (Day 360) 
and Visit 8 (Day 374).  The ECG obtained at the Screening visit will serve as the baseline 
measurement.  All scheduled ECGs will be performed after the subject has rested quietly for at 
least 10 minutes in a supine position.  The QT correction derived by the ECG machine or 
computed manually should be recorded. 
To ensure safety of the subjects, a qualified individual at the Investigator site will make 
comparisons with baseline measurements.  If the QTc is >60 msec from the baseline; or an 
absolute QTc value is >500 msec for any scheduled ECG, the ECG will be repeated 2 more times, 
approximately 2-4 minutes apart.   
If a machine-read QTc value is prolonged, as defined above, repeat measurements may not be 
necessary if a qualified physician’s interpretation determines that the QTc values are in the 
acceptable range. 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality such as readings of ischemia, T wave changes, 
or infarct. 
 
Laboratory Assessments 
For all subjects, blood samples for safety laboratory assessments will be drawn at every visit 
(Table 1).  All blood samples for clinical chemistry and hematology should be drawn in a fasted 
state (approximately 10 hours).  A certified central clinical laboratory will be used to perform all 
routine hematology, clinical chemistry and urinalysis.  Table 2 provides a summary of safety 
laboratory tests performed during the study. 
All clinical laboratory tests will be performed by the central laboratory specified in Form 
FDA 1572 Section 4.  The central laboratory reference ranges will be used.  Eligibility at 
screening will be based on central laboratory assessments.  


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Local laboratory assessments may be used to manage patient care during the conduct of the study 
(eg, routine care, unscheduled visits, urgent care).  Such laboratory data will not be entered into 
the study database and local laboratories will not be included on the FDA 1572 form.   
Table 2. 
Safety Laboratory Tests 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hemoglobin 
Albumin 
Bilirubin, Blood 
 
Hematocrit 
Alkaline phosphatase 
Glucose, Ketones, pH, 
creatinine, 
 
Platelets, RBC with 
indices 
ALT, AST, BUN, Bicarbonate 
Protein, Specific gravity 
Pregnancy testb,c  
FSHb,c 
WBC with differential 
Calcium, Chloride, Creatinine, Fasting 
Plasma Glucose, Fasting Insulin, FFA 
Microscopic exama 
 
hsCRP  
CK-18 [M30 & 
M65] 
HbA1c 
LDH, Phosphorus 
 
HMW adiponectin 
INR, PT 
Potassium, Sodium 
 
osteocalcin 
 
Gamma-glutamyl transpeptidase 
 
Serum CTX 
 
Total Bilirubin 
 
TIMP-1 
 
Total Protein, Uric acid 
 
PIIINP 
 
Cholesterol (total, HDL, LDL, VLDL) 
 
HA 
 
Triglycerides 
 
Pro-C3 
a Only if positive for blood or protein 
b Only at Screening (β-hCG), Day 1 (urine dipstick), and Day 374 (urine dipstick) 
c Females only.   
 
 


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Efficacy and Pharmacokinetic Assessments 
For all subjects, blood samples for pharmacologic (efficacy and safety) assessments will be drawn 
at all visits except Screening (Table 1).  All blood samples should be drawn in a fasted state 
(approximately 10 hours).  Instructions for collecting, processing, storing and shipping of blood 
samples for pharmacologic and pharmacokinetic analyses will be provided in the Laboratory 
Manual. 
Blood samples for trough PK analysis of MSDC-0602 and MSDC-0597 will be collected pre-dose 
at Study Visits 2, 4, 5, 6 and 7 (Days 30, 90, 180, 270 and 360).   
Blood samples for analysis of FPG and HbA1c will be collected at Screening. 
Blood samples for analysis of insulin, HOMA-IR, FPG, HbA1c, TG, FFA and fasting cholesterol 
(total, HDL, LDL, VLDL) will be collected as part of the standard chemistry profile at Study 
Visits 1, 5, and 7 (Days 1, 180 and 360).   
Blood samples for analysis of liver function tests (AST, ALT, bilirubin, PT/INR, ALP, GGT and 
albumin) will be collected at Study Visits 1, 2, 3, 4, 5, 6 and 7 (Days 1, 30, 60, 90, 180, 270 and 
360). 
Blood samples for analysis of HMW adiponectin, hsCRP, osteocalcin, serum CTX concentrations 
will be collected at Study Visits 1, 5, and 7 (Days 1, 180, and 360).  
Blood samples for biomarkers of liver apoptosis (CK-18 [M30 and M65]) will be collected at 
Visits 1, 5 and 7 (Days 1, 180, and 360), whereas blood samples for TIMP-1, PIIINP, HA will be 
collected at Visits 1 and 7 (Days 1 and 360). 
Serum samples for NMR analysis of lipoprotein particle size will be collected at Study Visits 1 
and 7 (Days 1 and 360).  
Blood samples will be collected at Visit 1 (Day 1) to be analyzed for genotyping.  
Plasma samples for future miRNA measurements and additional biomarkers of interest will be 
collected at Study Visits 1, 5 and 7 (Days 1, 180 and 360).   
Data obtained from the circulating liver function tests and other biomarkers will be used to 
calculate composite scores that may provide an indirect measure of changes in fibrosis from 
baseline to the 12 month endpoint (Days 1 and 360). 
It is estimated that approximately 226 mL of blood for the safety, pharmacokinetic, and 
pharmacodynamic parameters will be drawn from each subject who completes the trial. 
 
Transient elastography (FibroScan) measurement of liver fibrosis 
Vibration-Controlled Transient Elastography or FibroScan is a non-invasive methodology that 
assesses liver fibrosis/steatosis by measuring liver stiffness using ultrasonographic 
elastometry.  The measures are expressed in kilopascals (kPa) and db/m, and values increase with 
greater fibrosis/steatosis. FibroScan will be conducted at Days 1 and 360 using M or XL probe as 


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needed.  Averages of ten measurements for kPa and CAP scores will be recorded as suggested by 
the manufacturer for the baseline and end of study measurements. FibroScan values of CAP ≥ 
270 db/m and kPa ≥ 8.5 will be used to qualify subjects for liver biopsy if no historical liver 
biopsy is available.  
 
Liver Biopsies  
All subjects will have a liver biopsy at screening/baseline and at Visit 7. Qualifying liver biopsy 
must be within 9 months prior to Screening. If no usable liver biopsy is available within 9 months 
prior to Screening, a liver biopsy must be performed during Screening after the following criteria 
are confirmed: 
a. AST ≥ 20 U/L  
b. FibroScan with CAP score ≥ 270 db/m and kPa ≥ 8.5 
The primary clinical diagnosis to enter the study will be performed by a central clinical 
pathologist.  Slides/paraffin blocks will be shipped to the central laboratory where slides will be 
digitized using a Scanscope™ XT (Aperio Technologies, Inc.)  ultra-fast, high-capacity slide 
scanner. Digitized slides will be sent to a single expert histopathologist who is a member of the 
NASH Clinical Research Network.  The expert pathologist reader will provide individual scores 
for both NAS components and fibrosis scores.  
At the completion of the study, the liver biopsy slides at Visit 7 will be used for diagnosis by the 
local pathologist and then scanned, digitized and sent for blinded reading by the expert 
histopathologist. 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the 
biopsy, and the risks to the subject should not outweigh the potential benefits. 
The subject’s platelet count and PT (or INR) may be checked prior to the liver biopsy according 
to local standards.  Local guidelines and thresholds for hemostatic parameters should be used as 
they are in everyday clinical practice.  Usually a platelet count > 60,000/µL, a PT > 60% or 
longer by no more than 4 seconds over the control or INR < 1.3, and a normal bleeding time are 
acceptable for performing percutaneous liver biopsy in a subject that has stopped taking any 
antiaggregant therapy for > 5 days.  If these conditions are not all respected, a safer option would 
be to perform the liver biopsy by trans-jugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with 
caution in liver disease. 
The recommended biopsy procedure to be applied is: 
• Needle core biopsy 
• Biopsy obtained with a 16 or lower gauge needle 
• A tissue core ≥ 2 cm long (≥ 10 portal tracts) represents optimal biopsy length 


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• Preferably obtain biopsy from the right lobe.  If left lobe biopsy is used for inclusion, a left 
lobe biopsy should be used for future biopsies. 
Post-biopsy observation: It is recommended that the subject should remain in the hospital 
consistent with the standard of care of that institution.  
The biopsies will be sent to the central laboratory and then to a central reader who will read the 
biopsies to determine the eligibility to the study according to the fibrosis stage and consistency 
with NASH diagnosis.  Biopsy slides will be blinded for subject and visit identification prior to 
central reading. 
 
Concomitant Medications and Other Therapy 
For diabetic subjects, use of any diabetic medication other than metformin (generic or 
Glucophage®), GLP-1 agonists, SGLT2 inhibitors, sulfonylureas or DPP4 inhibitors 3 months 
prior to the diagnostic liver biopsy or during the study is prohibited.  Subjects on metformin, 
GLP1 agonists, SGLT2 inhibitors, sulfonylureas or DPP4 inhibitors must have been stabilized on 
their current dose for a period of 3 months prior to diagnostic liver biopsy and the doses should 
not be altered during the study except as provided in the rescue medication instructions 
(Section 6.4).   
Use of other prescription or over-the-counter (OTC) medications or herbal remedies is allowed 
during the study, as long as the subject has been stabilized on a dose for 6 weeks prior to study 
entry.  Antiaggregants are allowed but should be discontinued for at least 5 days prior to the liver 
biopsy.  Any concomitant medication taken during the study must be recorded in the eCRF.   
Use of ursodeoxycholic acid is prohibited as there is insufficient knowledge of its effects in this 
subject population.  
MSDC-0602K is metabolized to its hydroxymetabolite by a carbonyl reductase.  This is a 
ubiquitous enzyme and there is no prior evidence to indicate that any concomitant medications 
would interfere with this metabolism.  There is minimal interaction of MSDC-0602K or its 
metabolite with CYP P450 systems, either by direct inhibition or induction.  However, there is a 
potential for inhibition of CYP2C8 and CYP2C9 particularly with the active metabolite, which is 
the predominant moiety in circulation.  For these reasons, the following medications are also 
prohibited in this trial:  paclitaxel, phenytoin, warfarin, celecoxib, tolbutamide and repaglinide. 
 
Alcohol, Caffeine and Tobacco 
Use of alcohol should be consistent with Exclusion Criterion 5 (no substance abuse within the 
past 6 months).  If change in use of alcohol, caffeinated products or tobacco, as reported by the 
subject (not solicited by site at each visit), results in an adverse event, note this change in event 
term (e.g., headache from caffeine reduction, jittery from quitting or reducing tobacco use).   
 Physical Activity 
Subjects will abstain from strenuous exercise other than normal activity (e.g., heavy lifting, 
weight training, calisthenics, or aerobics) for 48 hours prior to each blood collection for clinical 
laboratory tests.  Walking at a normal pace will be permitted. 


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 Dietary Guidance 
Beginning at Visit 1, subjects who are not diabetics will be counseled to follow the NCEP Step 1 
diet (Appendix 2).  Subjects who are diabetic who have been following a diet consistent with 
ADA recommendations for type 2 diabetics (Appendix 1) should be counseled to continue that 
diet.  
 Meals and Fluid Intake 
Subjects must abstain from all food and drink (except water) at least 10 hours prior to any safety 
laboratory evaluations and 10 hours prior to the start of PK sample collections.  
 Contraception 
Only females who are postmenopausal (verified by FSH) or are surgically sterilized (bilateral 
tubal ligation, bilateral oophorectomy and/or hysterectomy) will be included in the study 
population; those with bilateral tubal ligation must use a barrier method of birth control during the 
study.  Male subjects must use a condom, plus another form of contraception (e.g., spermicide, 
intrauterine device, birth control pills taken by female partner, diaphragm with spermicide) if 
engaging in sexual intercourse with a woman who could become pregnant.  Male subjects must 
also be willing to abstain from sexual intercourse or use a condom during sexual intercourse with 
pregnant or lactating females.  Male subjects must adhere to these contraceptive criteria from 
administration of study drug through the follow up visit on Day 374. 
 Premature Termination of Study/Closure of Site 
The study may be terminated prematurely if new toxicological findings, or results affecting the 
safety of the subjects, become available.  The sponsor reserves the right to terminate the study at 
any time for any reason. 
A site may be closed based on issues identified with subject recruitment, GCP compliance, poor 
quality data, evidence of attempted or proven fraud, or for any reason at the sponsor’s discretion. 
In the event the sponsor prematurely terminates a particular study site, the site staff will promptly 
notify the Institutional Review Board (IRB). 
8 STUDY DRUG 
 
Investigational and Control Drugs 
The sponsor will provide the following double blind study drugs: 
• MSDC-0602K 62.5 mg capsules  
• MSDC-0602K 125 mg capsules  
• MSDC-0602K 250 mg capsules  
• Matching Placebo #00 capsules 
MSDC-0602K Tablets were manufactured by USV Limited, Daman, India.  MSDC-0602K 
Capsules and Placebo Capsules were prepared, packaged and labeled by TEAM Pharmaceuticals, 
Kalamazoo, Michigan.  All medication will be over-encapsulated in matching opaque capsules 


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and supplied to the Investigator as double-blind study drug in high-density polyethylene bottles 
(HDPE) with child resistant caps.  Each bottle will contain medication for 31 days + 2 additional 
days of treatment.  Three bottles/kit will be assigned and dispensed to each subject at each of 
Visits 1, 4, 5 and 6. Medication labels will include storage conditions for the drug and the 
subject’s initials. 
 
Treatments 
At Visit 1 (Day 1), all eligible subjects will be equally randomized to one of the 4 treatment arms 
listed below:  
• MSDC-0602K 62.5 mg capsules 
• MSDC-0602K 125 mg capsules  
• MSDC-0602K 250 mg capsules  
• Matching Placebo #00 capsules  
 
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee will generate the randomization schedule.  
All randomization information will be stored in a secured area, accessible only by authorized 
personnel. 
 
Study Drug Blinding 
The study is double-blind in that neither the subjects nor the Investigator will be aware of the 
treatment or dose administered.  Blinding will be maintained throughout the study by use of 
active and placebo capsules of similar appearance.  The series of random numbers from which the 
randomization algorithm operates will be created by personnel who will have no other 
involvement with analysis or statistical decision making for the study.  The random number series 
will be sequestered from all blinded study personnel, assuring there will be no unblinding 
information available to them until the study completes. 
 
Study Drug Assignment and Dispensing Procedures  
At Visit 1 (Day 1), subjects who fulfill all the inclusion/exclusion criteria will be randomized to 
one of the 4 treatment arms using a stratification criterion based on presence of T2DM (Yes/No), 
use of Vitamin E ≥ 400 IU (Yes/No) and fibrosis score (F1 or F≥2).  The Investigator or his/her 
delegate will confirm that the subject fulfills all the inclusion/exclusion criteria prior to 
randomization.  Treatment will be comprised of a 360-day double-blind period, followed by a 14-
day safety follow-up period. Each subject is uniquely identified in the study by a combination of 
his/her center number and subject number.  Only the assigned subject number should be entered 
in the field labeled “subject ID” on the electronic data capture (EDC) form.  Once assigned to a 
subject, the subject number will not be reused. 
Subjects, Investigator staff, and persons performing the assessments will remain blinded to the 
identity of the treatment from the time of randomization until database lock, using the following 
methods: 


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1. Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the conduct of the study (except for emergency 
unblinding as noted in Section 8.9). 
2. The identity of the treatments will be concealed by the use of study drugs that are identical 
in packaging, labeling, and schedule of administration, appearance, taste and odor. 
Data analysts, who are not directly involved with data management and monitoring of the trial, 
will remain blinded to individual treatment assignments until the interim analysis (see 
Section 11.3.4); an unblinded statistician may monitor the randomization process during the trial. 
The Interactive Response System (IXRS) will maintain a record that identifies each subject and 
the treatment/study drug of an individual subject’s treatment assignment. Unblinding of all 
subjects’ treatment assignments will occur at the conclusion of the trial following final database 
lock. 
 Dispensing the Study Drug  
Each study site will be supplied by Sponsor or Designee with study drug in identically appearing 
packaging.  The clinical supplies will be packaged and labeled in a double blind fashion.  
Medication will be supplied to the site in kits (containing 3 bottles per kit) for each subject.  Each 
bottle will contain medication for 31 days + 2 additional days of treatment, and will have a total 
of 33 capsules per bottle.  Three bottles will be packaged in a kit.  A three bottle kit will be 
dispensed to subjects at Visits 1, 4, 5, and 6.  Instructions will be provided in order to advise the 
site on the proper method of randomizing the subject and selecting the correct medication ID 
numbered kit/bottles for dispensing to a given subject at a specific visit.  Sites will be resupplied 
additional kits as supplies diminish.   
On Day 1, site personnel will administer the first dose of drug with approximately 240 mL of 
water following a minimum 10-hour overnight fast.  The study drug kit will then be dispensed to 
the subject (1 kit containing 3 bottles each that will be dispensed at Visits 1, 4, 5 and 6).  Subjects 
will be instructed to self-administer study drug once daily in the morning at least 30 minutes 
before the morning meal.  They will be instructed to swallow the drug whole and not to chew or 
open the contents of the capsule.   
One component of the packaging (kit) has a 2-part label.  Each part of this label contains a 
medication ID number that will correspond to one of the treatment arms.  Investigator staff will be 
informed which study drug package to dispense to the subject by contacting and obtaining the 
medication number via IXRS.  Immediately before dispensing study drug to the subject, 
Investigator staff will detach the outer part of the label from the kits and affix them to the source 
document (Drug Label Form). 
 
Study Drug Interruptions 
Treatment interruptions should be avoided.  A drug interruption occurring at any time during any 
period will be considered a protocol deviation.  An occasional missed tablet is not considered 
treatment interruption.  All changes will be recorded in the study records. 


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Compliance 
Treatment compliance will be assessed using capsule counts conducted at Visits 4, 5, 6, and 7.     
 
Study Drug Supply, Storage and Tracking  
Study drugs must be received by a designated person at the study site, handled and stored safely 
and properly, and kept in a secured location to which only the Investigator and designated site 
staff  have access.  Upon receipt, all study drugs should be stored according to the instructions 
specified on the drug labels.  Study drug must be kept in a secure cabinet or room with access 
restricted to only necessary study site personnel until it is used. Unused medication may be 
destroyed onsite with sponsor’s approval or returned to the sponsor or designee for destruction.  
Clinical supplies are to be dispensed only in accordance with the protocol. 
Medication labels will comply with the legal requirements of the U.S.  They will include storage 
conditions for the drug, but no information about the subject.  The Investigator must maintain an 
accurate record of the receipt of shipments and dispensing of study drug in a drug accountability 
ledger.  Monitoring of drug accountability will be performed by the monitor during site visits and 
at the completion of the trial.  
At the conclusion of the study, and as appropriate during the course of the study, the Investigator 
will return all used and unused study drug to the Sponsor or designee. 
 
Emergency Unblinding   
Unblinding is restricted to emergency situations and should be used only under circumstances 
where knowledge of the treatment is necessary for the proper management of the subject.  When 
possible, the investigator should attempt to contact the medical monitor at Sponsor or designee 
before unblinding a subject’s treatment assignment. The randomization code can only be broken 
if an emergency situation arises that, in the Investigator’s opinion, requires knowledge of the drug 
product dosed for management of the emergency medical condition. To unblind a subject’s 
treatment assignment, the investigator will access the unblinding module within the interactive 
response system.  Instructions for breaking the blind will be provided to the site.  Unless 
discontinued for a safety reason, study drug may be continued following unblinding of the 
subject’s treatment assignment. 
Copies of the randomization code will be made available to the analytical laboratory performing 
the PK analysis of plasma samples at the end of the study.   
9 ADVERSE EVENTS 
 
Adverse Events 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
subject using concise medical terminology.  In addition, each subject will be questioned, in a non-
directed manner about AEs at times specified in Table 1. 
The AE reporting period for this trial begins upon signing of the informed consent form and ends 
at the final study visit (Visit 8). 


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All AEs that occur in subjects during the AE reporting period specified in the protocol, whether 
reported in response to a query, observed by site personnel, or reported spontaneously by the 
subject, must be recorded on the eCRF in the EDC system regardless of whether or not the event 
is considered medication related.  Information to be collected and reported includes severity of the 
AE, relationship to study drug, duration of the AE, the treatment the subject is receiving at the 
time of the AE, and the outcome of the AE.  The Investigator should attempt, if possible, to 
establish a diagnosis.  For any AE which remains unresolved after completion of the study, the 
Investigator is responsible for following the AE to resolution or until a reasonable explanation for 
its persistence is found.  In addition, any known untoward event that occurs subsequent to the 
adverse event reporting period that the Investigator assesses as possibly related to the 
investigational medication/product should also be reported as an adverse event.  
 Adverse Event Definitions 
An AE is any untoward medical occurrence in a subject or trial subject that is administered a drug 
or biologic (medicinal product) or that is using a medical device; the event does not necessarily 
have a causal relationship with that treatment or usage.  Adverse events include the following: 
• All suspected adverse reactions 
• All reactions from overdose, abuse, withdrawal, sensitivity, or toxicity.   
• Apparently unrelated illnesses, including the worsening of a preexisting illness  
• Injury or accidents.  Note that if a medical condition is known to have caused the injury or 
accident (e.g., a fall secondary to dizziness or orthostasis), the medical condition 
(dizziness) and the accident (fall) should be reported as 2 separate adverse events.  The 
outcome of the accident (e.g., hip fracture secondary to the fall) should be recorded in 
source documents. 
• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat test). 
• Laboratory abnormalities that require clinical intervention or further investigation (beyond 
ordering a repeat test) unless they are associated with an already reported clinical event.  
Laboratory abnormalities associated with a clinical event (e.g., elevated liver enzymes in a 
subject with jaundice) should be captured in the source documents. 
Each adverse event is to be classified by the Investigator as serious or non-serious.  This 
classification of the gravity of the event determines the reporting procedures to be followed. 
 Serious Adverse Event Definition 
An AE that meets one or more of the following criteria/outcomes is classified as an SAE: 
• Death 
• Life-threatening (i.e., at immediate risk of death) 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity  
• Congenital anomaly/birth defect 
Important AEs that may not result in death, may not be life-threatening, or do not require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 


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may jeopardize the subject or subject may require medical or surgical intervention to prevent one 
of the outcomes listed above. 
Serious also includes any other event that the Investigator or sponsor company judges to be 
serious or which is defined as serious by the regulatory agency in the country in which the event 
occurred. 
A life-threatening AE is any AE that places the subject at immediate risk of death from the event 
as it occurred.  A life-threatening event does not include an event that might have caused death 
had it occurred in a more severe form but that did not create an immediate risk of death as it 
actually occurred.  For example, drug-induced hepatitis that resolved without evidence of hepatic 
failure would not be considered life threatening, even though drug-induced hepatitis of a more 
severe nature can be fatal. 
Hospitalization is to be considered only as an overnight admission with observation for a 
minimum of 24 hours.  Hospitalization or prolongation of a hospitalization is a criterion for 
considering an AE to be serious.  In the absence of an AE, the participating Investigator should 
not report hospitalization or prolongation of hospitalization as an SAE.  This is the case in the 
following situations: 
• Hospitalization or prolongation of hospitalization is needed for a procedure required by 
the protocol.  Day or night survey visits for biopsy or surgery required by the protocol are 
not considered serious. 
• Hospitalization or prolongation of hospitalization is part of a routine procedure followed 
by the study site (e.g., stent removal after surgery).  This should be recorded in the study 
file. 
• Hospitalization for survey visits or annual physicals fall in the same category. 
In addition, a hospitalization planned before the start of the study for a preexisting condition that 
has not worsened does not constitute an SAE (e.g., elective hospitalization for a total knee 
replacement due to a pre-existing condition of osteoarthritis of the knee that has not worsened 
during the course of the study). 
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
If there is any doubt whether the information constitutes an AE or SAE, the information is to be 
treated as a SAE. 
 Pre-existing Condition Definition 
In this trial, a pre-existing condition (i.e., a disorder present before the AE reporting period started 
and noted on the pretreatment medical history/physical examination form) should not be reported 
as an AE unless the condition worsens or episodes increase in frequency during the adverse event 
reporting period. 


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 Procedures 
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not be 
reported as AEs.  However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an AE.  For example, an acute appendicitis that begins 
during the adverse event reporting period should be reported as the AE and the resulting 
appendectomy should be recorded in the source documents.  If a subject undergoes a surgical 
procedure that was planned prior to entry into the trial, and the surgery is not performed due to a 
worsening of a baseline (at the time of informed consent) condition, this should not be reported as 
an AE. 
 Grading of Adverse Event Severity 
If required on the AE CRFs, the Investigator will use the adjectives MILD, MODERATE, or 
SEVERE to describe the maximum intensity of the adverse event.  For purposes of consistency, 
these intensity grades are defined as follows: 
MILD  
Does not interfere with subject's usual function 
MODERATE Interferes to some extent with subject's usual function 
SEVERE 
Interferes significantly with subject's usual function 
Note the distinction between the gravity and the intensity of an AE.  Severe is a measure of 
intensity; thus, a severe reaction is not necessarily a serious reaction.  For example, a headache 
may be severe in intensity but would not be classified as serious unless it met one of the criteria 
for serious events listed above. 
 Relationship to Study Drug 
The causal relationship of the AE to study drug will be assessed by both the Investigator and the 
sponsor.  The following definitions will be used in assessment. 
• Probably Related: The AE follows a reasonable temporal sequence from the time of drug 
administration.  It follows a known response pattern to the study drug. The AE cannot be 
reasonably explained by other factors such as the subject’s clinical state, therapeutic 
interventions or concomitant drugs. 
• Possibly Related: The AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the subject’s 
clinical state, other therapeutic interventions or concomitant drugs. 
• Unrelated: An AE does not follow a reasonable temporal sequence from administration of 
the product or the AE is clearly related to other factors such as the subject’s clinical state, 
other therapeutic interventions or concomitant drugs administered to the subject. 
 Reporting Serious Adverse Events 
All SAEs, regardless of causal relationship, occurring from the time of signing the informed 
consent through the final study visit (Visit 8), must be reported within 24 hours after the 
Investigator becomes aware of the SAE.  SAEs will be reported by completing the AE eCRF in 
the EDC system. The SAE information must be entered into the eCRF within 24 hours.  Upon 


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completion of the eCRF, Chiltern Clinical Safety will be notified and receive the form 
electronically.  In addition, the clinical site is to report the SAE using a SAE report form. The 
contact information for submission of SAEs is as follows:    
E-mail:  GlobalSAEInbox@chiltern.com 
Facsimile:  1-888-726-8416 
Clinical safety personnel are available for SAE reporting on a 24-hour basis.  Reports are 
reviewed during normal business hours. The Investigator is required to submit SAE reports to the 
IRB/EC in accordance with local requirements.  
Follow-up information relating to an SAE must be updated in the EDC system and SAE form 
within 24 hours of awareness of the SAE. Chiltern Clinical Safety will be notified via email when 
the information has been updated in the EDC system.  
The subject should be observed and monitored carefully until the condition resolves or stabilizes. 
Any emergency event deemed related to study drug must be reported to the Chiltern Clinical 
Safety (within 24 hours of the site’s awareness of the event). 
All deaths are to be thoroughly investigated and reported.  Autopsy reports are to be obtained, if 
possible. 
In the rare event that the Investigator does not become aware of the occurrence of an SAE 
immediately (for example, if an outpatient trial subject initially seeks treatment elsewhere), the 
Investigator is to report the event within 24 hours after learning of it and document his/her first 
awareness of the AE. 
Any SAE brought to the attention of the Investigator after cessation of the investigational 
medication/product and considered to be caused, with a reasonable possibility, by the 
investigational product should be reported to Cirius Therapeutics, Inc. or its designee. 
The Sponsor and/or its Contract Research Organization (CRO) designee is responsible for 
reporting SAEs to all applicable regulatory agencies and the central ethics committees within the 
required timeline. 
The Investigators are responsible for submitting to their local Institutional Review Board (IRB) 
the required safety information including any safety alert letter received from the Sponsor as well 
as any SAEs occurring at their site. 
Exposure in Utero during Clinical Trials 
Any pregnancy diagnosed in a female subject or a male subject’s partner while receiving or 
within 30 days of discontinuing the investigational study drug, must be reported to Cirius 
Therapeutics, Inc. or its designee within 24 hours of learning of the pregnancy.  The Investigator 
should contact the SAE hotline and report information related to the pregnancy on an Exposure in 
Utero form provided by Cirius Therapeutics, Inc. or its designee.  If a female subject who is 


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enrolled in the study does become pregnant during the course of the study, the study drug will be 
discontinued immediately, and the subject will continue to be followed throughout the study. 
The Investigator is also responsible for a telephone contact with the subject to assess the outcome 
of the pregnancy.  These findings must be reported on the Exposure in Utero form and transmitted 
to Cirius Therapeutics, Inc. or its designee. 
10 STUDY DURATION 
The total duration of the study will be approximately 416 days; comprised of a Screening period 
of up to 42 days, maximum, a treatment period of 360 days and a 14-day follow-up period. 
11 STATISTICS 
This section outlines the statistical analysis strategy and procedures.  A separate statistical 
analysis plan (SAP) that details the statistical methods for the study will be finalized prior to any 
unblinded analysis of the study. 
 Sample Size and Power Calculations 
Each active treatment group will be compared with the placebo group at the two-sided 0.05 
significance level; 85 subjects per arm provides approximately 80% power to detect a difference 
in the proportions of subjects achieving the primary efficacy endpoint of 39.5% in any MSDC-
0602K group versus 20% response rate in the placebo group. These response rates are similar to 
effects reported after 18 months daily treatment with 45 mg pioglitazone (58% response) or 
placebo (17% response) in subjects with pre-diabetes or T2DM (32); after 96 weeks daily 
treatment with 30 mg pioglitazone (34% response) or placebo (19%) in non-diabetic adults with 
NASH in the PIVENS study (34); and in the GOLDEN study, after 52 weeks daily treatment with 
120 mg elafibranor (32% response) or placebo (21%) in the subset of NASH subjects with a 
baseline NAS ≥ 4 (35).  Assuming 10% of subjects will not complete the 12-month assessment 
due to early dropout, 380 subjects will be randomized to the study. 
 Analysis Set 
Final decisions regarding the assignment of subjects to analysis sets will be made during the 
Validity Review Meeting and documented in the Validity Review Report. Data from sites with 
serious GCP or quality concerns may be excluded from the analyses.  
Enrolled Set 
All subjects who signed informed consent. 
Modified Intent-to-Treat Analysis Set  
The modified Intent-to-Treat (mITT) analysis set includes all subjects who are randomized and 
who receive at least one dose of study drug. Pre-treatment baseline measures and post-baseline 
assessments through 14 days after the last dose of study drug will be included in the analyses.  
Subjects in the mITT will be analyzed as randomized regardless of treatment received.  This 
means that subjects who are randomized who receive the incorrect study drug (i.e., not the study 
drug to which they were randomized) will be analyzed for efficacy under mITT as in the 


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treatment group to which the subject was randomized.  The primary population for efficacy 
analyses is the mITT. 
Safety Analysis Set  
Safety analysis set (SAF) includes all subjects who are randomized and received at least one dose 
of study drug.  SAF will be used in the analyses of all safety endpoints.  Subjects will be included 
in the analyses according to the actual treatment they received.  If a subject incorrectly receives 
more than one dose of study drug, the subject will be analyzed in the treatment group 
corresponding to the highest dose received. Pre-treatment baseline measures and post-baseline 
assessments through 14 days after the last dose of study drug will be included in the analyses. 
Per-Protocol Analysis Set 
The per-protocol analysis set (PPS) includes all subjects in the mITT population without major 
protocol deviations.  Identification of all subjects in the PPS will be determined before the 
database lock and unblinding.   Post-baseline measures during follow-up periods where the 
subject was < 80% compliant with study drug dosing may be excluded from the PPS.  The PPS 
will be used as an additional sensitivity analysis for key efficacy endpoints.   
 Planned Methods of Analysis  
The principal analysis for the primary endpoint will employ the mITT analysis set and the per-
protocol approach will be considered supportive.  Safety analyses will be performed using the 
safety analysis set. 
Continuous variables will be summarized using mean, median, standard deviations, 25th and 75th 
percentiles, min, and max.  Categorical variables will be summarized using number and 
percentages.  All statistical tests and confidence intervals are two-sided unless otherwise stated. 
 Analysis of Key Study Endpoints 
 Efficacy Analysis 
Primary Endpoint 
The primary efficacy endpoint is hepatic histological improvement in NAS (NASH CRN 
scoring). A responder (subjects with hepatic histological improvement) is defined as having all of 
followings: 
(1) At least 2 point reduction in NAS at 12 months. The reduction in NAS must also include 
at least a 1 point reduction in either ballooning or inflammation. 
(2) No worsening of fibrosis, defined as no increase in CRN fibrosis score.  
Each MSDC-0602K dose group will be compared with the placebo group at the two-sided 0.05 
significance level. For each comparison, the null hypothesis is that there is no difference in 
response rates between the MSDC-0602K dose and placebo. The alternative hypothesis is that 
there is a difference in response rates between the MSDC-0602K dose and placebo.  The primary 
analysis of the primary efficacy endpoint will be performed in the mITT, with supportive analysis 


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in the PPS. The number and percentage of responders will be summarized by treatment group.  
The primary analysis will be conducted using observed data included in the analysis dataset.  
Sensitivity analyses will be conducted where missing values are multiply imputed, and where 
subjects with missing data will be treated as non-responders. Comparisons between each active 
treatment group and the placebo group will be evaluated using appropriate contrasts from a 
logistic regression model that includes adjustments for the randomization stratification factors 
(presence of diabetes mellitus, Vitamin E use ≥ 400 IU, and baseline fibrosis 1 versus ≥ 2) and 
baseline NAS. Model-adjusted odds ratios for each active dose group relative to placebo and their 
associated 95% confidence intervals (CIs) will be provided. In addition, stratification-adjusted 
differences in response rates between each active dose group and placebo and their associated 
95% CIs will be provided.  
Supportive analyses of the primary endpoint will include comparisons of each active dose group 
with placebo using Cochran-Mantel-Haenszel (CMH) tests adjusting for the randomization 
stratification factors. Sensitivity analysis for primary endpoint will be performed using a logistic 
regression model adjusting for treatment, gender, presence of diabetes mellitus, Vitamin E use ≥ 
400 IU, baseline fibrosis and baseline NAS.  Adjusted odds ratios relative to placebo and the 
corresponding 95% CIs and p-values will be provided.  
Further details will be provided in the SAP. 
 
Secondary Endpoints 
Primary analyses of the secondary efficacy endpoints will be conducted in the mITT with 
supportive analyses in the PPS. 
Proportion of subjects with resolution of NASH  
Resolution of NASH is defined as a ballooning score of 0 and an inflammation score of 0-1 
without worsening of fibrosis at month 12.  No worsening of fibrosis is defined as no increase in 
CRN fibrosis score.  
The incidence rate of resolution of NASH will be summarized by treatment group.  Each active 
treatment group will be compared to the placebo group using appropriate contrasts from a logistic 
regression model that includes adjustments for the randomization stratification factors and 
baseline NAS. Model-adjusted odds ratios for each active dose group relative to placebo and their 
associated 95% CIs will be provided.  In addition, stratification-adjusted rate differences and their 
associated 95% CIs will be provided.  Supportive analyses will include comparisons of each 
active dose group with placebo using Cochran-Mantel-Haenszel (CMH) tests adjusting for the 
randomization stratification factors.  A logistic regression model adjusting for treatment, gender, 
presence of diabetes mellitus, Vitamin E use ≥ 400 IU, baseline fibrosis and baseline NAS will be 
used as sensitivity analysis.  Adjusted odds ratios relative to placebo and the corresponding 95% 
CIs and p-values will be provided.   
Proportion of subjects with improvement of fibrosis by at least 1 stage with no worsening of 
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Reduction of fibrosis is measured by CRN staging score.  All subjects with CRN staging score ≥ 
1 decrease from baseline will be considered as responders. Worsening of NASH is defined as an 
increase of either ballooning or inflammation.  
The incidence rate of the responders will be summarized by treatment group.  Each active 
treatment group will be compared to the placebo group using appropriate contrasts from a logistic 
regression model that includes adjustment for the randomization stratification factors and baseline 
NAS. Adjusted odds ratios relative to placebo and their associated 95% CIs will be provided.  In 
addition, stratification-adjusted rate differences and their associated 95% CIs will be provided.  A 
logistic regression model adjusting for treatment, gender, presence of diabetes mellitus, baseline 
fibrosis and baseline NAS will be used as sensitivity analysis.  Adjusted odds ratios relative to 
placebo and the corresponding 95% CIs and p-values will be provided.   
Mean change from baseline in NAS and each one of its components (steatosis, inflammation 
and ballooning) at 12 months. 
For each of these outcomes separately, the change from baseline to 12 months will be analyzed 
using an Analysis of Covariance (ANCOVA) model with fixed terms for treatment, type 2 
diabetes, Vitamin E ≥ 400 IU, gender, fibrosis stage, baseline NAS and the baseline value of the 
component score where applicable.    Least square mean treatment differences relative to placebo 
and associated 95% CIs will be presented.   
Mean change from baseline in fibrosis score at 12 months 
Mean change in fibrosis score will be analyzed similarly as the mean change in NAS above.   
Exploratory Endpoints 
For change from baseline endpoints, the mean change will be summarized by treatment groups at 
each evaluation time point.  Highly skewed variables will be log-transformed for analysis, and 
geometric mean changes presented.  Comparisons between each active dose and placebo will be 
done using ANCOVA models, similarly as for secondary endpoints.  
 Safety Analysis 
Adverse Events 
Safety data will be summarized in the Safety analysis set.  All AEs will be coded using the 
Medical Dictionary for Regulatory Authorities (MedDRA).  Treatment-emergent AEs are those 
with an onset after the first dose of study drug or any event already present that worsens in either 
intensity or frequency following exposure to the study treatment. Adverse events with an onset 
between signing of informed consent and study drug initiation, and those with an onset more than 
14 days after the last dose of study drug will be listed separately.  The incidence of treatment-
emergent AEs, serious AEs, AEs resulting in study drug discontinuation, AEs at least possibly 
related to study drug, and fatal SAEs will be summarized by system organ class and AE preferred 
term in each treatment group.  A summary of treatment-emergent AEs by preferred term and 
severity, using the worst reported severity grade for each event for a given subject, will be 
presented. 


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Clinical Laboratory  
Descriptive statistics for laboratory parameter values, and for values of changes from baseline, by 
treatment group and visit, will be provided.  The occurrence of significantly abnormal changes in 
laboratory values from baseline will be summarized by treatment group.  Graphical 
representations may also be presented.  
 Demographic and Baseline Characteristics 
Summary statistics will be provided by treatment group for demographics (e.g. age, sex, race, and 
ethnicity) and for baseline characteristics including medical history and randomization 
stratification factors. 
 Study Drug Exposure, Compliance, and Concomitant Therapies 
Overall percent compliance to study drug dosage regimen, calculated as percent of doses taken 
relative to doses scheduled to be taken, will be summarized by treatment group.  Extent of 
exposure in days will be evaluated and summarized from the first dose date to the last dose date 
of randomized study drug. 
Study drug capsule count will be conducted at Visit 2 (1 month), Visit 3 (2 months), Visit 4 
(3 months), Visit 5 (6 months), Visit 6 (9 Months), and Visit 7 (12 months).  For the periods of 
Visit 1 to Visit 4, Visit 4 to Visit 5, Visit 5 to Visit 6, and Visit 6 to Visit 7, percent compliance 
with study drug during each period will be calculated as the actual number of capsules taken 
divided by the number of capsules required, then multiplied by 100.  The required number of 
capsules will be calculated as the number of capsules per day (1) times the number of treatment 
days in the period, which will be determined using the start date and the end date of the period.  
For example, the number of treatment days for Visit 4 to Visit 5 will be calculated by the date of 
Visit 5 minus the date of Visit 4.  If a subject’s study drug or study participation is discontinued 
early during any of the periods, last dose date +14 days will be used as the end of period.  If the 
date of last dose is missing, the last clinic visit date during the period will be used to estimate the 
end of the period.  As a summary, the following formula will be used to calculate the compliance: 
       
 
At the end of each period, efficacy measurements with a compliance less than 80% will be 
considered for exclusion from per-protocol analyses.  The subjects with a compliance less than 
80% will be reviewed by the medical monitor and Cirius Therapeutics, Inc.  Efficacy 
measurements to be excluded from the per-protocol analyses will be pre-specified prior to 
unblinding treatment codes for analyses.  
Overall compliance of the 12-month double-blind treatment period will also be calculated and 
summarized.  In addition, counts and percents will be produced to show in each treatment group 
with exposure in the following categories: 1 – ≤ 90 days, 91 – ≤ 180 days, 181 – ≤ 270 days, and 
271 – ≤ 360 days.  Similarly to the compliance at each period, overall compliance will be 
calculated as the total number of capsules taken divided by the total number of capsules required, 
period)
 
in the
 
days
 
of
 
no.
 
(total
returned)
 
capsules
 
of
 
no.
 
 total
- 
dispensed
 
capsules
 
of
 
no.
 
total
(
100×


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then multiplied by 100.  The required number of capsules will be calculated as the number of 
capsules per day (1) times the number of treatment days, which will be determined using the 
randomization date and clinic visit date for Visit 7/Day 360.  For subjects who discontinue the 
study or who discontinue study drug early, the last clinic visit date during period when the subject 
was on double-blind treatment will be used.  
Concomitant medication/therapy verbatim terms will be coded using the latest version of the 
World Health Organization (WHO) Drug Dictionary.  The number and percentage of subjects 
taking concomitant medications will be summarized by Anatomic & Therapeutic Chemical 
classification and preferred term for each treatment group. 
No formal statistical tests are planned for all of the variables stated above. 
 Subgroup Analysis 
Subgroup analysis will be performed for the primary and key secondary efficacy endpoints.   
The subgroups examined will include diabetics vs. non-diabetics, use of Vitamin E ≥ 400 IU (Yes 
v. No), F2+3 vs. F1, and by PNPLA3 genotype.  The homogeneity of the effect of each active 
dose relative to placebo across each subgroup will be assessed using appropriate contrasts in a 
logistic regression model that includes terms for the treatment groups, the subgroup under 
consideration, and their interaction, together with the randomization stratification factors.  
Additional subgroup analyses will be described in the SAP.  
 Other endpoints 
Vital signs, physical exam and ECG QTc intervals will also be summarized descriptively.   
 Pharmacokinetic Analysis 
Plasma concentrations will be summarized by treatment group using descriptive statistics. 
Individual subject and mean plasma MSDC-0602 and MSDC-0597 concentrations will be plotted 
vs. time.  Additional details for pharmacokinetic analysis will be specified in the pharmacokinetic 
analysis plan. 
 Interim Analysis 
An interim analysis of exploratory and safety endpoints is planned after all subjects have been 
randomized into the study and 6-month data are available for a minimum of 300 randomized 
subjects. Changes in serum biomarkers from baseline to 6 months will be assessed. Biomarkers 
include: 
• Liver function tests (ALT, AST, ALP, GGT, bilirubin, albumin, PT and INR) 
• Circulating inflammatory markers (HMW adiponectin and hsCRP) 
• Markers of bone metabolism (osteocalcin and serum CTX), FFA, serum triglycerides and 
fasting cholesterol (total, HDL, LDL, VLDL),) 
• Markers of insulin sensitivity (HOMA-IR, HbA1c, fasting plasma glucose and fasting 
insulin).  Markers of insulin sensitivity will be analyzed separately in subjects with and 
without T2DM.  


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• CK-18 [M30 & M65] 
• Fibrosure, ELF score, APRI, FIB-4 index, Pro-C3 
Statistical methods similar to those employed for mean changes in secondary efficacy 
endpoints will be employed.  Only summary statistics by treatment group will be presented 
and results shared with a limited group of people to be identified by the Sponsor. The 
treatment assignments of individual subjects will not be presented, i.e., data listings will not 
be included for this interim analysis.  Details will be provided in a SAP for the interim 
analysis. 
12 BIOLOGICAL SPECIMENS 
Blood and urine samples will be collected, processed, stored, and shipped as outlined in 
respective Study Manuals or instructions provided by responsible assay laboratories for clinical 
chemistry, hematology, PK, pharmacodynamics (PD) and urinalysis. 
It is the responsibility of the Investigator to ensure that all personnel who will be handling, 
packaging, and/or shipping clinical specimens act in conformance with International Air 
Transport Association (IATA) regulations relating to the handling and shipping of hazardous 
goods. 
13 CLINICAL AND LABORATORY DATA COLLECTION 
 Case Report Forms 
An electronic version of the CRF data collection form (eCRFs) for each subject will be provided.  
All appropriate subject data gathered during the study will be recorded in English on these forms. 
Whenever possible, all information requested on a CRF sheet or entered directly into an eCRF 
should be completed.  If information is not available, it should be documented as such.  Paper 
based forms should be filled out with a black or blue ballpoint pen.  All deletions and corrections 
must be made by drawing a single line through the error and writing the correct information next 
to the change.  All corrections must be initialed and dated.  Correction fluid must not be used.  A 
tracking system for changes to the eCRFs (i.e., an audit system) will be available. 
The completed CRFs or completed print out and/or electronic copy of the eCRFs for this study 
are the property of Cirius Therapeutics, Inc. and should not be made available to third parties, 
except for authorized representatives of appropriate health/regulatory authorities, without written 
permission from Cirius Therapeutics, Inc. 
 Laboratory Results 
Laboratory tests (clinical chemistry and hematology) will be analyzed by a central laboratory and 
reported to the clinical site as results are generated.  The Investigator will review and comment on 
any laboratory value reported outside the normal range provided by the central laboratory.  The 
laboratory report must be signed and kept in the study subject file at the site for the Sponsor.  The 
electronic copies of the laboratory data will represent the clinical chemistry and hematology 
source data. 


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14 STUDY DOCUMENTATION AND RECORDS RETENTION 
 Access to Records 
As required by the International Conference on Harmonization (ICH)-Good Clinical Practice 
(GCP) guidelines and regulatory authorities, the Investigator will allow sponsor’s 
representative(s) direct access to all pertinent medical records in order to allow for the verification 
of data gathered in the CRFs or the electronic data forms and for the review of the data collection 
process.  The records, including source documentation, must also be available for inspection by 
relevant regulatory health authorities. 
 Source Documents 
Source documents may include, but are not limited to, laboratory reports, ECG tracings, x-rays, 
radiologist reports, biopsy slides or reports, ultrasound photographs, clinic notes or pharmacy 
records and any other similar reports or records of any procedure performed in accordance with 
the protocol.  Source documents may also include CRFs or electronic devices when information is 
recorded directly onto such forms or devices. 
Whenever possible, the original recording of an observation should be retained as the source 
document; however, a photocopy is acceptable provided that it is a clear, legible, and exact 
duplication of the original document. 
 Record Retention (Investigator’s Study File) 
Government agency regulations and directives require that all study documentation pertaining to 
the conduct of a clinical study must be retained by the Investigator.  They shall be retained until at 
least 2 years after the last approval of a marketing application in an ICH region.  The Investigator 
may neither assign archiving of the files to someone else nor remove them to another location, 
without previously obtaining written approval from the sponsor.  The sponsor will notify the 
Investigator in writing when retention is no longer necessary. 
15 INSTITUTIONAL REVIEW BOARD / ETHICS COMMITTEE 
The Investigator is responsible for obtaining an approval for conduct of the study from the 
Institutional Review Board (IRB) / Ethics Committee (EC), as well as approval of all subsequent 
major changes to the study, in compliance with local law.  These approvals must be forwarded to 
the sponsor.  The IRB/EC will comply with all federal, state, and local laws.   
The Investigator shall also obtain from the IRB/EC and submit to the sponsor, a signed statement 
indicating that it complies with GCP. 
16 ETHICAL CONDUCT OF THE STUDY 
The study will be performed according to the Declaration of Helsinki, seventh edition (Edinburgh, 
Scotland, 2013) with approval from the IRB. 


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17 INFORMED CONSENT 
It is the responsibility of the Investigator to give each potential study subject, prior to inclusion 
into the study, full and adequate verbal and written information regarding the objectives and 
procedures of the study.  The study subjects must be informed about their right to withdraw from 
the study at any time.  It is the responsibility of the Investigator (who may delegate this task to 
other members of the study team) to obtain signed informed consent from all study subjects 
before any study related assessments are performed.  Consent must be documented by the 
subject’s dated signature on an informed consent form along with the dated signature of the 
person conducting the consent discussion.  A copy of the signed and dated consent form should be 
given to the subject before participation in the trial. 
The initial informed consent form and any subsequent revised written informed consent form, and 
any written information provided to the subject must receive the IRB approval/favorable opinion 
in advance of use. 
18 CONFIDENTIALITY 
 Confidentiality of Data 
By signing this protocol, the Investigator affirms to the sponsor that information furnished to the 
Investigator by the sponsor will be maintained in confidence and such information will be 
divulged to the IRB and regulatory agency, or similar expert committee; affiliated institution; and 
employees only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees.  Data generated by this study will be considered 
confidential by the Investigator, except to the extent that it is included in a publication as provided 
in Section 21, Publications. 
 Confidentiality of Subject Records 
By signing this protocol, the Investigator agrees that the Sponsor (or Sponsor representative), IRB 
or regulatory agency representatives may consult and/or copy study documents in order to verify 
case report form data.  By signing the consent form, the subject agrees to this process.  If study 
documents will be photocopied during the process of verifying CRF information, the subject will 
be identified by subject number only, full names/initials will be masked prior to transmission to 
the Sponsor, IRB or regulatory agency. 
19 COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT 
By signing this protocol, the Investigator agrees to conduct the study in an efficient and diligent 
manner and in conformance with this protocol; generally accepted standards of GCP; and all 
applicable local laws, rules and regulations relating to the conduct of the clinical study. 
The Investigator also agrees to allow monitoring, audits, IRB review and regulatory agency 
inspection of trial-related documents and procedures and provide for direct access to all study-
related source data and documents. 
The Investigator shall prepare and maintain complete and accurate study documentation in 
compliance with GCP standards and applicable local laws, rules and regulations; and, for each 


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subject participating in the study, provide all data, and upon completion or termination of the 
clinical study submit any other reports to the Sponsor as required by this protocol or as otherwise 
required pursuant to any agreement with the Sponsor. 
Study documentation will be promptly and fully disclosed to the sponsor by the Investigator upon 
request and also shall be made available at the Investigator’s site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any regulatory 
agencies.  The Investigator agrees to promptly take any reasonable steps that are requested by the 
Sponsor as a result of an audit to correct deficiencies in the study documentation and case report 
forms. 
International Conference on Harmonization’s GCP guidelines recommend that the Investigator 
inform the subject’s primary physician about the subject’s participation in the study if the subject 
has a primary physician and if the subject agrees to the primary physician being informed. 
The Investigator will promptly inform the Sponsor of any regulatory agency inspection conducted 
for this study and provide the final results (i.e., final observations and responses). 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
agency will not be allowed to conduct or work on this study.  The Investigator will immediately 
disclose in writing to the Sponsor if any person who is involved in conducting the study is 
debarred or if any proceeding for debarment is pending or, to the best of the Investigator’s 
knowledge, threatened. 
In the event the sponsor prematurely terminates a particular study site, the Sponsor will promptly 
notify the IRB. 
20 QUALITY CONTROL AND QUALITY ASSURANCE 
By signing this protocol, the Sponsor agrees to ensure that studies are conducted and data are 
generated, documented, and reported in compliance with the protocol, accepted standards of GCP 
under quality assurance systems with written standard operating procedures, and all applicable 
local laws, rules and regulations relating to the conduct of the clinical study. 
21 PUBLICATIONS 
No publication or disclosure of study results will be permitted, except under the terms and 
conditions of a separate, written agreement between sponsor and the Investigator and/or the 
Investigator’s institution.  The Sponsor must have the opportunity to review and approve all 
proposed abstracts, manuscripts, or presentations regarding this study prior to submission for 
publication/presentation.  Any information identified by the sponsor as confidential must be 
deleted prior to submission. 


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22 REFERENCES 
1. 
Colca JR, Tanis SP, McDonald WG, et al.  Insulin Sensitizers in 2013:  new insights for the 
development of novel therapeutic agents to treat metabolic diseases. Expert Opin Investig 
Drugs (2013) 23(1):1-7. 
2. 
Colca JR, McDonald WG, Kletzien, RF. Mitochondrial target of thiazolidinediones. Diab. 
Obes. Metab. (2014) doi:10.1111/dom.12308. 
3. 
Colca JR, RF Kletzien RF. What has prevented the expansion of insulin sensitisers. Expert 
Opin Investig Drugs (2006) 15(3):205-10. 
4. 
Chen Z, Vigueira PA, Chambers KT, et al. Insulin resistance and metabolic derangements in 
obese mice are ameliorated by a novel peroxisome proliferator-activated receptor γ-sparing 
thiazolidinedione.  J Biol Chem (2012) 287:23537-48. 
5. 
Neurobehavioral Evaluation of Orally Administered MSDC-0602 in Rats.  MPI Study 1263-
034.  09 Nov 2009. 
6. 
Respiratory Evaluation of Orally Administered MSDC- 0602 in Rats. MPI Study 1263-035.  
09 Nov 2009. 
7. 
Evaluation of the Effects of MSDC-0602 and Its Metabolite, MSDC-0597, on Cloned hERG 
Channels Expressed in Human Embryonic Kidney (Hek293) Cells.  MPI Study 1263-036.  
24 Nov 2009. 
8. 
In vitro Protein Binding of [14C]MSDC-0602 and Its Metabolite, [14C] MSDC-0597, in CD-
1 Mouse, Sprague Dawley Rat, New Zealand White Rabbit, Cynomolgus Monkey, and 
Human Plasma Using Equilibrium Dialysis. QPS Study No. 355N-1102.  11 Oct 2011. 
9. 
Potential Cardiovascular Effects of Orally Administered MSDC-0602 in the Cynomolgus 
Monkey.  MPI Study 1263-037. 01 Dec 2009. 
10. MSDC 0602: A 4-Week Oral Toxicity Study in Rats.  MPI Study 1263-025. 11 Dec 2009. 
11. MSDC 0602: A 4-Week Oral Toxicity Study in Monkeys.  MPI Study 1263-026. 
11 Dec 2009. 
12. Pharmacokinetics and comparative oral bioavailabilities of suspension formulations of the 
sodium and potassium salts of MSDC-0602 in the male Sprague-Dawley rat.  MPI Study 
No. 1263-050.  14 Nov 2011. 
13. A crossover oral bioavailability study of two formulations of MSDC-0602 in cynomolgus 
monkeys. MPI Study No. 1263-063.  10 Nov 2011. 
14. MSDC-0602K: A 13-Week Oral Toxicity Study in Mice with a 4-Week Recovery Period. 
MPI Study 1263-057.  27 Dec 2011. 


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15. MSDC-0602K: A 13-Week Oral Toxicity Study in Monkeys with a 4-Week Recovery 
Period. MPI Study 1263-056.  27 Dec 2011. 
16. MSDC-0602K: A 13-Week Oral Toxicity Study in Rats with a 4-Week Recovery Period. 
MPI Study 1263-058, 27 Dec 2011. 
17. MSDC-0602K: A 26-Week Oral Toxicity Study in Rats.  MPI Study 1263-070.  
08 Nov 2013. 
18. MSDC-0602K: A 26/52 Week Oral Toxicity Study in Monkeys.  MPI Study 1263-069.    31 
Jan 2014. 
19. Colca, J.R.  Insulin sensitizers may prevent metabolic inflammation.  Biochem Pharmacol 
(2006) 72:125-31. 
20. Colca JR, VanderLugt JT, Adams WJ, et al.  Clinical proof of concept with MSDC-0160, a 
prototype mTOT modulating insulin sensitizer.  Clin Pharm Therap (2013) 93:352-359. 
21. 104-Week Oral Oncogenicity Study in Mice.  MPI Study 1263-062.  16 Dec 2014. 
22. 104-Week Oral Oncogenicity Study in Rats.  MPI Study 1263-061.  16 Dec 2014. 
23. Cohen SM, Storer RD, Criswell KA, et al. Hemangiosarcoma in rodents: mode of action 
evaluation and human relevance.  Toxicol Sci (2009) 111:4-18. 
24. Liu L, Kakiuchi-Kiyota S, Arnold LL, et al.  Pathogenesis of human hemangiosarcomas and 
hemangiomas.  Hum Pathol (2013) 44:2302-11. 
25. Cohen SM.  Effects of PPARγ and combined agonists on urinary tract of rats and other 
species.  Toxicol Sci (2005) 87:322-7. 
26. Dominick MA, White SR, Sanderson TP, et al.  Urothelial carcinogenesis in the urinary 
bladder of male rats treated with muraglitazar, a PPARα/γ agonist: evidence for urolithiasis 
as the inciting event in the mode of action.  Toxicol Pathol (2006) 34:903-20. 
27. MSDC-0602-C001.  Clinical Study Report: A Randomized, Double-Blind, Placebo-
Controlled, Ascending Single- and Multiple-Dose Study to Evaluate the Safety, Tolerability 
and Pharmacokinetics of MSDC-0602 in Healthy Subjects. 28 Dec 2011. 
28. MSDC-0602-C003.  Clinical Study Report.  An Open Label, Single Dose, Crossover Study 
of the Pharmacokinetics of Three Different Doses of Micronized MSDC-0602 Tablets 
Compared to the Pharmacokinetics of Micronized MSDC-0602 Powder in Capsule.  19 Jan 
2012. 
29. MSDC-0602K-C004.  Clinical Study Report.  An Open-label, Single Dose, Crossover Study 
of the Pharmacokinetics of Three Different Doses of MSDC-0602K Tablets Compared to 
the Pharmacokinetics of Micronized MSDC-0602 Free Acid Tablets.  15 Jan 2013. 


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30. MSDC-0602-C002.  Clinical Study Report.  A Phase 2a, Randomized, Double-Blind, 
Comparator- and Placebo-Controlled, Multiple-Dose Study to Evaluate the Safety, 
Tolerability, and Efficacy of Three Dose Levels of MSDC-0602 in Type 2 Diabetic Patients.  
07 Dec 2011. 
31. MSDC-0602K-C007UT.   UT Clinical Study Protocol.  On file. 
32. Cusi, K.  Management of NAFLD/NASH in Patients with T2DM: New Concepts and Future 
Directions.  Presented at American Diabetes Association Annual Meeting, San Francisco, 
California, June 13-17, 2014. 
33. Bajaj M, Baig R, Swangjit S, et al.  Effects of pioglitazone on intramyocellular fat 
metabolism in patients with type 2 diabetes mellitus.  J Clin Endocrinol Metab, (2010) 
95:1916-23. 
34. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. 
Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 
(2010) 362:1675-1685. 
35. Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an 
agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of 
nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology (2016) 
May;150(5):1147-1159. 
 
 


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APPENDIX 1 - ADA DIABETIC DIET GUIDELINES 
• 
Meal plans are balanced 
o They include breakfast, lunch, dinner, and two snacks. 
o Each one-day plan includes about 8 servings of fruits and vegetables. 
o Fruits and vegetables are included at almost every meal and snack. 
• 
1550-1650 calories per day 
o Your calorie level may vary based on your age, gender, activity level and whether or not you need 
to lose weight. 
o Calories are spaced throughout the day between meals and two snacks. 
o We also include tips each month to add or cut total calories by 200. 
• 
Moderate-carbohydrate (about 45% of calories come from carbohydrate) 
o Carbohydrate intake is spread throughout the day. 
o Most meals have 45-60 grams of carbohydrate. 
o Most snacks have 10-25 grams of carbohydrate. 
o We also provide tips on how to adjust each meal plan to make it lower in carbohydrates. 
• 
Limit trans-fat as much as possible, <10% of calories from saturated fat, and focus on 
healthy or "good" fat sources 
o People with diabetes have a higher-than-average risk of having a heart attack or stroke. Due to 
their connection with heart disease risk, the amount of saturated and trans-fats in our meal plans is 
limited. Trans fat and saturated fats are sometimes referred to as "bad fats." 
o "Good fats" include monounsaturated and polyunsaturated fats and may promote heart health. 
Meal plans include these over "bad fats" as much as possible. 
• 
300 mg of cholesterol per day 
o Your body makes some cholesterol on its own but you also get cholesterol from food. People with 
diabetes should have 300 mg or less per day. 
o Some foods, like shrimp and eggs, are fairly nutritious foods but are somewhat high in 
cholesterol. Meal plans may include these foods because they provide other benefits or help to 
balance the plan. 
• 
>25 grams of dietary fiber per day 
o You get fiber from plant-based foods like whole grains, fruit, vegetables, nuts, seeds and beans. 
o People with diabetes should consume at least the recommended amount of fiber for the general 
population: about 25 grams per day for women and 38 grams per day for men. Many Americans 
only get about half of what is recommended. 
• 
2300 mg of sodium or less per day 
o Watching sodium is important for blood pressure control. 
o The American Diabetes Association recommends 2300 mg of sodium or less per day. 
o If you have diabetes and hypertension, you should work with your health care team to see if 
further reduction of sodium intake is necessary. 
o The current food supply is packed with hidden sources of sodium, and most Americans are 
consuming closer to 3400 mg of sodium per day. You can take some simple steps to reducing the 
sodium in your diet by learning what foods are major sources of sodium, making smart food 
choices, and controlling portion sizes. 
 
 


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APPENDIX 2 - THE NCEP DIETARY GUIDELINES 
• 
Less than 7% of the day’s total calories from saturated fat. 
• 
25-35% of the day’s total calories from fat. 
• 
Less than 200 milligrams of dietary cholesterol a day. 
TLC diet tips 
Meat, Poultry, Fish, Dry Beans, Eggs, and Nuts 
• 
Limit the total amount of meat to 5 ounces or less per day 
• 
Choose chicken and turkey without skin or remove skin before eating 
• 
Eat fish, like cod, that has less saturated fat than either chicken or meat 
• 
Dry peas and beans and tofu (bean curd) are great meat substitutes 
• 
Limit egg yolks to no more than 2 yolks per week, including egg yolks in baked goods 
• 
Substitute egg whites for whole eggs 
Milk, Yogurt, and Cheese 
• 
Eat 2 to 3 servings per day of low-fat or nonfat dairy products 
• 
Choose varieties that have 3 grams of fat or less per ounce, including low-fat (1%) or 
nonfat cottage cheese 
• 
Buy frozen desserts that are lower in saturated fat, like ice milk, low-fat frozen yogurt, 
sorbet 
• 
Try low-fat or nonfat sour cream or cream cheese blends 
Fats and Oils 
• Replace saturated fats with unsaturated fat and limit the total amount of fats or oils 
• Use liquid vegetable oils that are high in unsaturated fats (canola, corn, olive, peanut, 
safflower, sesame, soybean, sunflower oils) 
• Use margarine made with unsaturated liquid vegetable oils as the first ingredient 
• Limit butter, lard, fatback, and solid shortenings 
• Buy light or nonfat mayonnaise and salad dressing 
Fruits and Vegetables 
• Eat at least 3 to 5 servings of fruits and vegetables each day 
• Buy fruits and vegetables to eat as snacks, desserts, salads, side dishes, and main dishes 

SAP_001.pdf: 
CONFIDENTIAL 
Page 1 of 35 
 
Cirius Therapeutics, Inc. 
Protocol No.: MSDC-0602K-C009NASH 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 12-Month, Multiple-Dose Study to 
Evaluate the Safety, Tolerability and Efficacy of Three Dose Levels of MSDC-0602K in Patients 
with NASH (EMMINENCE™) 
Study ID: MSDC-0602K-C009NASH 
 
 STATISTICAL ANALYSIS PLAN 
Version: Final 1.5 
Date of Issue: 16-May-2019 
Author: Stefanie Senger, PhD 
 
 
Cirius Therapeutics, Inc. 
Momentum Research Inc. 
12651 High Bluff Drive 
Suite 150 
San Diego, CA 92130 
 
161 East Michigan Avenue, 4th Floor 
Kalamazoo, MI 49007  
3100 Tower Blvd., Suite 802 
Durham, NC  27707 
 
 
 
 


Statistical Analysis Plan  
Version: Final 1.5 
Date of Issue: 16-May-2019 
Cirius Protocol No. MSDC-0602K-C009NASH 
 
 
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Page 2 of 35 
APPROVALS 
The undersigned agree that all required reviews of this document are complete and approve this 
Statistical Analysis Plan as final.   
 
 
 
  
 
Signature 
 
Date 
 
Howard C. Dittrich, MD 
Chief Medical Officer, Cirius Therapeutics, Inc. 
Printed Name/Title 
 
  
 
 
 
  
 
Signature 
 
Date 
 
Thomas H. Oliphant, PhD 
Executive Director, Clinical Statistics, Innovative Analytics Inc. 
  
 
Printed Name/Title 
  
 
 
  
 
 
 
  
 
Signature 
 
Date 
 
Stefanie Senger, PhD 
Biostatistician, Momentum Research, Inc. 
Printed Name/Title 


Statistical Analysis Plan  
Version: Final 1.5 
Date of Issue: 16-May-2019 
Cirius Protocol No. MSDC-0602K-C009NASH 
 
 
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Page 3 of 35 
VERSION HISTORY 
Version Number 
Version Date 
Summary and rationale for change(s) 
Final 1.0 
21-June-2018 
N/A 
Final 1.1 
6-September-2018 
Added shift tables for analysis of changes in 
HbA1c 
Final 1.2 
21-September-2018 Definition of baseline assessment modified to 
allow inclusion of a few measures taken minutes 
after the first dose of study medication 
Final 1.3 
01-October-2018 
Added possible sensitivity analyses for changes in 
laboratory measures with imputations to assess 
impact of differential changes in glycemic control 
medications, and differential missing follow-up, in 
placebo versus active patients 
Final 1.4 
08-April-2019 
Added analyses of events to be adjudicated (cause 
of death, occurrence of major adverse 
cardiovascular and liver events, and severe 
hypoglycemia) and fractures requiring surgery or 
hospitalization. Added summary of log-
transformed LFTs. Modified visit windows for 
unscheduled visits to include Visit 8. Modified 
calculation of compliance based on capsule counts 
due to missing data. Clarification of statistical 
modelling of mean change from baseline of 
fibrosis score, and other minor corrections. 
Final 1.5 
16-May-2019 
Added further sensitivity analyses for primary and 
secondary efficacy endpoints. Corrected analysis 
of specialty biomarker Pro-C3. Modified analysis 
of study drug compliance.  
 
 


Statistical Analysis Plan  
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Date of Issue: 16-May-2019 
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TABLE OF CONTENTS 
APPROVALS .................................................................................................................................2 
VERSION HISTORY ....................................................................................................................3 
GLOSSARY OF ABBREVIATIONS ..........................................................................................6 
1 SOURCE DOCUMENTS ........................................................................................................8 
2 PROTOCOL DETAILS ..........................................................................................................8 
2.1 Study Objectives..............................................................................................................8 
2.2 Overall Study Design ......................................................................................................8 
2.3 Sample Size and Power ...................................................................................................8 
3 EFFICACY AND SAFETY VARIABLES ............................................................................9 
3.1 Primary Efficacy Endpoint ............................................................................................9 
3.2 Secondary Efficacy Endpoints .......................................................................................9 
3.3 Exploratory Efficacy Endpoints ....................................................................................9 
3.4 Safety Variables ............................................................................................................10 
4 PHARMACOKINETIC/PHARMACODYNAMIC VARIABLES ...................................10 
5 ANALYSIS POPULATIONS ...............................................................................................11 
5.1 Enrolled Set ...................................................................................................................11 
5.2 Modified Intent-to-treat Analysis Set..........................................................................11 
5.3 Safety Analysis Set ........................................................................................................11 
5.4 Per Protocol Analysis Set .............................................................................................11 
5.4.1 Important Protocol Deviations Leading to Exclusion from the PPS Analysis ...12 
6 DATA HANDLING ...............................................................................................................14 
6.1 Time points and Visit Windows ...................................................................................14 
6.2 Handling of Dropouts or Missing Data .......................................................................15 
6.2.1 Missing Dates......................................................................................................15 
6.2.2 NASH CRN Histological Scores ........................................................................16 
6.2.3 Imputation for Primary Endpoint ........................................................................16 
6.2.4 Imputation for Missing Changes in Laboratory Values ......................................17 
7 STATISTICAL METHODS .................................................................................................18 
7.1 General Principles .........................................................................................................18 
7.2 Subject Disposition and Data Sets Analyzed ..............................................................19 
7.3 Protocol Deviations .......................................................................................................19 
7.4 Demographics and Other Baseline Characteristics ...................................................19 
7.5 Medical History .............................................................................................................20 
7.6 Prior and Concomitant Medications ...........................................................................20 


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7.7 Treatment Compliance and Exposure ........................................................................21 
7.7.1 Exposure .............................................................................................................21 
7.7.2 Study Drug Administration Data ........................................................................21 
7.7.3 Pharmacokinetic Trough Levels .........................................................................22 
7.8 Efficacy...........................................................................................................................23 
7.8.1 Primary Efficacy Analysis ..................................................................................23 
7.8.2 Secondary Efficacy Analysis ..............................................................................25 
7.8.3 Subgroup Analysis ..............................................................................................26 
7.8.4 Exploratory Analysis ..........................................................................................27 
7.9 Safety ..............................................................................................................................28 
7.9.1 Adverse Events ...................................................................................................28 
7.9.2 Laboratory Evaluations .......................................................................................29 
7.9.3 Vital Signs ...........................................................................................................30 
7.9.4 Electrocardiograms .............................................................................................30 
7.9.5 Physical Examination..........................................................................................30 
7.9.6 Major Adverse Cardiovascular Events and Liver Events ...................................31 
7.9.7 Severe Hypoglycemic Events .............................................................................31 
7.9.8 Bone Fractures Requiring Surgery or Hospitalization ........................................31 
7.10 Interim Analysis ............................................................................................................32 
8 CHANGES FROM PROTOCOL-SPECIFIED ANALYSES ............................................32 
9 REFERENCES .......................................................................................................................33 
10 APPENDIX .............................................................................................................................34 
SCHEDULE OF ACTIVITIES ..................................................................................................34 


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GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse event 
ALP 
Alkaline phosphatase  
ALT 
Alanine transaminase (SGPT)  
ANCOVA 
Analysis of covariance 
APRI 
Aspartate aminotransferase-to-platelet ratio index  
AST 
Aspartate transaminase (SGOT)  
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CI 
Confidence Interval 
CEC 
Clinical Events Committee 
CK-18 
Cytokeratin-18  
CMH 
Cochran-Mantel-Haenszel 
CRN 
Clinical Research Network 
CTX 
C-terminal telopeptide  
DM 
Diabetes mellitus 
DPP4 
Dipeptidyl peptidase-4 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ELF 
Enhanced liver fibrosis score  
F1 
Fibrosis stage 1 
F2 
Fibrosis stage 2 
F3 
Fibrosis stage 3 
FFA 
Free fatty acids 
FIB-4 
Fibrosis 4 index for liver fibrosis 
GGT 
Gamma-glutamyl transpeptidase  
GLP1 
Glucagon-like peptide-1 
HA 
Hyaluronic acid  
HbA1c 
Glycosylated hemoglobin  
HBsAg 
Hepatitis B surface antigen 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein  
HF 
Heart failure 
HIV 
Human Immunodeficiency Virus 
HMW 
High molecular weight  
HOMA-IR 
Homeostasis model assessment-insulin resistance  
hsCRP 
High-sensitivity C-reactive protein  
ICF 
Informed consent form 
I/E 
Inclusion and exclusion 
INR 
International Normalized Ratio  


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IP 
Investigational product 
IXRS 
Interactive voice/web response system 
LDL 
Low-density lipoprotein  
MACE 
Major Adverse Cardiovascular Event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End-Stage Liver Disease 
MI 
Myocardial infarction 
mITT 
Modified Intent-to-treat 
NAFLD 
Non-alcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
Nonalcoholic Steatohepatitis 
NMR 
Nuclear magnetic resonance  
PIIINP 
Amino-terminal peptide of type III collagen  
PNPLA3 
Patatin-like phospholipase domain-containing protein 3 
PPARγ 
Peroxisome proliferator-activated receptor gamma 
PPS 
Per-protocol Set 
Pro-C3 
N-terminal type III collagen propeptide 
PT 
Prothrombin Time – or – Preferred Term 
QTcB 
Bazett corrected QT interval 
QTcF 
Fridericia corrected QT interval 
RNA 
Ribonucleic acid 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SGLT2 
Sodium-glucose cotransporter 2 
SOC 
System Organ Class 
T2DM 
Type 2 diabetes mellitus  
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
TIA 
Transient ischemic attack 
TIMP-1 
Tissue inhibitor of metalloproteinases  
USA 
Unstable angina 
VLDL 
Very low-density lipoprotein 
WHO 
World Health Organization 
 
 


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1 
SOURCE DOCUMENTS 
The Statistical Analysis Plan (SAP) was written based on the following documentation: 
Document 
Date 
Version 
Protocol  
31-July-2017 
Amendment 4 
eCRF  
11-October-2017 
2.0 
 
2 
PROTOCOL DETAILS 
2.1 Study Objectives 
To assess the preliminary safety and efficacy of 3 doses of MSDC-0602K (62.5, 125, or 250 mg) 
as compared to placebo in subjects with non-alcoholic steatohepatitis (NASH). 
2.2 Overall Study Design 
This is a randomized, double-blinded, placebo-controlled multiple-dose phase II study to 
evaluate the safety, tolerability and efficacy of three dose levels of MSDC-0602K in subjects 
with non-alcoholic steatohepatitis (NASH).  
Approximately 380 subjects will be randomized at 1:1:1:1 ratio to the following four treatment 
arms, and the drug is taken orally once per day for 12 months: 
• MSDC-0602K 62.5 mg 
• MSDC-0602K 125 mg 
• MSDC-0602K 250 mg 
• Placebo 
Randomization will be stratified by: 
• Presence of Type 2 diabetes mellitus (T2DM) (Yes/No) 
• Use of Vitamin E ≥ 400 IU (Yes/No) 
• Fibrosis score (F1 vs. F2/F3)  
This study will comprise a maximum 42-day Screening period, a treatment period of 360 days 
and a 14-day follow-up period.  The total duration of the study for each subject will be up to 416 
days, including follow-up. 
The primary efficacy endpoint will be assessed at 12 months after randomization. Visits to the 
clinic will be at baseline, 1, 2, 3, 6, 9, and 12 months, with one follow-up visit at study day 374. 
2.3 Sample Size and Power 
Each active treatment group will be compared with the placebo group at the two-sided 0.05 
significance level; 85 subjects per arm provides approximately 80% power to detect a difference 
in the proportions of subjects achieving the primary efficacy endpoint of 39.5% in any MSDC-
0602K group versus 20% response rate in the placebo group. These response rates are similar to 
effects reported after 18 months daily treatment with 45 mg pioglitazone (58% response) or 
placebo (17% response) in subjects with pre-diabetes or T2DM (Cusi 2014); after 96 weeks daily 
treatment with 30 mg pioglitazone (34% response) or placebo (19%) in non-diabetic adults with 
NASH in the PIVENS study (Sanyal 2010); and in the GOLDEN study, after 52 weeks daily 


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treatment with 120 mg elafibranor (32% response) or placebo (21%) in the subset of NASH 
subjects with a baseline NAS ≥ 4 (Ratziu 2016). Assuming 10% of subjects will not complete the 
12-month assessment due to early dropout, 380 subjects will be randomized to the study.  
Sample size calculations were made using nQuery Advisor® (Statistical Solutions Ltd., Boston, 
MA, USA).  
3 
EFFICACY AND SAFETY VARIABLES 
3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is hepatic histological improvement in NAS (NASH CRN 
scoring) at month 12. A responder (subjects with hepatic histological improvement) is defined as 
having all of the following: 
• A decrease of at least 2 points in NAS at 12 months. The reduction in NAS must also 
include at least a 1 point reduction in either ballooning or inflammation. 
• No concurrent worsening of fibrosis, defined as no increase in CRN fibrosis score (i.e., 
an increase of 1 stage or more).   
3.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following: 
• Proportion of subjects with resolution of NASH with no worsening of fibrosis at 12 
months. Resolution of NASH is defined as a ballooning score of 0 and an inflammation 
score of 0-1. No worsening of fibrosis is defined as no increase in CRN fibrosis score. 
• Proportion of subjects with improvement of fibrosis (CRN staging score) by at least 1 
stage with no worsening of NASH (defined as no worsening of lobular inflammation or 
hepatocellular ballooning) at 12 months 
• Mean change from baseline in NAFLD activity score (NAS) and each one of its 
components (steatosis, inflammation and ballooning) at 12 months 
• Mean change from baseline in fibrosis score at 12 months 
3.3 Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints include the following: 
• Mean change from baseline relative to placebo at 12 months in liver stiffness as measured 
using the FibroScan device 
• Change from baseline relative to placebo for liver function tests (ALT, AST, ALP, GGT, 
bilirubin, albumin, PT and INR), normalization of ALT and AST, and changes from 
baseline relative to placebo for biomarkers and indirect measures of apoptosis and liver 
fibrosis (CK-18 [M65], Fibrosure, APRI, FIB-4 index, Pro-C3, and ELF score and its 
individual components TIMP-1, PIIINP, HA) at 6 and 12 months. 


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• Changes from baseline relative to placebo in circulating inflammatory markers (HMW 
adiponectin and hsCRP) and markers of bone metabolism (osteocalcin and serum CTX) 
at 6 and 12 months.  
• Changes from baseline relative to placebo in FFA, serum triglycerides, and fasting 
cholesterol (total, HDL, LDL, VLDL) at 6 and 12 months, and changes from baseline in 
NMR analysis of lipoprotein particle size at 12 months. 
• Changes from baseline relative to placebo in markers of insulin sensitivity: HOMA-IR, 
HbA1c, fasting plasma glucose, and fasting insulin at 6 and 12 months.  
• Changes from baseline relative to placebo in blood pressure (systolic and diastolic), heart 
rate, weight, and abdominal girth at 6 and 12 months. 
• Changes from baseline relative to placebo at 12 months in the central pathologist’s 
general impression of NASH diagnosis: 1) Confirmed, or 2) Cannot be confirmed. 
3.4 Safety Variables 
The tolerability and safety will be assessed using the following endpoints: 
• The incidence of treatment-emergent adverse events 
• Changes from baseline to each time point in clinical laboratory (hematology, chemistry, 
urinalysis) values (some of which are also evaluated as efficacy parameters), and the 
occurrence of clinically significant abnormal changes 
• Changes from baseline in vital signs (systolic and diastolic blood pressure, heart rate, 
weight, and abdominal girth) at each visit, which will also be examined as exploratory 
efficacy endpoints 
• Changes from baseline in quantitative electrocardiogram (ECG) parameters (mean heart 
rate, PR interval, QRS duration, QT interval, QTcB interval, QTcF interval, RR interval) 
• Time to first event of death, adjudicated non-fatal myocardial infarction (MI) or unstable 
angina (USA) hospitalization, adjudicated hospital admission for heart failure (HF), or 
adjudicated non-fatal ischemic stroke  
• Time to first event of death, adjudicated non-fatal MI or USA hospitalization, adjudicated 
hospital admission for HF, adjudicated non-fatal ischemic stroke, or adjudicated liver 
event. A liver event consists of ascites, hepatic encephalopathy, variceal hemorrhage, 
hepatocellular carcinoma (HCC), or liver transplant   
• Incidence of adjudicated severe hypoglycemia events 
• Incidence of bone fracture requiring surgery or hospitalization 
4 
PHARMACOKINETIC/PHARMACODYNAMIC VARIABLES 
Steady-state trough measurement will be made for MSDC-0602 and MSDC-0597 (a major 
pharmacologically active metabolite), at Study Visits 2, 4, 5, 6, and 7 (Days 30, 90, 180, 270, 
360). The details for the population PK analysis will be covered in a separate Pharmacokinetic 
Analysis Plan.   


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5 
ANALYSIS POPULATIONS 
Final decisions regarding the assignment of subjects to analysis sets will be made during the 
Validity Review Meeting and documented in the Validity Review Report prior to final database 
lock and unblinding for the final analysis. Data from sites with serious GCP or quality 
concerns may be excluded from the analyses.  The Sponsor will provide a list of such sites, 
and during the review it will be decided from which analyses and from which sites data should 
be excluded.  
5.1 Enrolled Set 
The Enrolled set includes all subjects who signed informed consent.  
5.2 Modified Intent-to-treat Analysis Set  
The modified Intent-to-Treat (mITT) analysis set includes all subjects who are randomized and 
who receive at least one dose of study drug.  Baseline measures and post-baseline assessments 
through 14 days after the last dose of study drug will be included in the analyses unless stated 
otherwise below.  Subjects in the mITT will be analyzed as randomized regardless of treatment 
received.  This means that subjects who are randomized who receive the incorrect study drug 
(i.e., not the study drug to which they were randomized) will be analyzed for efficacy under 
mITT as in the treatment group to which the subject was randomized.  The primary population 
for efficacy analyses is the mITT. 
5.3 Safety Analysis Set 
The Safety analysis set (SAF) includes all subjects who are randomized and received at least one 
dose of study drug.  SAF will be used in the analyses of all safety endpoints.  Subjects will be 
included in the analyses according to the actual treatment they received.  If a subject incorrectly 
receives more than one dose of study drug, the subject will be analyzed in the treatment group 
corresponding to the highest dose received. Baseline measures and post-baseline assessments 
through 14 days after the last dose of study drug will be included in the analyses. 
5.4 Per Protocol Analysis Set 
The per-protocol analysis set (PPS) includes all subjects in mITT without major protocol 
deviations.  Major protocol deviations are defined as those deviations considered to have a major 
effect on the collection or interpretation of the primary efficacy endpoint. Section 5.4.1 details 
the classification of deviations. Additionally, subjects assigned to the active treatment groups 
with 2 or more samples in which PK trough levels of both the parent drug (MSDC-0602K) and 
its metabolite are below the level of detection will be assumed to have been non-compliant and 
may be excluded from the PPS, and/or all subjects at sites where the majority of subjects 
assigned to active treatment appear to have been non-compliant based on trough levels may be 
excluded. Identification of all subjects and measures to be included in the PPS analyses will be 
determined before the final database lock and unblinding for the final analysis. 
The PPS will be used as an additional sensitivity analysis for key efficacy endpoints. PPS 
subjects will be analyzed as randomized regardless of treatment received.   


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5.4.1 Important Protocol Deviations Leading to Exclusion from the PPS Analysis 
Only those deviations considered to have a major effect on efficacy will lead to complete 
exclusion of the subjects from the PPS population. For the purposes of this study, the following 
criteria have been identified as important protocol deviations as it is considered that the 
occurrences of any of these criteria might have an important influence on the primary efficacy 
endpoint.  Other deviations not specifically identified here may result in exclusion from the PPS 
analysis and will be identified prior to final database lock and unblinding. 
Type 
Deviation 
Method of Identification 
Inclusion 
and 
Exclusion 
(I/E) Criteria 
Subjects who 
fail to comply 
with key I/E 
criteria 
Programmatic check to identify subjects based on protocol 
deviations and CRF data who failed to meet the following major 
eligibility criteria: 
Exclusion Criteria (additions to the exclusion criterion specified in 
the protocol are marked in italics): 
1. Known history of HIV. 
2. Prior liver transplantation. 
3. Other well-documented causes of active chronic liver disease, 
including, but not restricted to: history of positive hepatitis B surface 
antigen (HBsAg) or HCV RNA (subjects must be viremia free for a 
minimum of 2 years), suspicion of drug-induced liver disease, 
alcoholic liver disease and auto-immune hepatitis, Wilson’s disease 
hemochromatosis, primary biliary cirrhosis, primary sclerosing 
cholangitis, genetic hemochromatosis, known or suspected HCC, 
history of planned liver transplant or current MELD score > 12. 
4. History of cirrhosis and/or hepatic decompensation including 
ascites, hepatic encephalopathy or variceal bleeding. Platelet count < 
100,000/μL of blood at Screening. 
5. AST or ALT >5 times the upper limit of normal at Screening. 
8. History of alcohol abuse or drug abuse within 6 months of 
Screening or discovery of heavy alcohol use during study treatment. 
12. Current use of any diabetes medications other than metformin, 
GLP-1 agonists, SGLT2 inhibitors, sulfonylureas or DPP4 inhibitors 
three months prior to the baseline diagnostic liver biopsy or during 
the study unless as specified in the protocol. Current use of insulin 
or PPARγ agonists (pioglitazone or rosiglitazone) is not allowed for 
the duration of the study. 
21. Participation in an investigational study (other than a non-
treatment registry study) or received an investigational drug within 
30 days or 5 half-lives (whichever is longer) prior to or any time 
after randomization. 
Inclusion Criteria: 
2. Histological evidence of NASH, based on the central read of the 
biopsy for purposes of determining eligibility, with a NAS (NASH 
CRN scoring) ≥ 4 with a score of at least 1 in each component of 
NAS. 
3. Histological evidence of liver fibrosis defined as NASH CRN 
System fibrosis score of F1 to F3. 


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Type 
Deviation 
Method of Identification 
Thus, subjects will be reviewed for exclusion if NAS < 4, or score of 
0 in any component of NAS, or fibrosis score of F0 or F4. 
5. Subjects with type 2 diabetes mellitus (DM) must be under 
stable and reasonable control, defined as under a healthcare 
provider’s care for DM with glycosylated hemoglobin [HbA1c] ≤ 
9.5%. Subjects taking permitted anti-diabetic therapies 
(metformin, GLP-1 agonists, SGLT2 inhibitors, sulfonylureas or 
DPP4 inhibitors) must be on stable doses for a period of at least 3 
months prior to randomization.  
Manual review will be performed for identifying subjects who 
violate the above I/E criteria, including review of prohibited changes 
reported for the 3 months prior to randomization (in reference to 
inclusion criterion #5 above). 
Prohibited 
Medication 
Use 
Subjects who 
took 
medications that 
are not 
permitted during 
the study 
Programmatic identification of subjects with CRF-reported post-
randomization use of PPARγ agonist, insulin, ursodeoxycholic acid, 
paclitaxel, phenytoin, warfarin, celecoxib, tolbutamide or 
repaglinide; and subjects with reported protocol deviations related to 
prohibited medication use. 
Manual review of blinded concomitant medications listing to 
identify subjects with prohibited changes post-randomization in 
therapeutic agents for diabetes. The medical monitor and Sponsor 
will review the listing and note any prohibited changes in these 
glycemic control medications; these subjects may be excluded from 
the PPS. 
Non-
compliance 
During the 
Study 
Subjects who 
had low study 
drug exposure 
and compliance 
Programmatic check of estimated compliance based on the study 
drug administration data, and programmatic identification of 
subjects assigned to an active treatment group with parent drug 
(MSDC-0602K) or MSDC-0597 (major metabolite) trough levels 
below the detection threshold at two or more visits. 
Manual review will be performed to identify subjects with 
compliance less than 80% based on study drug administration 
data (Section 7.7.2) and/or other compliance issues identified by 
sponsor. 
Errors in 
Treatment 
Allocation 
Subjects who 
received a 
wrong treatment 
at 1 or more 
study visits due 
to packaging or 
dispensing 
errors during the 
study 
Programmatic check based on unblinded IXRS database after the 
study is unblinded for the final analysis. The check will be done by 
comparing the bottle number that IXRS had assigned to the 
subject/visit against the bottle number actually used. 


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Type 
Deviation 
Method of Identification 
Other 
Significant 
Protocol 
Deviation 
Protocol 
deviations based 
on the clinical 
monitoring. 
Manual review: This list will be reviewed by the medical monitor 
and Sponsor and important protocol deviations leading to exclusion 
from the PPS will be identified. 
 
As defined in the table, the majority of the protocol deviations will be determined 
programmatically from the data. Those criteria that require clinical interpretation will be 
reviewed prior to final database lock, following discussion with the medical monitor and 
Sponsor. 
All important protocol deviations occurring during the study will be reviewed and approved by 
the Sponsor prior to final database lock and unblinding for the final analysis. Should other 
categories of important protocol deviations, not anticipated at the time of preparing this SAP be 
identified during the study (and prior to unblinding for the final analysis), they will be provided 
in a separate document and included in all relevant protocol deviation reviews and approvals. 
6 
DATA HANDLING 
6.1 Time points and Visit Windows 
Study Day 1 
Study day 1 is defined as the date of the first dose or the date of randomization for subjects who 
were not administered any dose of study drug.  
Study Day 
Study days after study day 1 are calculated as (assessment date – study day 1 date) + 1.  Study 
days prior to study day 1 are calculated as (assessment date – study day 1 date).  The day prior to 
study day 1 is study day -1, there is no study day 0. 
Scheduled and Unscheduled Visits 
For the purpose of statistical analysis, the nominal visit designations as assigned by the 
investigator will be used. Unscheduled visits will be programmatically assigned to a nominal 
visit designation according to the following definition of visit windows. 
Definition of visit windows to assign unscheduled visits to nominal visit designations 
Nominal 
Visit 
Target 
Day 
(Study 
Day) 
Parameter 
measured at 
all visits 
Parameter 
measured at 
all visits 
except Visit 
8 
Parameter 
measured at 
all visits 
except Visits 
2, 3, and 8 
Parameter 
measured at 
Visits 1, 5, 7 
and 8 
Parameter 
measured at 
Visits 1, 5, 
and 7 
Parameter 
measured at 
Visits 1 and 
7 
 1 Baseline 
1 
≤1 
≤1 
≤1 
≤1 
≤1 
≤1 
 2 Month 1 
30 
2-45 
2-45 
-- 
-- 
-- 
-- 
 3 Month 2 
60 
46-75 
46-75 
-- 
-- 
-- 
-- 


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 4 Month 3 
90 
76-135 
76-135 
2-135 
-- 
-- 
-- 
 5 Month 6 
180 
136-225 
136-225 
136-225 
2-270 
2-270 
-- 
 6 Month 9 
270 
226-315 
226-315 
226-315 
-- 
-- 
-- 
 7 Month 12 
360 
316-367 
≥316 
≥316 
271-367 
≥271 
≥271 
 8 Follow-up 
374 
≥368 
-- 
-- 
≥368 
-- 
-- 
 
For all populations, multiple visits for a given parameter with the same nominal visit designation 
will be dealt with as follows: 
• If both scheduled and unscheduled visit data are available, the scheduled visit data will be 
used for analysis with the exception of baseline, where the baseline value will be defined as 
the last scheduled or unscheduled value collected on or prior to the date of the first dose of 
treatment (or randomization for subjects who were not administered any dose of study drug). 
• If multiple unscheduled visits occur within the same visit window and no data from a 
scheduled visit is available for the corresponding nominal visit designation, then the 
unscheduled visit closest to the corresponding target day will be used in the analysis.  If there 
is a tie, the later unscheduled visit will be used in the analysis. 
6.2 Handling of Dropouts or Missing Data 
In order to achieve the goal of a well conducted clinical trial according to International Council 
on Harmonisation Good Clinical Practice, every effort should be made to collect all data (i.e., if a 
subject misses a scheduled assessment, the site personnel should contact the subject and request 
him/her to come to the clinic for the visit) (International Conference on Harmonisation, 1998; 
European Medicines Agency, 2011). However, despite best efforts, it may be inevitable that 
missing or incomplete data are reported. All missing or partial data will be presented in the 
subject data listings, as they were recorded on the eCRF. 
Missing data will not be imputed in statistical analyses, except as noted below (Section 6.2.1 - 
6.2.4). 
6.2.1 Missing Dates 
For AEs with partial or missing onset or stop dates: 
AE stop date will be imputed first as: 
• 
If stop date is completely missing, assume it is ongoing (no imputation); 
• 
For a partial AE stop date: if day is missing, use last day of the month; if both day and 
month are missing, use December 31st.  
Then AE onset date will be imputed as: 
• 
If onset date is completely missing: the first dose date; 
• 
For a partial AE onset date (day is missing, or both day and month are missing): 
o Partial date < the first dose date: last day of the month, or December 31st 
o Partial date = the first dose date: the first dose date 
o Partial date > the first dose date: first day of the month or January 1st 


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If the imputed AE onset date is after the AE stop date/imputed AE stop date, then the onset date 
will be set to the AE stop date/imputed AE stop date. 
The imputed dates will not be listed. Study day relative to the first dose of study drug associated 
with missing or partial dates will not be displayed in AE listings. 
In the event that a partial date (month/year or year) for concomitant medication is available, this 
information will be used as follows: 
• 
When both month and year are available – first day of the month will be used for start 
date and the last day of the month will be used for the stop date. 
• 
When only year is available – January 1st will be used for the start date and December 
31st will be used for the stop date. 
The imputed dates will only be used to determine whether a concomitant medication will be 
classified as prior medication or concomitant medication. 
6.2.2 NASH CRN Histological Scores 
Fibrosis scores are reported by the central histopathologist as 0, 1a, 1b, 1c, 2, 3, 4.  Scores of 1a, 
1b, and 1c will all be considered as fibrosis stage 1 for analysis.  Worsening of fibrosis will be 
considered as an increase of 1 stage or more.  Note that the baseline fibrosis score (F1 vs. F2/F3) 
to be included as a factor in the logistic regression, risk differences, and ANCOVA models will 
be the value used to determine the stratum at randomization and will come from the IXRS. The 
categorical fibrosis score summarized with counts and percentages and as a numeric score in the 
demographic summary, as well as the analyses of fibrosis score as a numeric endpoint will use 
those values reported by the central histopathologist as follows: 
• In case the liver biopsy was repeated due to a clinical reason as determined by the 
investigator and approved by Cirius, or because the sample was not readable the biopsy 
with the latest collection date will be used.  
• In case there are multiple samples (accession numbers) associated with a biopsy on a 
given collection date, the results for the accession number associated with the highest 
NAS will be used for analysis. 
• Results from the central histopathologist’s blinded reread of the qualifying screening 
biopsy utilized to determine eligibility will be used as baseline data. 
The NASH CRN histological scores as read by the local pathologist and recorded on the eCRF at 
Screening (BIOPFIB1) and at Visit 7 (BIOPFIB2) will not be used in any analyses but may be 
included in subject listings. 
6.2.3 Imputation for Primary Endpoint 
Sensitivity analyses will be performed on the primary endpoint using two different imputation 
methods. The sensitivity analyses will include all subjects who were randomized and who 
received at least one dose of study drug. Two approaches will be used to impute or substitute 
missing response at 12 months. Post-baseline observations that have been excluded from the 
primary analysis due to biopsies taken more than 14 days after last dose of study drug will be 
treated as missing and imputed or substituted as well. 


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When using multiple imputation, missing baseline and/or post-baseline values needed to 
determine response at 12 months will be imputed multiple times to account for the uncertainty 
about the true values to impute. To this end, each of the four categorical variables underlying the 
response definition of the primary endpoint will be imputed if missing, using the following 
categories: 
• Steatosis: 0, 1, 2, 3 
• Lobular inflammation: 0, 1, 2, 3 
• Ballooning: 0, 1, 2 
• Fibrosis score: 0, 1, 2, 3, 4 
Using the SAS procedure PROC MI 10 imputed data sets will be generated. The regression 
model will be adjusted for the corresponding baseline values and will further use presence of 
diabetes mellitus, Vitamin E use ≥ 400 IU, age, and sex as covariates. 
An example of the SAS code to be used is below:  
proc mi data=<input dataset> out=<output dataset> seed=1234 nimpute=10 
minimum=<…> maximum=<…> round=<…>; 
var 
<12 months steatosis> <baseline steatosis>  
<12 months lobular inflammation> <baseline lobular inflammation>  
<12 months ballooning> <baseline ballooning>  
<12 months fibrosis score> <baseline fibrosis score>  
<presence of diabetes mellitus> <Vitamin E use ≥ 400 IU> <sex><age at baseline>; 
run; 
 
The 10 multiple imputed datasets will be used separately in the statistical analysis model and the 
resulting odds ratios and 95% CIs will be combined via Rubin’s rules (using PROC 
MIANALYZE) to provide a global estimate of the odds ratio with a corresponding 95% CI and 
p-value. 
As a second sensitivity analysis of the primary endpoint, subjects with missing response data at 
12 months will be included as non-responders. Similar to above, this sensitivity analysis will 
include all subjects who were randomized and who received at least one dose of study drug. 
6.2.4 Imputation for Missing Changes in Laboratory Values 
 
HbA1c 
 
Additional sensitivity analyses may be performed conditional on the distribution of changes in 
glycemic control medications between the placebo and active treatment groups at 6 and 12 
months. 
 
If more than 35% of the subjects who had a major up-titration of glycemic control medications 
are in the placebo group, a sensitivity analysis may be done where the 6- and 12-month values of 
HbA1c for subjects who had a major up-titration of glycemic control medications will be 
imputed to be 0.5 % higher than the observed value. 


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If more than 15% of the subjects who had a major down-titration of glycemic control 
medications are in the placebo group, a sensitivity analysis may be done where the 6- and 12-
month values of HbA1c for subjects who had a major down-titration of glycemic control 
medications will be imputed to be 0.5 % lower than the observed value. 
 
If more than 35% of the subjects missing paired change-from-baseline values of HbA1c 
(separately at 6 and 12 months) are in the placebo group, a sensitivity analysis may be performed 
where the missing follow-up value will be assigned the baseline value plus 0.5%. 
 
Liver function tests and other markers 
Additional sensitivity analyses may be performed conditional on the distribution of missing 
values between the placebo and active treatment groups at 6 and 12 months. 
 
If > 35% of the subjects missing paired change-from-baseline values of the following laboratory 
tests (separately at 6 and 12 months) are in the placebo group, a sensitivity analysis may be 
performed where missing follow-up values will be assigned the corresponding baseline values 
plus 0.5 times the maximum change (maximum increase) from baseline for the parameter 
observed in any subject (i.e., regardless of treatment group) at the timepoint: ALT, AST, ALP, 
Total Bilirubin, GGT, pro thrombin time, APRI score, CK-18, ELF, FIB-4, Pro-C3, Fibro-test 
score, and HOMA-IR. Likewise for albumin, missing follow-up values may be assigned the 
corresponding baseline values minus 0.5 times the minimum change (maximum decrease) from 
baseline . 
 
7 
STATISTICAL METHODS 
7.1 General Principles 
All data processing, summarization and analyses will be performed using Version 9.3 (or later) of 
the SAS (SAS Institute, Cary, NC) statistical software package. 
Unless specified otherwise, data will be displayed using the following treatment group labels, in 
the order presented: 
• Placebo 
• MSDC-0602K 62.5 mg  
• MSDC-0602K 125 mg  
• MSDC-0602K 250 mg  
• Total (if applicable) 
All data collected will be presented in listings by treatment group, site, subject, and visit (where 
applicable), unless otherwise specified.  


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Data will be presented in summary tables by treatment group, assessment and visit (where 
applicable).  
Descriptive summary statistics for continuous variables will include the number of observations 
(N), mean, standard deviation (SD), median, 25th and 75th percentiles, minimum and maximum.  
Descriptive summary statistics for categorical variables will include frequency counts and 
percentages [n (%)]. Unless stated otherwise in the table shells, the denominator for percentage 
calculations will be the number of subjects in the analysis population with a non-missing value. 
Dates will be displayed as DDMMMYYYY. 
7.2 Subject Disposition and Data Sets Analyzed 
The number and percentage of subjects achieving some study milestones listed below will be 
summarized by treatment group and overall (if applicable): 
• Subjects randomized by site  
• Subjects randomized by randomization strata [IXRS data] 
• Number and percentage of subjects screened, randomized, treated, included in each study 
population (mITT, SAF, PPS) 
• Number and percentage of subjects who complete the study and who discontinue early, 
including a breakdown of the primary reasons for discontinuation 
• Number and percentage of subjects who complete the administration of study drug, 
discontinue the study drug early, and breakdown of the primary reasons for early 
discontinuation of study drug  
Listings will be provided for screen failure and discontinued subjects. 
7.3 Protocol Deviations 
The number and frequency of subjects with one or more protocol deviations identified through 
clinical monitoring within each protocol deviation category (failure to adhere to visit schedule, 
assessment not performed per protocol, IP non-compliance, use of prohibited medication, IP 
dispensing error, ICF issue, Inclusion/exclusion criteria (eligibility), other) will be summarized 
by treatment group in the mITT population. Additionally, important protocol deviations leading 
to exclusion from the PPS population (see Section 5.4.1) will be listed and summarized by 
treatment group for the mITT population. 
The important protocol deviations will be identified prior to the final database lock and prior to 
unblinding for the final analysis. 
7.4 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be listed and summarized by treatment group and 
overall for the mITT population. Standard descriptive statistics will be presented for the 
continuous variables of: 
• Age (years) 


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• Weight (kg) 
• Height (cm) 
• Body mass index (BMI) (kg/m2) 
• Waist circumference (cm) 
• NAFLD activity score (NAS) 
• Fibrosis score 
The total counts and percentages of subjects will be presented for the categorical variables of: 
• Age category (<55 vs. ≥55 years) 
• Sex (male vs. female) 
• Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Pacific Islander, White, Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Stated, Unknown) 
• Vitamin E ≥ 400 IU (Yes vs. No) [EDC data] 
• Fibrosis score (0, 1, 2, 3, 4)  
• Presence of T2DM (Yes vs. No) [EDC data] 
• Smoking (Never, Current, Former) 
• Alcohol abuse (Abstinent, Light, Moderate, Heavy) 
Fibrosis score is the score reported by the central histopathologist (see Section 6.2.2). 
No formal tests of statistical significance will be performed on the demographic and baseline 
data.  
7.5 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 19.0 (or a later version if updated during the study). The number and percentage of 
subjects with any medical history will be summarized for the mITT population by system organ 
class (SOC) and preferred term (PT) for each treatment group and overall.  
7.6 Prior and Concomitant Medications 
Medications received prior to or concomitantly with treatment will be coded using the WHO Drug 
Dictionary [Version B2-DDE March 2016 (or a later version if updated during the study)], 
Anatomical Therapeutic Chemical (ATC) Classification codes.  
Prior medications and concomitant medications are defined as follows: 
• Prior medications are those taken with a start date prior to the first dose date of study 
treatment 
• Concomitant medications are those with a start date on or after the first dose date of study 
treatment, or those with a start date before the first dose date of study treatment and a 


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stop date on or after the first dose date of study treatment (including those medications 
which are classified as ongoing). 
If a medication cannot be classified as “prior” or “concomitant” after applying imputation rules 
for missing/incomplete dates, it will be classified as concomitant. 
Prior medications, prohibited medications (refer to protocol sections 6.4 and 7.8) and 
concomitant medications taken during the study will be summarized for the mITT population. 
The number and percentage of subjects using each medication will be summarized by ATC-
Level 2 class and preferred term by treatment group. 
Prohibited medications include PPARγ agonists, insulin, ursodeoxycholic acid, paclitaxel, 
phenytoin, warfarin, celecoxib, tolbutamide and repaglinide. A disallowed change post-
randomization in dose of metformin, GLP1 agonists, SGLT2 inhibitors, sulfonylureas, DPP4 
inhibitors, or insulin will be included in the summary of prohibited concomitant medications. 
The number and percentage of diabetic subjects (subjects with T2DM) with an up-titration, 
down-titration, and no major change in glycemic control medications after randomization will 
also be summarized by treatment group. The classification of each subject into one of the three 
categories will be based on blinded adjudication based on a manual review of subjects’ use of 
glycemic control medications prior to final database lock and unblinding. The “no major change” 
category may include subjects with changes identified as not being clinically significant during 
blinded adjudication. 
In addition, all prior and/or concomitant medications will be presented in subject data listings, 
with additional listings presenting only prohibited medications and only glycemic control 
medications. 
7.7 Treatment Compliance and Exposure 
7.7.1 Exposure 
Overall treatment duration in days will be evaluated and summarized from the first dose date to 
the last dose date (as recorded on the End of Treatment CRF page) of randomized study drug 
using the following formula: 
Overall treatment duration = end of treatment date – first dose date + 1. 
Descriptive statistics for overall treatment duration (days) will be presented by treatment group 
and will also be summarized by duration categories: 
• < 90 days 
• ≥90 and < 180 days 
• ≥180 and < 270 days 
• ≥270 and <360 days 
• ≥360 days 
7.7.2 Study Drug Administration Data 
Study drug capsule count will be conducted at Visit 4 (3 months), Visit 5 (6 months), Visit 6 (9 
Months), and Visit 7 (12 months), and possibly at Visit 2 (1 month), Visit 3 (2 Months), and 
Visit 8 (Follow-up). Overall compliance will be calculated as the actual number of capsules 


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taken divided by the number of capsules required, then multiplied by 100. The required number 
of capsules will be calculated as the number of capsules per day (1) times the overall duration of 
treatment administration in days. The administration duration in days will be derived from the 
drug dispense date in the drug administration log as: 
Administration duration = last dose date – first dispense date + 1. 
The last dose date will be the recorded end of treatment date if available. If the end of treatment 
date is missing, the end of study date will be used instead if available. 
The following special cases may apply per subject: 
• If the return capsule count is missing for a drug dispensation record other than the last, 
the duration of the corresponding period will be subtracted from the overall 
administration duration. The duration to be subtracted will be derived as return date 
minus dispense date of that record. If the return date is missing as well, the dispense date 
of the following record will be used as end date. 
• If the return capsule count is missing for the last drug dispensation record (e.g. patient 
was lost to follow-up), the administration duration will be calculated using the return date 
of the latest available record with non-missing dispense and return counts as last dose 
date. 
• If only the return date is missing for any record but dispense count, return count, and 
dispense date are available, the dispense date of the following record will be used as 
substitute return date if available. Otherwise the last dose date as defined above will be 
used. 
• If study drug was dispensed after last dose date by mistake, the corresponding records 
will not contribute to the overall compliance result. 
As a summary, the following formula will be used to calculate overall compliance across records 
with available data and after taking special cases as described above into account: 
100 × (𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑛𝑛𝑛𝑛. 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑−𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑛𝑛𝑛𝑛. 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟)
𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑖𝑖𝑖𝑖 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
  
Subjects with an overall compliance less than 80% will be reviewed by the medical monitor and 
Cirius Therapeutics, Inc., for potential exclusion from the per-protocol analyses. Exclusion of 
non-compliant subjects from the per-protocol analysis set will be pre-specified prior to the final 
database lock and prior to unblinding for the final analysis. 
7.7.3 Pharmacokinetic Trough Levels 
Trough levels of parent drug (MSDC-0602K) and its metabolite (MSDC-0597) will be listed, 
with subjects assigned to active treatment identified as potentially non-compliant based on these 
levels. 


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7.8 Efficacy 
7.8.1 Primary Efficacy Analysis 
The primary efficacy endpoint is hepatic histological improvement in NAS (NASH CRN 
scoring). A responder (subjects with hepatic histological improvement) is defined as having all 
of following: 
• A decrease of at least 2 points in NAS at 12 months. The reduction in NAS must also 
include at least a 1 point reduction in either ballooning or inflammation. 
• No worsening of fibrosis, defined as no increase in CRN fibrosis score of ≥ 1 stage.   
Each MSDC-0602K dose group will be compared with the placebo group at the two-sided 0.05 
significance level. For each comparison, the null hypothesis is that there is no difference in 
response rates between the MSDC-0602K dose and placebo. The alternative hypothesis is that 
there is a difference in response rates between the MSDC-0602K dose and placebo. The primary 
analysis of the primary efficacy endpoint will be performed in the mITT population, with 
supportive analysis in the PPS population. The number and percentage of responders will be 
summarized by treatment group. Analyses of liver biopsy findings will be based on the central 
expert histopathologist’s repeat read of the Screening biopsy and read of the Visit 7 biopsy. The 
central read of the Screening biopsy for purposes of determining subject eligibility, and the local 
pathologist’s assessments, will not be considered for these analyses. Covariate adjustment for 
randomization stratification factors diabetes mellitus, baseline fibrosis (F1 versus F2/F3), and 
vitamin E use will utilize values reported at randomization and which determined the stratum in 
which the subject was randomized. 
The primary analysis will be conducted using observed data included in the analysis dataset. Five 
additional sensitivity analyses will be conducted in the mITT population where (1) missing 
values are multiply imputed, (2) subjects with missing data will be treated as non-responders, as 
outlined in Section 6.2.3, (3) subjects with biopsy results up to and including (≤) 1 day after last 
dose of study drug will be included, (4) subjects with biopsy results up to (<) 7 days after last 
dose of study drug will be included, and (5) all observed data will be used (including biopsy 
results obtained more than 14 days after last dose of study drug). These sensitivity analyses will 
include all subjects who were randomized and who received at least one dose of study drug. 
Comparisons between each active treatment group and the placebo group will be evaluated using 
appropriate contrasts from a logistic regression model including treatment and adjusted for 
presence of diabetes mellitus, baseline fibrosis F1 versus F2/F3, and ordinal baseline NAS. 
Model-adjusted odds ratios for each active dose group relative to placebo and their associated 
95% confidence intervals (CIs) and p-values will be provided.  
In addition, stratification-adjusted differences in response rates (risk differences) adjusted for 
presence of diabetes mellitus, baseline fibrosis F1 versus F2/F3, and ordinal baseline NAS 
between each active dose group and placebo and their associated 95% CIs and p-values will be 
provided (LaVange et al 2005; Zink and Koch 2012). 


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Supportive analyses of the primary endpoint will include comparisons of each active dose group 
with placebo using Cochran-Mantel-Haenszel (CMH) tests stratified by presence of diabetes 
mellitus.  
Sensitivity analysis for the primary endpoint will be performed using a logistic regression model 
including treatment and adjusting for presence of diabetes mellitus, baseline fibrosis F1 versus 
F2/F3, sex, age, and ordinal baseline NAS. Adjusted odds ratios relative to placebo and the 
corresponding 95% CIs and p-values will be provided. 
A summary of the planned primary efficacy analyses is given below: 
Method 
mITT 
Observed 
data 
PPS 
Observed 
data, data 
exclusions 
possible 
due to non-
compliance 
mITT 
Multiply 
imputed 
response 
data 
mITT 
Missing 
response 
status at 
12 months 
set to non-
responder 
mITT 
Observed 
data ≤1 
day after 
last dose 
of study 
treatment 
mITT 
Observed 
data <7 
days after 
last dose 
of study 
treatment 
mITT 
Observed 
data 
including 
results 
any time 
after last 
dose of 
study 
treatment 
Logistic regression (odds 
ratios) including treatment 
group and adjusted for 
presence of diabetes 
mellitus, baseline fibrosis 
F1 versus F2/F3, ordinal 
baseline NAS.  
X* 
X 
X 
X 
X 
X 
X 
Stratification-adjusted 
differences in response 
rates (risk differences) 
between each active dose 
group and placebo adjusted 
for presence of diabetes 
mellitus, baseline fibrosis 
F1 versus F2/F3, ordinal 
baseline NAS. 
X 
X 
X 
X 
X 
X 
X 
CMH tests of each active 
dose group versus placebo 
stratified by presence of 
diabetes mellitus. 
X 
X 
 
 
 
 
 
Logistic regression (odds 
ratios) including treatment 
group and adjusted for 
presence of diabetes 
mellitus, baseline fibrosis 
F1 versus F2/F3, sex, age, 
ordinal baseline NAS. 
X 
X 
 
 
 
 
 
*Primary analysis. 


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7.8.2 Secondary Efficacy Analysis 
Primary analyses of the secondary efficacy endpoints will be conducted in the mITT population 
with supportive analyses in the PPS population. Descriptive statistics for secondary efficacy 
endpoints will be presented by treatment group and by study visit where appropriate. 
Proportion of subjects with resolution of NASH at month 12 
Resolution of NASH is defined as a ballooning score of 0 and an inflammation score of 0-1 
without worsening of fibrosis at month 12. No worsening of fibrosis is defined as no increase in 
CRN fibrosis score of ≥ 1 stage.  
The incidence rate of resolution of NASH will be summarized by treatment group. Each active 
treatment group will be compared to the placebo group using appropriate contrasts from a 
logistic regression model including treatment and adjusted for presence of diabetes mellitus, 
baseline fibrosis F1 versus F2/F3, and ordinal baseline NAS. Model-adjusted odds ratios for each 
active dose group relative to placebo and their associated 95% CIs and p-values will be provided. 
In addition, stratification-adjusted rate differences and their associated 95% CIs and p-values 
will be provided, with adjustment for presence of diabetes mellitus, baseline fibrosis F1 versus 
F2/F3, and ordinal baseline NAS. Supportive analyses will include comparisons of each active 
dose group with placebo using Cochran-Mantel-Haenszel (CMH) tests stratified by presence of 
diabetes mellitus. A logistic regression model adjusting for treatment, presence of diabetes 
mellitus, baseline fibrosis F1 versus F2/F3, sex, age, and ordinal baseline NAS will be used as 
sensitivity analysis. Adjusted odds ratios relative to placebo and the corresponding 95% CIs and 
p-values will be provided. Additional sensitivity analyses will be conducted in the mITT 
population where (1) subjects with biopsy results up to and including (≤) 1 day after last dose of 
study drug will be included, (2) subjects with biopsy results up to (<) 7 days after last dose of 
study drug will be included, and (3) all observed data will be used (including biopsy results 
obtained more than 14 days after last dose of study drug). These additional sensitivity analyses 
will be applied to the logistic regression model including treatment and adjusted for presence of 
diabetes mellitus, baseline fibrosis F1 versus F2/F3, and ordinal baseline NAS, and to the 
analysis of stratification-adjusted rate differences with adjustment for presence of diabetes 
mellitus, baseline fibrosis F1 versus F2/F3, and ordinal baseline NAS. 
Proportion of subjects with improvement of fibrosis by at least 1 stage with no worsening 
of NASH at 12 months  
Reduction of fibrosis is measured by CRN staging score. All subjects with CRN staging score ≥ 
1 decrease from baseline will be considered as responders. Worsening of NASH is defined as an 
increase of either ballooning or inflammation. 
The incidence rate of the responders will be summarized by treatment group. Each active 
treatment group will be compared to the placebo group using appropriate contrasts from a 
logistic regression model including treatment and adjusted for presence of diabetes mellitus, 
baseline fibrosis F1 versus F2/F3, and ordinal baseline NAS. Adjusted odds ratios relative to 
placebo and their associated 95% CIs and p-values will be provided. In addition, stratification-
adjusted risk differences and their associated 95% CIs and p-values will be provided, with 
adjustment for presence of diabetes mellitus, baseline fibrosis F1 versus F2/F3, and ordinal 
baseline NAS. A logistic regression model adjusting for treatment, presence of diabetes mellitus, 
baseline fibrosis F1 versus ≥ F2/F3, sex, age, and ordinal baseline NAS will be used as 


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sensitivity analysis. Adjusted odds ratios relative to placebo and the corresponding 95% CIs and 
p-values will be provided. Additional sensitivity analyses will be conducted in the mITT 
population where (1) subjects with biopsy results up to and including (≤) 1 day after last dose of 
study drug will be included, (2) subjects with biopsy results up to (<) 7 days after last dose of 
study drug will be included, and (3) all observed data will be used (including biopsy results 
obtained more than 14 days after last dose of study drug). These additional sensitivity analyses 
will be applied to the logistic regression model including treatment and adjusted for presence of 
diabetes mellitus, baseline fibrosis F1 versus F2/F3, and ordinal baseline NAS, and to the 
analysis of stratification-adjusted rate differences with adjustment for presence of diabetes 
mellitus, baseline fibrosis F1 versus F2/F3, and ordinal baseline NAS.  
Mean change from baseline in NAS and each one of its components (steatosis, inflammation 
and ballooning) at 12 months  
For each outcome separately, the change from baseline to month 12 will be analyzed using an 
Analysis of Covariance (ANCOVA) model with fixed terms for treatment, age, sex, presence of 
diabetes mellitus, Vitamin E ≥ 400 IU, baseline fibrosis F1 versus F2/F3, and either ordinal 
baseline NAS or the baseline value of the component score as applicable (and used as an ordinal 
covariate). Least square mean treatment differences relative to placebo and associated 95% CIs 
and p-values will be presented. Summary statistics for baseline values, 12-months values, and 
change from baseline will be presented for each treatment group. 
Mean change from baseline in fibrosis score at 12 months 
Mean change from baseline in fibrosis score will be analyzed similarly as the mean change from 
baseline in NAS above using an ANCOVA model with fixed terms for treatment, age, sex; 
randomization stratification factors presence of diabetes mellitus, Vitamin E ≥ 400 IU, baseline 
fibrosis F1 versus F2/F3; and baseline fibrosis score from the repeat read of the screening biopsy 
(used as an ordinal covariate with possible values 0-4).  
7.8.3 Subgroup Analysis 
Subgroup analyses of the primary endpoint and secondary efficacy endpoints will be performed 
for different categories of baseline characteristics and the randomization stratification factors: 
• Age at study entry (< 55 years vs. ≥ 55 years) 
• Sex (Male vs. Female) 
• Race (White vs. Non-white) 
• Presence of diabetes mellitus (Yes vs. No) 
• Use of Vitamin E ≥ 400 IU (Yes vs. No) 
• Fibrosis scores (F1 vs. F2/F3) 
• Baseline NAS (≤ 4 vs. > 4) 
• PNPLA3 genotype variant (cc/cg vs. gg) 
For each dichotomous endpoint, the homogeneity of the effect of each active dose relative to 
placebo across each subgroup will be assessed using appropriate contrasts in a logistic regression 
model that includes terms for the treatment groups, the subgroup under consideration, and their 
interaction, together with adjustment for presence of diabetes mellitus, baseline fibrosis F1 
versus F2/F3, and ordinal baseline NAS or the baseline component score, as appropriate. For 


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quantitative outcomes, similar analyses using ANCOVA will be performed. All subgroup 
analyses will be exploratory and performed for the mITT population only.  
7.8.4 Exploratory Analysis 
Exploratory efficacy endpoints are listed in Section 3.3. 
The analysis of mean change from baseline at 12 months in liver stiffness will be restricted to 
subjects for whom liver stiffness has been measured using the FibroScan device. The type of 
device for each subject and time-point was not recorded in the eCRF but will be captured in an 
external spreadsheet and provided by the Sponsor prior to unblinding for the final analysis. 
All exploratory analysis will be performed for the mITT population. For change from baseline 
endpoints, baseline values, post-baseline values, and change from baseline will be summarized 
by treatment groups at each evaluation time point. Highly skewed variables will be log-
transformed for analysis, and geometric mean changes presented. Comparisons between each 
active dose and placebo will be done using ANCOVA models for continuous variables, similarly 
as for secondary endpoints (refer to Section 7.8.2). Regardless of skewness, summaries and 
ANCOVA results will be presented for log-transformed values of ALT, AST, ALP, and GGT, in 
addition to results based on non-transformed values. 
Fibrosure numeric results (rather than results expressed as fibrosis stage) will be analyzed. 
Changes in diagnostic category (NASH diagnosis confirmed or cannot be confirmed) from 
baseline to month 12 will be presented by means of a shift table. 
Changes in markers of insulin sensitivity (HOMA-IR, HbA1c, fasting plasma glucose, and 
fasting insulin) will be analyzed overall and then separately in subjects with T2DM, and in 
subjects with T2DM without a major up- or down-titration in glycemic control medications 
during the study (categorized into the “no major change” category during blinded adjudication).   
Mean change from baseline with standard error bars will be plotted for each treatment group by 
visit for insulin sensitivity markers (HOMA-IR, HbA1c, fasting plasma glucose, and fasting 
insulin) in the mITT population for (1) subjects with T2DM, and (2) subjects with T2DM 
without major changes in their glycemic control medications during the study.  
Normalization of ALT and AST will be evaluated with shift tables presenting movement in and 
out of reference range from baseline to each scheduled post-baseline visit as defined in Section 
7.9.2 and will be provided for each treatment group in the mITT population. 
Changes in HbA1c will also be evaluated with shift tables presenting movement in and out of 
reference ranges from baseline to 6 and to 12 months.  These shift tables will be presented in (1) 
subjects without T2DM, (2) subjects with T2DM, and (3) subjects with T2DM without major 
changes in glycemic control medications.  The HbA1c “normal range” will be considered 4.0-
5.6% in subjects without T2DM and 5.7-6.4% in subjects with T2DM. 


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7.9 Safety 
7.9.1 Adverse Events 
All adverse events (AEs) recorded on the eCRF will be coded using the MedDRA dictionary 
Version 19.0 (or a later version if updated during the study) and classified as treatment-emergent 
AEs (TEAEs) as follows: 
• TEAEs are events with start date on or after the date of first dose of study treatment and 
up to 14 days after date of last dose of study treatment or events with start date prior to 
the date of first dose of study treatment whose severity worsens on or after the date of 
first dose of study treatment.  
Listings of Serious AEs (SAEs), AEs leading to discontinuation of study treatment, and AEs 
resulting in death will be produced by treatment group. Adjudicated cause of death will be 
described. AEs with an onset between signing of informed consent and study drug initiation, and 
those with onset more than 14 days after the last dose of study drug will be listed separately. 
The number and percentage of subjects reporting each TEAE will be summarized by System Organ 
Class (SOC) and Preferred Term (PT) by treatment group and overall in the SAF population. Each 
subject will be counted only once within each PT or SOC and recording period. If a subject 
experiences more than one AE within a PT for the same recording period, only the AE with the 
strongest relationship or the worst severity, as appropriate, will be included in the summaries of 
relationship and severity. AEs with missing classifications regarding relationship to study drug 
and start date greater or equal to start of study drug will be considered as related to study drug. 
AEs that were reported to be at least possibly related to study drug will be considered as related to 
study drug. 
Tables will be produced for the following TEAEs overall and by SOC and PT, preceded by an 
overview table: 
• 
Any TEAE 
• 
Most common TEAEs (≥ 5% in any treatment group) 
• 
TEAEs by maximum severity 
• 
TEAE related to study drug   
• 
TEAEs related to study drug by maximum severity 
• 
TEAE leading to study drug discontinuation  
• 
TEAEs related to study drug and leading to study drug discontinuation 
• 
TEAEs leading to study drug interruption 
• 
Any TESAE (treatment-emergent serious AE) 
• 
TESAE related to study drug   
• 
TESAE leading to study drug discontinuation  
• 
TESAEs related to study drug and leading to study drug discontinuation 
• 
TESAEs leading to study drug interruption 


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• 
TESAE leading to death 
No statistical comparisons of TEAEs between treatment groups will be performed. 
7.9.2 Laboratory Evaluations 
Values for the following safety laboratory tests (hematology, serum chemistry, and urinalysis) 
will be listed and summarized by treatment group and visit.  
Hematology 
Serum Chemistry 
Urinalysis 
Hemoglobin 
Hematocrit 
Platelets, RBC with indices 
WBC with differential  
HbA1c*  
INR* 
PT* 
 
Albumin* 
Alkaline phosphatase (ALP)* 
Alanine aminotranferase (ALT)* 
Aspartate Aminotransferase (AST)* 
Blood Urea Nitrogen (BUN) 
Bicarbonate 
Calcium  
Chloride 
Creatinine  
Fasting plasma glucose (FPG)* 
Fasting insulin* 
Free fatty acid (FFA)* 
Lactate dehydrogenase (LDH) 
Phosphorus 
Potassium 
Sodium 
Gamma-Glutamyl transpeptidase (GGT)* 
Total Bilirubin* 
Total protein 
Uric acid 
Cholesterol (total, HDL, LDL, VLDL)* 
Triglycerides* 
Bilirubin 
Blood 
Glucose 
Ketones 
pH 
Creatinine 
Protein 
Specific gravity 
Microscopic exam (if blood or 
protein positive) 
 
 
*Also considered an efficacy parameter. 
 
All laboratory data will be reported in International System of Units (SI).  
For analysis purposes, values preceded by a “<” or a “>” sign (i.e., those below or above the 
limits of quantification) will be considered equal to 0.5 × the lower limit or 1.5 × the upper limit 
of quantification, respectively.  The proportion of subjects with values below the lower limit and 
above the upper limits of quantification will be provided among the summary statistics. 
Laboratory evaluations measured on a continuous scale will be summarized by visit using 
standard descriptive statistics for the SAF population. Changes from baseline will also be 
summarized. Summaries will be presented for log-transformed values of ALT, AST, ALP, and 
GGT, in addition to summaries of non-transformed values. For analysis by visit, analysis 
windowing as described in Section 6.1 will be used for each scheduled visit such that 
unscheduled visits will also be considered. For each laboratory analyte, the baseline value will be 
defined as last scheduled or unscheduled value collected prior to the first dose of treatment.  
For hematology and serum chemistry, shift tables presenting movement in and out of reference 
range from baseline to each scheduled post-baseline visit will be provided for each treatment 
group. An additional shift table will be produced for ALT where the upper normal limit is 
defined as 19 U/L for women and 30 U/L for men. Corresponding shift tables (normal vs. high / 


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normal vs. abnormal) will be produced for urinalysis. Additional tables will summarize the 
occurrence at each visit of clinically significant abnormal changes from baseline by treatment 
group for the following analytes: ALT, AST, GGT, and alkaline phosphatase with abnormal 
change defined as ratio to baseline ≥ 5, and total bilirubin with abnormal change defined as ratio 
to baseline ≥ 2. 
Mean change from baseline with standard error bars will be plotted for each treatment group by 
visit for select laboratory parameters (hemoglobin, ALT, ALP, AST, Creatinine, total bilirubin) 
for the SAF population. 
7.9.3 Vital Signs 
The following vital signs will be summarized by treatment group and visit. 
• Sitting systolic and diastolic blood pressure (mm Hg)* 
• Heart rate (bpm)* 
• Weight (kg)* 
• Waist circumference (cm)* 
*Also evaluated as an efficacy parameter. 
Vital signs data and changes from baseline in vital signs will be summarized by visit using 
standard descriptive statistics for the SAF population. The baseline value will be defined as last 
scheduled or unscheduled value collected prior to the first dose of treatment. For analysis by 
visit, analysis windowing as described in Section 6.1 will be utilized for each scheduled visit 
such that unscheduled visits will also be considered. 
Mean change in weight from baseline with standard error bars will be plotted for each treatment 
group by visit in the SAF population. 
7.9.4 Electrocardiograms 
Electrocardiogram (ECG) measurements and changes from baseline in ECG measurements will 
be summarized by visit using standard descriptive statistics for the SAF population. If a subject 
has both central and local ECGs for a given time point, the local values will be used for analysis. 
Summary statistics for the following parameters will be presented: ECG mean heart rate, PR 
interval, QRS duration, QT interval, QTcB interval, QTcF interval, RR interval. Number and 
percentage of subjects with atrial fibrillation, sinus rhythm, or other rhythm will be presented by 
visit. 
7.9.5 Physical Examination 
Physical examination results (normal or abnormal) and details of abnormalities will be listed for 
each subject. 
For each physical examination body system, the number and percentage of subjects with 
abnormalities at baseline and post-baseline will be summarized by treatment group for the SAF 
population.   
The distribution of edema grades reported at baseline and at each post-baseline visit will be 
presented by treatment group. 


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7.9.6 Major Adverse Cardiovascular Events and Liver Events 
A Clinical Events Committee (CEC) will adjudicate Major Adverse Cardiovascular Events 
(MACE), which are defined as death, adjudicated non-fatal MI or USA hospitalization, 
adjudicated hospital admission for HF, or adjudicated non-fatal ischemic stroke. Time from 
baseline to occurrence of first event will be computed in days. Subjects without an event will be 
censored at the earlier of the end of the time period of interest and the last contact date.  
Time to first MACE through 14 days after last dose of study treatment will be presented as 
number of events with Kaplan-Meier estimates of the cumulative risk of event. Hazard ratios and 
corresponding 95% confidence intervals comparing each active treatment group to placebo will 
be estimated from a Cox proportional hazards model including a factor for treatment group;  and 
the model will be stratified by randomization stratification factors (presence of diabetes mellitus, 
Vitamin E ≥ 400 IU, and baseline fibrosis F1 versus F2/F3) if the number of events permits. 
Treatment groups will be compared using a log-rank test. 
Similarly, time to first MACE or adjudicated liver event (ascites, hepatic encephalopathy, 
variceal hemorrhage, hepatocellular carcinoma, or liver transplant) through 14 days after last 
dose of study treatment will be analyzed and presented. 
Results will also be provided for each component of these composite events. For non-fatal 
events, subjects who die before the time point of interest and who did not reach the event of 
interest before death will be censored on the day of death. Results will be presented through 14 
days after last dose of study treatment for: 
• Time to death 
• Time to first adjudicated non-fatal MI 
• Time to first adjudicated USA hospitalization 
• Time to first adjudicated hospital admission for HF 
• Time to first adjudicated non-fatal ischemic stroke 
• Time to first adjudicated liver event 
In addition, deaths will be presented in a listing including investigator-reported data and the 
adjudicated primary cause of death. 
7.9.7 Severe Hypoglycemic Events  
The CEC will also adjudicate severe hypoglycemia events. The total number of events and the 
number and percentage of subjects with any event through 14 days after last dose of study 
treatment will be presented by treatment group, as adjudicated by the CEC. 
7.9.8 Bone Fractures Requiring Surgery or Hospitalization 
The number of fractures requiring surgery or hospitalization as well as the number and 
percentage of subjects with any fracture requiring surgery or hospitalization, as reported by the 
investigator, through 14 days after last dose of study treatment will be presented by treatment 
group. 


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7.10 Interim Analysis 
An interim analysis of exploratory and safety endpoints is planned after all subjects have been 
randomized into the study and 6-month data are available for a minimum of 300 randomized 
subjects. Changes in selected serum biomarkers from baseline to 6 months will be assessed. 
Descriptive summary statistics by treatment group will be presented and results shared with a 
limited group of people to be identified by the Sponsor. The treatment assignments of individual 
subjects will not be presented, i.e., data listings will not be included for this interim analysis. 
Details will be provided in a separate SAP for the interim analysis. 
8 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES 
The specialty biomarkers to be analyzed were changed following finalization of the protocol. 
The following biomarker described in the protocol will not be analyzed: CK-18 [M30].  Changes 
from baseline in biomarkers and indirect measures of apoptosis and liver fibrosis at 6 months 
were added as pre-specified exploratory efficacy endpoints. 
The exploratory endpoint “Changes from baseline relative to placebo at 12 months in the 
pathologist’s general impression” has been corrected to reporting the general impression as 
provided by the central histopathologist: NASH diagnosis 1) confirmed, or 2) cannot be 
confirmed. While the local pathologists provide the information as initially planned in the 
protocol, this is not available from the central histopathologist. 
The last exploratory endpoint “Changes from baseline relative to placebo in subjects with 
PNPLA3 variants and other genotypes” has been removed from the list as it is not an endpoint 
per se but refers to subgroup analyses of efficacy endpoints with respect to genetic variants (see 
Section 7.8.3). 
The definition of the per protocol analysis set was expanded to allow possible exclusion of 
subjects based on trough levels of study drug and its metabolite. 
For the derivation of treatment compliance, the last dose date will be used instead of last dose 
date +14 days to define the end of the treatment period if study treatment was discontinued early. 
The derivation of compliance measures per treatment period as well as production of listings 
and/or presentation of summary statistics of per-period and of overall compliance will be 
omitted. The rationale for these changes is that because capsule counts are known to be 
unreliable and despite our best efforts to clean the data there are still discrepancies that cannot be 
resolved. 
The methods for efficacy analysis have been clarified. Due to the expected highly unequal 
marginal distribution of the stratification factor “use of Vitamin E ≥ 400 IU” (Yes vs. No) this 
factor was removed from all logistic regression models (except for the corresponding subgroup 
analysis).  
The pairwise comparisons of active treatment versus placebo through CMH tests have been 
revised to only include stratification for presence of diabetes mellitus as to avoid overly sparse 
cross-classification frequencies of the originally included stratification factors, treatment, and 
outcome. 
According to the protocol, sensitivity analyses had been planned for the primary and secondary 
dichotomous efficacy endpoints examining the addition of sex to the primary logistic regression 


Statistical Analysis Plan  
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Date of Issue: 16-May-2019 
Cirius Protocol No. MSDC-0602K-C009NASH 
 
 
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models. The sensitivity analyses have been updated to include age at baseline as well because 
age is expected to be associated with response, and to exclude use of Vitamin E ≥ 400 IU similar 
to the primary analysis. Further sensitivity analyses have been added to examine different time 
restrictions for the biopsies taken at 12 months. 
Adjudication of Major Adverse Cardiovascular Events, liver events, and severe hypoglycemic 
events by a Clinical Events Committee, and collection of information regarding fractures were 
introduced after finalization of the protocol. Corresponding analyses have been added to the 
SAP. 
9 
REFERENCES 
Cusi, K. Management of NAFLD/NASH in Patients with T2DM: New Concepts and Future Directions. 
Presented at American Diabetes Association Annual Meeting, San Francisco, California, June 13-17, 
2014.  
European Medicines Agency Committee for Medicinal Products for Human Use. Guideline on Missing 
Data in Confirmatory Clinical Trials. European Medicines Agency: London, 2011. Available at 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/09/WC500096793.p
df  
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. Statistical Principles for Clinical Trials, Guideline E9, 1998. Available 
at 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/E9_Guideli
ne.pdf 
LaVange LM, TA Durham, and GC Koch. Randomization-based nonparametric methods for the analysis 
of multicenter trials. Statistical Methods in Medical Research (2005); 14:281-301. 
Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an agonist of the 
peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis 
without fibrosis worsening. Gastroenterology (2016) May;150(5):1147-1159. 
Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin 
E, or placebo for nonalcoholic steatohepatitis. N Engl J Med (2010) 362:1675-1685. 
Zink RC and Koch G. NParCov3: A SAS/IML Macro for Nonparametric Randomization-Base Analysis 
of Covariance. Journal of Statistical Software (2012); July 50(3):1-17. 


Statistical Analysis Plan  
Version: Final 1.5 
Date of Issue: 16-May-2019 
Cirius Protocol No. MSDC-0602K-C009NASH 
 
 
CONFIDENTIAL 
Page 34 of 35 
10 APPENDIX 
Schedule of Activities  
 
 
1. ICF may be obtained before the 42-day screening window. Re-testing is allowed within the 42-day Screening period if, in the 
opinion of the Investigator, the subject may become eligible upon repeat testing.  
2. Height and body weight are collected at Screening only; body weight, waist circumference measured midway between the 
lowest rib and the iliac crest, and signs of peripheral edema are collected at all study visits.  
3. Vital sign measurements including seated BP and heart rate are collected at every visit; oral temperature is collected at 
screening, pre-dose on Day 1 and Visit 8.  
4. FibroScan is required within 90 days prior to or during Screening.  
 
Screen1 
Treatment 
Follow-
up 
Visit Number 
 
1 
2 
3 
4 
5 
6 
7 
8 
Study Months 
 
Rando-
mization 
1 
2 
3 
6 
9 
12 
 
Study Day 
-42 to -
1 
1 
30 
60 
90 
180 
270 
360 
374 
Window 
 
N/A 
± 7 days 
± 3 days 
General Activities 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Complete Physical Examination2 
X 
 
 
 
 
 
 
 
X 
Limited Physical Examination2 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
X 
 
X 
X 
Pregnancy test (females only) 
X 
X 
 
 
 
 
 
 
X 
FSH (post-menopausal females 
only) 
X 
 
 
 
 
 
 
 
 
FibroScan4 
X 
 
 
 
 
 
 
X 
 
Liver Biopsy5 
X 
 
 
 
 
 
 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Dietary guidance and assessment of 
alcohol intake6 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event review  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
 
Monthly phone assessment7 
 
 
 
 
X 
X 
X 
 
 
Study drug dispensing8  
 
X 
 
 
X 
X 
X 
 
 
Central Lab Evaluations 
 
 
 
 
 
 
 
 
 
Hematology & serum chemistry 9, 10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver function tests 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
X 
 
 
X 
X 
X 
X 
X 
HMW adiponectin, hsCRP, CK-18 
[M65], osteocalcin, and CTX 
 
X 
 
 
 
X 
 
X 
 
Fibrosure, ELF score, APRI, FIB-4 
index, Pro-C3 
 
X 
 
 
 
X 
 
X 
 
Serum sample for NMR analysis 
 
X 
 
 
 
 
 
X 
 
Blood sample for genotyping 
analyses (optional)11 
 
X 
 
 
 
 
 
 
 
Plasma samples for future miRNA 
and biomarker testing12 
 
X 
 
 
 
X 
 
X 
 
Trough PK sample13 
 
 
X 
 
X 
X 
X 
X 
 


Statistical Analysis Plan  
Version: Final 1.5 
Date of Issue: 16-May-2019 
Cirius Protocol No. MSDC-0602K-C009NASH 
 
 
CONFIDENTIAL 
Page 35 of 35 
5. A qualifying liver biopsy is required within 9 months prior to Screening. If a historical liver biopsy result is not available 
within this period, a liver biopsy must be performed during Screening for eligible subjects who meet all other entry criteria. A 
liver biopsy is also performed at Visit 7.  
6. Non-diabetic subjects are provided the NCEP dietary guidance at Screening and diabetic subjects are provided the ADA 
dietary guidance at Screening. Guidance regarding alcohol consumption is also provided to all subjects at Screening. All subjects 
are assessed for compliance with dietary guidelines and alcohol consumption at each visit.  
7. Study staff will contact the subjects by phone every month between Visits 4-7 to inquire about adverse events and serious 
adverse events.  
8. 3 bottles dispensed at Visits 1, 4, 5, and 6.  
9. Minimum 10-hour fasting blood sample collected pre-dose.  
10. FPG and HbA1c will also be measured at Visits 1, 5 and 7.  
11. A separate genotyping informed consent is required to enable collection of blood sample for genotyping analyses.  
12. At each timepoint, plasma samples will be split into two separate vials and stored for biomarker testing, including miRNA, to 
be determined at a later date.  
13. Pre-dose trough PK sample collected for analysis of MSDC-0602 and MSDC-0597.