Clinical trial NCT03061721
Conditions: Non-Alcoholic Fatty Liver Disease Nonalcoholic Steatohepatitis
Keywords: NASH NAFLD Saroglitazar
Sponsor: Zydus Therapeutics Inc.
Start date: 2017-04-06; Completion date: 2019-08-22
Enrollment: 106 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled study in up to 104 patients with a diagnosis of Non-alcoholic fatty Liver disease (NAFLD) and/or Non-alcoholic steatohepatitis (NASH). The study will be conducted over a period of up to 22 weeks and will include an optional Prescreening, Screening (Days -35 to -7) Phase, a 16-week Treatment Phase following randomization on Day 1. Patients will be randomly assigned in a ratio of 1:1:1:1 to receive Saroglitazar Magnesium 1mg or 2 mg or 4 mg or matching placebo once daily in the morning before breakfast for 16 Weeks. The primary endpoint of the study is percentage change from baseline in serum Alanine transaminase (ALT) levels at Week 16 in the Saroglitazar Magnesium groups as compared to the placebo group.

Detailed description:

Arms: arm 1: Saroglitazar magnesium 1 mg tablet orally once daily in the morning before breakfast for 16 weeks. arm 2: Saroglitazar magnesium 2 mg tablet orally once daily in the morning before breakfast for 16 weeks. arm 3: Saroglitazar magnesium 4 mg tablet orally once daily in the morning before breakfast for 16 weeks. arm 4: Placebo tablet orally once daily in the morning before breakfast for 16 weeks.
Interventions: intervention 1: Saroglitazar magnesium 1 mg intervention 2: Saroglitazar magnesium 2 mg intervention 3: Saroglitazar magnesium 4 mg intervention 4: Placebos
Intervention descriptions: intervention 1: Patients randomly assigned to this group will receive Saroglitazar magnesium 1 mg tablet orally once daily for 16 weeks. intervention 2: Patients randomly assigned to this group will receive Saroglitazar magnesium 2 mg tablet orally once daily for 16 weeks. intervention 3: Patients randomly assigned to this group will receive Saroglitazar magnesium 4 mg tablet orally once daily for 16 weeks. intervention 4: Patients randomly assigned to this group will receive placebo tablet orally once daily for 16 weeks.

Protocol documents:
Prot_000.pdf: 
Zydus Discovery DMCC 
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Clinical Study Protocol 
A Phase 2, Prospective, Multicenter, Double-blind, Randomized 
Study of Saroglitazar Magnesium 1 mg, 2 mg or 4 mg Versus 
Placebo in Patients with Nonalcoholic Fatty Liver Disease and/or 
Nonalcoholic Steatohepatitis 
Sponsor: 
Zydus Discovery DMCC 
Unit No 909, Armada 2 
Plot No: JLT-PH2-P2A,  
Jumeriah Lakes Towers 
Dubai UAE 
P.O Box 113536
Clinical Research Organization: 
Zydus Study No.: 
SARO.16.005 
Zydus Protocol No.: 
SARO.16.005.03.PROT 
05.02.PROT ; 27 November 2017 
IMP Name: 
Saroglitazar Magnesium 
IND No.: 
IND 128791 
Development Phase: 
Phase 2  
Date of Final Protocol: 
26 March 2018 
The study will be conducted according to the protocol and in accordance with the International Council 
for Harmonisation Tripartite Guideline for Good Clinical Practice (E6-R2) and with other applicable 
regulatory requirements. 
Confidentiality Statement 
This document contains confidential information of Zydus Discovery DMCC. Do not copy or distribute 
without written permission from the Sponsor. 
NCT03061721






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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Declaration of the Site Principal Investigator 
Protocol Title: A Phase 2, Prospective, Multicenter, Double-blind, Randomized Study of 
Saroglitazar Magnesium 1 mg, 2 mg or 4 mg Versus Placebo in Patients with Nonalcoholic Fatty 
Liver Disease and/or Nonalcoholic Steatohepatitis.  
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure, electronic Case Report Forms (CRFs) and other scientific data. 
The study will not be commenced without the prior written approval of Institutional Review 
Board (IRB) or Independent Ethics Committee (IEC). No changes will be made to the study 
protocol without the prior written approval of the Sponsor and the IRB or IEC, except where 
necessary to eliminate an immediate hazard to the patients. 
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol.   
Principal Investigator 
 
Signature 
 
 
Date 
Printed Name  
 
Title 
 
 


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LIST OF STUDY STAFF 
Sponsor: 
Zydus Discovery DMCC 
Medical Monitor 
Sponsors’ Medical 
Expert’s 
Serious Adverse Event 
Reporting: 
Contract Research 
Organization 


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PROTOCOL SYNOPSIS 
Protocol Title: 
A Phase 2, Prospective, Multicenter, Double-blind, Randomized Study of Saroglitazar 
Magnesium 1 mg, 2 mg or 4 mg Versus Placebo in Patients with Nonalcoholic Fatty 
Liver Disease and/or Nonalcoholic Steatohepatitis 
Protocol  Number: 
IND Number: 
IND 128791 
Development Phase: 
Phase 2  
Sponsor: 
Zydus Discovery DMCC 
Clinical Research 
Organization: 
   
Study Objectives: 
Primary Objective 
 
To investigate the effect of a 16-week treatment regimen of Saroglitazar 
Magnesium 1 mg, 2 mg or 4 mg on serum alanine aminotransferase (ALT) levels 
in patients with nonalcoholic fatty liver disease (NAFLD) and/or nonalcoholic 
steatohepatitis (NASH). 
Secondary Objectives 
 
To assess the effect of a 16-week treatment regimen of Saroglitazar Magnesium 
1 mg, 2 mg or 4 mg on the following parameters in patients with NAFLD and/or 
NASH: 
1 
Change in liver fat content at Week 16 as measured by magnetic 
resonance imaging-derived proton density-fat fraction (MRI-PDFF). 
2 
Proportion of patients who sustain a decrease in serum ALT levels 
observed at Week 4, Week 8 and Week 12 and Week 16 of therapy.  
3 
Changes in serum-based predictors of liver injury and fibrosis 
(cytokeratin-18 [CK-18], Enhanced liver fibrosis [ELF] and aspartate 
aminotransferase-to-platelet ratio index [APRI]), at Week 8 and 
Week 16 of therapy.  
4 
Pharmacokinetics of Saroglitazar Magnesium following first dose 
and last dose. 
5 
Quality of life (QoL). 
6 
Safety and tolerability of repeat dosing of 1 mg, 2 mg or 4 mg 
Saroglitazar Magnesium.  
Exploratory Objectives 
 
To explore the effect of a 16-week treatment regimen of Saroglitazar Magnesium 
1 mg, 2 mg or 4 mg on the following parameters in patients with NAFLD: 
1. Liver stiffness as measured by transient elastography/FibroScan®. 
2. Continuous attenuation parameter (CAP) as measured by transient 
elastography/FibroScan. 
3. Fasting lipid and lipoprotein profiles (lipoprofiles) at Week 4, 
Week 8, Week 12 and Week 16 of treatment. 
4. Insulin resistance and glycemic control at Week 8 and Week 16 of 
treatment. 


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Study Design: 
This is a randomized, double-blind, placebo-controlled study in up to 104 patients with 
a diagnosis of NAFLD and/or NASH. The study will be conducted over a period of up 
to 22 weeks and will include an optional Pre-screening , a Screening (Days -35 to -7), a 
16-week Treatment Phase following randomization on Day 1 to either Saroglitazar 
Magnesium (1 mg, 2 mg or 4 mg) or placebo orally once daily in the morning before 
breakfast.  
Pre-screening 
The study sites may identify potential subjects by conducting a laboratory evaluation of 
the ALT levels. This optional pre-screening can be conducted before the actual study 
screening. A subject with an ALT ≥50 U/L may be considered for the actual study 
screening. 
Also, along with the evaluation of the ALT levels, in those potential subjects who do 
not have a documented diagnosis of NAFLD through any imaging method, an optional 
abdominal ultrasound may be performed during the pre-screening. 
The evaluation of the ALT levels during the pre-screening will be done at the local 
laboratory, whereas the laboratory evaluations during the Screening and the Treatment 
Phase will be done at the central laboratory. 
An informed consent has to be obtained from the potential subjects before any pre-
screening evaluations. 
Screening  
Visit 1 (Day -35): Patient eligibility for participation in the study will be assessed. 
Medical history will be obtained; physical examination, electrocardiogram (ECG) and 
laboratory evaluations (including serology, clinical chemistry, hematology, liver 
enzymes and urinalysis) will be performed. Female patients will undergo a serum 
pregnancy test. Serum ALT must be ≥50 U/L to proceed further in the study. In 
addition, Investigator will instruct the patient to maintain their current diet and physical 
activity at each visit. 
Visit 2 (Day -14 to -7): Liver enzymes (AST, ALT, ALP and total bilirubin (TB) will 
be re-measured approximately 3 weeks from Day -35 to determine eligibility. Elevated 
ALT ≥50 U/L on 2 occasions in the Screening is necessary for study entry. The 
variance in the levels of the repeat measures of serum ALT and total bilirubin (TB) at 
Day -14 (Visit 2) must be ≤30%, compared to the Day -35 (Visit 1) levels to be eligible 
for study entry. The liver function test values at Day -14 to -7 (Visit 2) will be 
considered as baseline for the efficacy assessment. 
Randomization & Treatment Phase 
The Randomization & Treatment Phase will include 5 additional outpatient visits over 
a period of 16 weeks including the randomization visit. Efficacy assessments will be 
conducted on these 5 visits by measuring liver enzymes (AST, ALT, ALP and TB, 
CK-18 fragments, ELF, fasting glucose, serum insulin levels, lipoprofile, homeostasis 
model assessment (insulin resistance [HOMA-IR]) and homeostasis model assessment 
(β 
cell 
function 
[HOMA-β], 
liver 
stiffness 
and 
CAP 
by 
transient 
elastography/FibroScan, liver fat content with MRI-PDFF and QoL. In addition, safety 
assessments will be conducted and there will be no clinically significant changes in 
dietary, physical activity or alcohol consumption. 
Visit 3 (Day 1): Patients will be randomly assigned to receive Saroglitazar Magnesium 
(1 mg, 2 mg or 4 mg) or placebo orally once daily, starting on Day 1 of a 16-week 
outpatient treatment period. Patients will commence with a once daily oral dosing 


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regimen.  
Visits 4, 5 and 6: Patients will visit the study site at Week 4 (Visit 4), Week 8 (Visit 5) 
and Week 12 (Visit 6) for clinical assessment, dispensation and reconciliation of study 
drug, measurements of efficacy endpoints and assessment of adverse events (AEs).  
End-of-Treatment Visit (Visit 7): An End-of-treatment Visit will occur at Week 16 for 
clinical assessment, reconciliation of study drug, and measurements of efficacy and 
AEs.   
Telephone follow-up will occur 7 days (± 3 days) after the End-of-treatment Visit for 
safety monitoring. 
Study Drug: 
Study drugs include oral tablets containing 1 mg, 2 mg or 4 mg Saroglitazar 
Magnesium and matching placebo tablets. Patients will be randomly assigned to 
receive Saroglitazar Magnesium 1 mg, 2 mg or 4 mg or matching placebo once daily in 
the morning before breakfast for 16 Weeks.     
Number of Patients: 
One-hundred-four (104) patients are planned for enrollment. Patients will be randomly 
assigned to receive active drug (Saroglitazar Magnesium 1 mg, 2 mg or 4 mg) or 
placebo in a 1:1:1:1 ratio.   
Approximately eight patients in each group are planned for pharmacokinetic 
assessments therefore a total of approximately 32 patients will be included in the 
pharmacokinetic study.   
Study Population: 
Patients with NAFLD and/or NASH who have elevated ALT (defined as ≥50 U/L at 
the Screening Visits) will be eligible for the study if they meet all of the inclusion 
criteria and none of the exclusion criteria. 
Inclusion Criteria 
1. Males or females, 18 to 75 years of age, with body mass index (BMI) ≥25 kg/m2. 
2. Documented diagnosis of NAFLD established either by imaging (ultrasound, CT 
scan or MRI) or liver biopsy showing NASH or simple steatosis, within the 
24 months preceding Visit 1. The diagnosis of NAFLD is made according to the 
American Association for the Study of Liver Diseases (AASLD) criteria 
(Chalasani et al. Hepatology 2012; 55:2005-2023). 
3. ALT level of ≥50 U/L at Visit 1 and Visit 2 with ≤30% variance between the 
levels at Visit 1 and Visit 2. 
4. Patient’s demonstration of understanding of study requirements and treatment 
procedures, willingness to comply with all protocol-required evaluations; 
provision of written informed consent before any study specific tests or procedures 
are performed. 
Exclusion Criteria 
1. Consumption of >3 units of alcohol per day (>21 units per week) if male and 
>2 units of alcohol per day (>14 units per week) if female for at least 
3 consecutive months in the 5 years preceding Visit 1 (Note:  1 unit = 12 ounces of 
beer, 4 ounces of wine or 1 ounce of spirits/hard liquor). 
2. Presence of alternative causes of fatty liver, including: 
a. Weight change >5% within the 3 months preceding Visit 1 
b. Total parenteral nutrition, starvation or protein-calorie malnutrition 


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within the 90 days preceding Visit 1. 
c. Use of drugs associated with NAFLD for more than 12 consecutive 
weeks in the 1 year before Visit 1, including amiodarone, tamoxifen, 
methotrexate, systemic glucocorticoids, anabolic steroids, tetracycline, 
estrogens in doses higher than used in oral contraceptives, vitamin A, 
L asparaginase, valproate, chloroquine or antiretroviral drugs 
3. Initiation of vitamin E at doses >100 IU/day, or multivitamins containing >100 
IU/day of vitamin E in the 3 months preceding Visit 1.  
4. Use of drugs with potential effect on NASH such as ursodeoxycholic acid, 
S-adenosylmethionine (SAM-e), betaine, pentoxifylline, obeticholic acid or milk 
thistle in the 3 months prior to Visit 1.  
5. Changing doses of statins (simvastatin, pitavastatin, pravastatin, atorvastatin, 
fluvastatin, lovastatin, rosuvastatin) or fibrates (clofibrate, fenofibrate) in the 3 
months preceding Visit 1.  
6. Use of thiazolidinediones (pioglitazone, rosiglitazone). 
7. Use of drugs that are known CYP2C8 inhibitors/substrate (please refer to 
Section 5.8.1.1 Excluded Concomitant Medications). 
8. History of bowel surgery (gastrointestinal (bariatric) surgery or undergoing 
evaluation for bariatric surgery for obesity, extensive small-bowel resection or 
orthotopic liver transplant (OLT) or listed for OLT. 
9. History of other chronic liver disease (chronic hepatitis C, (HCV) infection, 
irrespective of their mRNA HCV assay status or active hepatitis B infection, (i.e., 
serum positive for hepatitis B surface antigen) or autoimmune hepatitis, cholestatic 
and metabolic liver diseases) or hemochromatosis  
10. Patient has known cirrhosis, either based on clinical criteria or liver histology. 
11. Patient with INR >1.3.   
12.  Type 1 diabetes mellitus. 
13. Poorly controlled type 2 diabetes mellitus, i.e., glycosylated hemoglobin (HbA1c) 
>9%. 
14. Unstable cardiovascular disease, including: 
a. 
unstable angina, (i.e., new or worsening symptoms of coronary heart 
disease within the 3 months preceding Visit 1), acute coronary syndrome 
within the 6 months preceding Visit 1,  acute myocardial infarction within 
the 3 months preceding Visit 1 or heart failure of New York Heart 
Association class (III – IV) or worsening congestive heart failure, or 
coronary artery intervention, within the 6 months preceding Visit 1  
b. history of (within 3 months preceding Visit 1) or current unstable cardiac 
dysrhythmias   
c. 
uncontrolled hypertension (systolic blood pressure [BP]  >160 mmHg 
and/or diastolic BP >100 mmHg) 


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d. stroke or transient ischemic attack within the 6 months preceding Visit 1. 
15. History of myopathies or evidence of active muscle disease. 
16. History of malignancy in the 5 years preceding Visit 1 and/or active neoplasm with 
the exception of resolved superficial nonmelanoma skin cancer. 
17. Any of the following laboratory values: 
a. 
Hemoglobin <9 g/dL 
b. White blood cell count <2.5 × 103/µL 
c. 
Neutrophil count <1.5 × 103/µL 
d. Platelets <100 × 103/µL 
e. 
Total Serum bilirubin >1.5 mg/dL (except in patient with known Gilbert 
bilirubin where TB up to 2.5 mg/dL is allowed), if it is <1.5 mg/dL at 
screening and >30% variance in the levels at Visit 1 and Visit 2 
f. 
Albumin <3.2 g/dL 
g. Serum creatinine >1.5 mg/dL 
h. Serum ALT or AST >250 U/L at Visit 1 or Visit 2. 
18. Contraindications to Saroglitazar Magnesium or has any conditions affecting the 
ability to evaluate the effects of Saroglitazar Magnesium.  
19.  Known allergy, sensitivity or intolerance to the study drug, placebo or formulation 
ingredients. 
20. Participation in any other therapeutic clinical study within the 3 months preceding 
Visit 1, including participation in any other NAFLD/NASH clinical trials. 
21. History of bladder disease and/or hematuria or has current hematuria except due to 
a urinary tract infection. 
22. Illicit substance abuse within the 12 months preceding Visit 1. 
23. Pregnancy-related exclusions, including: 
a. 
Pregnant/lactating female (including a positive serum pregnancy test at 
Visit 1) 
b. A male patient has to use a condom with spermicide, and the female 
partner of the male patient has to use an intrauterine device OR a 
diaphragm with spermicide OR oral contraceptive pills. 
c. 
If a male patient has undergone a vasectomy, the female partner does not 
have to use any contraception. 
d. A female patient has to use either an intrauterine device OR a diaphragm 
with spermicide OR oral contraceptive pills. The male partner of the 
female patient has to use a condom with spermicide. 
e. 
If the female patient is surgically sterilized for at least the 6 months 
preceding Visit 1 or postmenopausal, defined as at least 12 months with 
no menses and without an alternative cause, the male partner of the 


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female patient does not have to use any contraception. 
24. History or other evidence of severe illness or any other conditions that would make 
the patient, in the opinion of the investigator, unsuitable for the study (such as 
poorly controlled psychiatric disease, HIV, coronary artery disease or active 
gastrointestinal conditions that might interfere with drug absorption). 
Criteria for Evaluation: 
Primary Efficacy Endpoint 
Percentage change from baseline in serum ALT levels at Week 16 in the Saroglitazar 
Magnesium groups as compared to the placebo group. 
Secondary Efficacy Endpoints 
1 
Change in liver fat at Week 16 as measured by magnetic resonance imaging-
derived proton density-fat fraction (MRI-PDFF). 
2 
Percentage change from baseline and absolute change from baseline in serum ALT 
levels at Week 4, Week 8 and Week 12 of treatment in the Saroglitazar 
Magnesium groups as compared to the placebo group. 
3 
Proportion of patients who sustain a decrease in ALT observed at Week 4, Week 8 
Week 12 and Week 16 in the Saroglitazar Magnesium groups as compared to the 
placebo group. 
4 
Proportions of patients with ≥25% and ≥50% reduction from baseline in ALT 
levels at Week 4, Week 8, Week 12 and Week 16 in the Saroglitazar Magnesium 
groups as compared to the placebo group. 
5 
Percentage change from baseline and absolute change from baseline in CK-18 
fragments, ELF score and APRI at Week 8, and Week 16 after treatment in the 
Saroglitazar Magnesium groups as compared to the placebo group. 
6 
Absolute change from baseline in AST/ALT ratio at Week 4, Week 8, Week 12 
and Week 16 after treatment in the Saroglitazar Magnesium groups as compared to 
the placebo group. 
7 
Pharmacokinetics of Saroglitazar Magnesium following first dose and last dose in 
patients with NAFLD/NASH. 
8 
Absolute change in the Short-Form 36 Health Survey Version 2.0 (SF 36) 8 
domain scores and 2 component scores (separate analyses) change from baseline in 
QoL scores at Week 16 after treatment in the Saroglitazar Magnesium groups as 
compared to the placebo group. 
Exploratory Efficacy Endpoints 
1. 
Changes in liver stiffness/CAP as measured by transient elastography/FibroScan in 
the Saroglitazar Magnesium groups as compared to the placebo group.  
2. 
Absolute changes in fasting lipid and lipoprofiles at Week 4, Week 8, Week 12 
and Week 16 after treatment in the Saroglitazar Magnesium groups as compared to 
the placebo group. 
3. 
Absolute changes in insulin resistance and glycemic control (adiponectin, fasting 
insulin, fasting blood glucose, C peptide, HOMA-IR and HOMA-ß, free fatty 
acids) at Week 8 and Week 16 after treatment in the Saroglitazar Magnesium 
groups as compared to the placebo group. Absolute change in HbA1c will be 
assessed at Week 16. 
Safety Endpoints 
 
Frequency and severity of AEs and serious AEs. 




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Secondary analyses (of the primary endpoint) will be analyzed using a similar analysis 
in the PP Analysis Set. Residual analysis will be used to check assumptions for the 
ANCOVA model. Should any of the assumptions of the analysis method not be 
adequately met, an alternative procedure will be used and fully documented. 
Secondary Efficacy Analysis: Due to this being a proof-of-concept study, no 
adjustment of any P values will be made to account for inflation of the Type 1 error 
rate arising from testing multiple endpoints, or testing the same endpoint at different 
times.  
Each secondary efficacy endpoint will be summarized by treatment group at each time 
point, as appropriate. 
Endpoints such as percentage change from baseline to Week 4, Week 8 and Week 12 in 
serum ALT levels; absolute changes from baseline in AST/ALT ratio and ELF score; 
absolute and percentage changes from baseline in CK-18 and APRI after Week 8 and 
Week 16; and change in liver fat at Week 16 will be analyzed using ANCOVA model 
with treatment as factor and baseline level as covariate. Analysis will be presented 
similar to primary analysis. These analyses will also be supported by simple summaries 
(n, mean, standard deviation, median, minimum and maximum) at each visit, without 
covariate adjustment.  
Proportions of patients with percentage reductions of ≥25% and ≥50% from baseline in 
ALT levels at Week 4, Week 8, Week 12 and Week 16 will be analyzed using logistic 
regression including terms for baseline ALT levels and treatment. Endpoints based on 
proportion of patients will be summarized. For the categorical data, descriptive 
summary statistics will be, summarizing the number and percentage of patients in each 
category at each visit.  
Descriptive statistics will be provided for each pharmacokinetic parameter. 
Safety Analysis: Safety analyses will be based on the Safety Analysis Set which will 
consist of all patients who are known to have received at least 1 dose of study 
treatment, with patients grouped according to the actual treatment received.  
Demographics and other safety endpoints (AEs, clinical laboratory testing, ECG and 
vital signs) will be summarized by using the following descriptive statistics: N, mean, 
median, standard deviation, minimum and maximum for continuous variables, and 
patient counts and percentages for categorical variables. Safety summaries will be 
presented by treatment group for all treated patients. 
Exploratory Analysis: The individual values of the exploratory endpoints will be listed 
and summary statistics will be calculated for each treatment group. The exploratory 
analyses will be based primarily on the FAS, and analyses based on the PP Analysis 
Set will be secondary to this.    


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ................................................................................................... 2 
COORDINATNG INVESTIGATOR SIGNATURE PAGE .......................................................... 3 
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE ......................................................... 4 
LIST OF STUDY STAFF ............................................................................................................... 5 
PROTOCOL SYNOPSIS ............................................................................................................... 6 
TABLE OF CONTENTS .............................................................................................................. 14 
List of Tables ................................................................................................................... 16 
LIST OF ABBREVIATIONS ....................................................................................................... 17 
1. 
INTRODUCTION ........................................................................................................... 20 
1.1 
Background......................................................................................................... 20 
1.1.1 
Nonalcoholic Fatty Liver Disease ................................................................... 20 
1.1.2 
Saroglitazar Magnesium ................................................................................. 20 
1.2 
Rationale for the Clinical Study ......................................................................... 21 
1.3 
Risk-Benefit Assessment .................................................................................... 22 
2. 
Study Objectives .............................................................................................................. 23 
2.1 
Primary Objective ............................................................................................... 23 
2.2 
Secondary Objectives ......................................................................................... 23 
2.3 
Exploratory Objectives ....................................................................................... 23 
3. 
Overall Design and Plan of the Study.............................................................................. 24 
3.1 
Overview ............................................................................................................ 24 
3.2 
Endpoints ............................................................................................................ 26 
3.2.1 
Primary Efficacy Endpoint ............................................................................... 26 
3.2.2 
Secondary Efficacy Endpoints .......................................................................... 26 
3.2.3 
Exploratory Efficacy Endpoints ........................................................................ 27 
3.2.4 
Safety Endpoints .............................................................................................. 27 
3.3 
Justification of the Study Design ........................................................................ 27 
4. 
Study population .............................................................................................................. 29 
4.1 
Number of Patients ............................................................................................. 29 
4.2 
Inclusion Criteria ................................................................................................ 29 
4.3 
Exclusion Criteria ............................................................................................... 29 
4.3.1 
Screen Failures ................................................................................................. 32 
4.3.2 
Patient Withdrawal .......................................................................................... 33 
4.3.3 
Discontinuation of Patients from the Study or Study Drug ............................... 33 
4.3.4 
Patients Lost to Follow-up ............................................................................... 34 
4.4 
Stopping Criteria for Individual Patients ............................................................ 34 
4.5 
Termination of the Clinical Study ...................................................................... 36 
4.6 
Planned Sample Size .......................................................................................... 36 


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5. 
Investigational medicinal product.................................................................................... 37 
5.1 
Identity of the Study Drugs ................................................................................ 37 
5.2 
Supply, Packaging, Labeling and Storage .......................................................... 39 
5.3 
Dispensing and Administration .......................................................................... 39 
5.4 
Drug Accountability ........................................................................................... 40 
5.5 
Patient Identification and Randomization .......................................................... 40 
5.5.1 
Screening Numbers ......................................................................................... 40 
5.5.2 
Randomization Scheme, Randomization Numbers and Allocation of 
Patients to Treatment ...................................................................................... 41 
5.5.3 
Patient Replacements ...................................................................................... 41 
5.6 
Compliance ......................................................................................................... 41 
5.7 
Blinding and Breaking the Blind ........................................................................ 41 
5.8 
Previous and Concomitant Medications and Other Restrictions ........................ 42 
5.8.1 
Previous and Concomitant Medications ......................................................... 42 
5.8.2 
Other Restrictions ........................................................................................... 43 
5.9 
Overdose and Drug Interaction .......................................................................... 43 
6. 
Variables and Methods of Assessment ............................................................................ 45 
6.1 
Safety Variables.................................................................................................. 45 
6.1.1 
Medical History, Demographic and Other Baseline Information ................... 45 
6.1.2 
Adverse Events ............................................................................................... 46 
6.1.3 
Clinical Laboratory Assessments .................................................................... 50 
6.1.4 
Vital Signs ...................................................................................................... 52 
6.1.5 
Twelve-lead Electrocardiograms .................................................................... 52 
6.1.6 
Physical Examinations .................................................................................... 53 
6.2 
Efficacy Variables ............................................................................................... 53 
6.2.1 
Blood Samples ................................................................................................ 53 
6.2.2 
Quality of Life ................................................................................................ 54 
6.2.3 
Transient Elastography/FibroScan .................................................................. 54 
6.2.4 
Magnetic Resonance Imaging-Derived Proton Density-Fat Fraction 
(MRI PDFF) .................................................................................................... 54 
6.3 
Pharmacokinetics Assessment ............................................................................. 55 
6.4 
Biobanking Samples for Exploratory Analyses .................................................... 56 
6.5 
Total Amount of Blood ....................................................................................... 56 
7. 
Study Conduct ................................................................................................................. 57 
7.1 
Schedule of Assessments ..................................................................................... 57 
7.2 
Data Monitoring Committee ................................................................................ 61 
7.3 
Adjudication ....................................................................................................... 61 
8. 
Statistical methods ........................................................................................................... 62 
8.1 
Study Population ................................................................................................ 62 
8.1.1 
Disposition of Patients .................................................................................... 62 
8.1.2 
Patient Characteristics..................................................................................... 62 
8.1.3 
Protocol Deviations ........................................................................................ 62 
8.1.4 
Analysis Populations ...................................................................................... 62 


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8.2 
General Considerations ...................................................................................... 63 
8.3 
Safety Analyses .................................................................................................. 63 
8.3.1 
Adverse Events ............................................................................................... 63 
8.3.2 
Clinical Laboratory Tests................................................................................ 64 
8.3.3 
Vital Signs ...................................................................................................... 64 
8.3.4 
Electrocardiogram ........................................................................................... 64 
8.3.5 
Physical Examination ..................................................................................... 64 
8.4 
Efficacy Analyses ............................................................................................... 64 
8.4.1 
Primary Efficacy Analyses ............................................................................. 65 
8.4.2 
Secondary Efficacy Analyses ......................................................................... 65 
8.4.3 
Exploratory Efficacy Analyses ....................................................................... 67 
8.5 
Interim Analyses ................................................................................................. 67 
8.6 
Determination of Sample Size ............................................................................ 67 
9. 
Ethical, Legal and administrative Aspects....................................................................... 68 
9.1 
Data Quality Assurance ...................................................................................... 68 
9.1.1 
Database Management and Quality Control ................................................... 68 
9.2 
Case Report Forms and Source Documentation ................................................. 68 
9.2.1 
Data Collection ............................................................................................... 69 
9.3 
Access to Source Data ........................................................................................ 70 
9.4 
Data Processing .................................................................................................. 70 
9.5 
Archiving Study Documents .............................................................................. 70 
9.6 
Good Clinical Practice ........................................................................................ 71 
9.7 
Informed Consent ............................................................................................... 71 
9.8 
Protocol Approval and Amendment(s) ............................................................... 71 
9.9 
Confidentiality Data Protection .......................................................................... 72 
9.10 
Other Ethical and Regulatory Issues .................................................................. 72 
9.11 
Publication Policy ............................................................................................... 72 
10. 
Reference list ................................................................................................................... 73 
11. 
Appendices ...................................................................................................................... 75 
11.1 
Appendix 1: Quality of Life Assessment Questionnaire .................................... 75 
11.2 
Appendix 2: List of Known CYP2C8 Inhibitors/Substrates .............................. 76 
 
List of Tables 
Table 1 Identity of Study Drugs .................................................................................................... 37 
Table 2 Composition and Proportion of Ingredients in Investigational Products ......................... 38 
Table 3 Safety Laboratory Assessments ....................................................................................... 50 
Table 4 Schedule of Assessments ................................................................................................. 58 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AASLD 
American Association for the Study of Liver Diseases 
AE 
Adverse event 
ALP  
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
ANCOVA 
Analysis of covariance  
API 
Active pharmaceutical ingredient 
apo A  
Apolipoprotein A 
apo B  
Apolipoprotein B 
APRI 
Aspartate aminotransferase-to-platelet ratio index  
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BL 
Baseline 
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CAP 
Continuous attenuation parameter 
CK-18 
Cytokeratin-18  
CTCAE 
Common Terminology Criteria for Adverse Event 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CRO 
Contract research organization 
CRP 
C-reactive protein 
DILI 
Drug-induced liver injury 
DPP-4 
Dipeptidyl peptidase 4  
ECG 
Electrocardiogram 
EDC 
Electronic data capture  
ELF 
Enhanced liver fibrosis 
FA 
Fatty acid 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FFA 
Free fatty acids 


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GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HbA1c 
Glycosylated hemoglobin 
HBsAg 
Hepatitis B surface antigen 
hCG 
human chorionic gonadotropin  
HCV  
Hepatitis C virus 
HDL 
High-density lipoprotein 
HepB 
Hepatitis B 
HIV  
Human immunodeficiency virus 
HOMA-IR  
Homeostatic model assessment – insulin resistance 
HOMA-ß  
Homeostatic model assessment – β-cell function 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Institutional Ethics Committee 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LFT 
Liver function test  
LPL 
Lipoprotein lipase  
LS 
Least squares  
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI-PDFF 
Magnetic resonance imaging-derived proton density-fat fraction  
NAFLD 
Nonalcoholic fatty liver disease 
NASH 
nonalcoholic steatohepatitis  
OLT 
Orthotropic liver transplant 
OTC 
Over-the-counter 
PI  
Principal Investigator 
PP 
Per protocol 


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PPAR 
Peroxisome proliferator-activated receptor  
PoC 
Proof-of-concept  
PT 
Prothrombin time 
QoL 
Quality of life  
QT 
The QT interval is measured from the beginning of the QRS complex to the 
end of the T wave  
QTc 
Corrected QT interval  
SAE(s) 
Serious adverse event(s) 
SAP 
Statistical analysis plan 
SF-36 
Short-Form 36 Health Survey Version 2.0 (SF-36) 
TEAE(s) 
Treatment-emergent adverse event(s) 
TG 
triglycerides  
ULN 
Upper limit of normal 
VLDL 
Very low-density lipoprotein  
WBC 
White blood cell 
 
 
 


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1. INTRODUCTION 
1.1 
Background 
1.1.1 
Nonalcoholic Fatty Liver Disease 
Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease 
(Angulo, 2002; Wieckowska and Feldstein, 2005). The severity of NAFLD ranges from 
relatively benign simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which is 
characterized by hepatocellular injury, inflammation and risk of progression to cirrhosis with 
complications of portal hypertension, liver failure and hepatocellular carcinoma (Matteoni et al., 
1999; McCullough, 2004; Brunt and Tiniakos, 2005). Nonalcoholic steatohepatitis is considered 
a hepatic manifestation of the metabolic syndrome. In many patients, insulin resistance underlies 
the development of the metabolic syndrome; consequently, NASH is highly prevalent among 
patients with type 2 diabetes. Currently, obesity and associated type 2 diabetes have reached 
epidemic proportions and are considered burgeoning public health problems (Hu, 2011).  
Control of lipids and weight loss by diet and exercise are recommended for treatment of patients 
with NAFLD, including NASH, but their long-term effectiveness is questionable because many 
patients are unable to comply with the required dietary and lifestyle changes (Bellentani et al., 
2008; Musso et al., 2010). Therefore, an alternative and effective pharmacotherapeutic approach 
is needed.   
Peroxisome proliferator-activated receptor (PPAR) agonists are known to lower high blood 
triglyceride levels (PPARα agonists) and improve insulin resistance (PPARγ agonists), and 
therefore offer a potential treatment for NAFLD or NASH. 
1.1.2 
Saroglitazar Magnesium 
Saroglitazar, 
 is a novel peroxisome PPAR agonist with dual 
PPAR agonistic properties – it is a potent and predominant PPARα agonist with moderate 
PPARγ agonistic activity. 
PPARs are nuclear lipid-activated transcription factors that regulate the expression of various 
genes involved in the control of lipid and lipoprotein metabolism, glucose homeostasis and 
inflammatory processes. The pharmacological effects of Saroglitazar Magnesium were 
extensively evaluated in various preclinical models. Saroglitazar Magnesium showed both 


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antidyslipidemic and antidiabetic effects, mainly mediated via activation of PPARα and PPARγ, 
respectively.  
PPARα activation by Saroglitazar Magnesium increases the hepatic oxidation of fatty acids (FA) 
and reduces the synthesis and secretion of triglycerides (TG). This, in turn, increases diversion of 
FA from peripheral tissues (e.g., skeletal muscle and fat tissue) to the liver, thereby decreasing 
both FA synthesis and delivery of TG to peripheral tissues. In addition, Saroglitazar Magnesium 
causes increased lipolysis and elimination of TG-rich particles from plasma by activating 
lipoprotein lipase (LPL) and reducing production of apolipoprotein C-III (an inhibitor of LPL 
activity). Consistent with the above mechanism, Saroglitazar Magnesium was also found to 
reduce plasma low-density lipoprotein (LDL) cholesterol. PPARα activation by Saroglitazar 
Magnesium also induces an increase in the synthesis of apolipoproteins, A-I, A-II and high-
density lipoprotein (HDL) cholesterol. 
Although Saroglitazar Magnesium is predominantly a PPARα agonist, it also causes activation of 
PPARγ and regulates the transcription of insulin-responsive genes involved in the control of 
glucose production, transport and utilization. Saroglitazar Magnesium increases the expression of 
numerous PPARγ-responsive genes involved in carbohydrate and lipid metabolism, including 
adiponectin, adipocyte fatty-acid-binding protein (aP2), LPL, fatty acid transport protein and 
fatty acid translocase (CD36). By increasing the expression of these genes, Saroglitazar 
Magnesium decreases the post-prandial rise of plasma free fatty acids (FFA), improves 
postabsorptive insulin-mediated suppression of hepatic glucose output, reduces the metabolic 
burden on liver and muscle and promotes glucose utilization. Robust antidiabetic and insulin 
sensitizing effects of Saroglitazar Magnesium were observed in preclinical models, in which 
hyperglycemia and/or impaired glucose tolerance is a consequence of insulin resistance in target 
tissues. 
Saroglitazar Magnesium has been the first glitazar granted marketing authorization in India and 
is indicated for treatment of diabetic dyslipidemia. The drug was developed with an expectation 
to achieve optimum antidyslipidemic and antihyperglycemic effects, while avoiding adverse 
events (AEs) such as peripheral edema, weight gain, cardiovascular events, renal and/or liver 
toxicity, etc., which are commonly seen with other dual PPAR or PPARα agonists. 
1.2 
Rationale for the Clinical Study 
Saroglitazar Magnesium is known to safely and effectively improve dyslipidemia by reducing 
TG, LDL cholesterol, very low-density lipoprotein (VLDL) cholesterol, non-high-density 
lipoprotein (non-HDL) cholesterol and increasing HDL cholesterol. In addition, Saroglitazar 


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Magnesium can improve glycemic indices in diabetic patients by reducing fasting serum glucose 
and glycosylated hemoglobin. Considering the association between insulin resistance, 
dyslipidemia and the development of NASH, Saroglitazar Magnesium could potentially benefit 
patients with NAFLD including those with NASH. Therefore, the purpose of the present 
proof-of-concept (PoC) study is to examine the efficacy of Saroglitazar Magnesium in improving 
various measures of hepatic inflammation and injury associated with NAFLD, with improvement 
in ALT being the primary endpoint. 
1.3 
Risk-Benefit Assessment 
Considering the results of earlier studies with Saroglitazar Magnesium, patients could benefit 
from the Saroglitazar Magnesium 1 mg, 2 mg or 4 mg treatment because of the drug’s ability to 
improve dyslipidemia and glycemic indices. It is possible that treatment with Saroglitazar 
Magnesium may be associated with a reduction in elevated liver enzyme levels and/or liver 
elasticity. Controlled phase 3 clinical studies in patients with dyslipidemia with Saroglitazar 
Magnesium 2 mg or 4 mg over periods of 12 or 24 weeks had a very favorable safety profile. 
Therefore, the available information suggests that the present study has a favorable risk-benefit 
ratio. 
 
 


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2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
 To investigate the effect of a 16-week treatment regimen of Saroglitazar Magnesium 
1 mg, 2 mg or 4 mg on serum alanine aminotransferase (ALT) levels in patients with 
nonalcoholic fatty liver disease (NAFLD) and/or nonalcoholic steatohepatitis (NASH). 
2.2 
Secondary Objectives 
 To assess the effect of a 16-week treatment regimen of Saroglitazar Magnesium 1 mg, 
2 mg or 4 mg on the following parameters in patients with NAFLD and/or NASH: 
1 Change in liver fat content at Week 16 as measured by magnetic resonance 
imaging-derived proton density-fat fraction (MRI-PDFF). 
2 Proportion of patients who sustain a decrease in serum ALT levels observed at 
Week 4, Week 8, Week 12 and Week 16 of therapy.  
3 Changes in serum-based predictors of liver injury and fibrosis [cytokeratin-18 
(CK-18), Enhanced liver fibrosis (ELF) and aspartate aminotransferase-to-platelet 
ratio index (APRI)], at Week 8 and Week 16 of therapy.  
4 Pharmacokinetics of Saroglitazar Magnesium following first dose and last dose. 
5 Quality of life (QoL). 
6 Safety and tolerability of repeat dosing of 1 mg, 2 mg or 4 mg Saroglitazar 
Magnesium. 
2.3 
Exploratory Objectives  
 
To explore the effect of a 16-week treatment regimen of Saroglitazar Magnesium 
1 mg, 2 mg or 4 mg on the following parameters in patients with NAFLD and/or 
NASH: 
1. Liver stiffness as measured by transient elastography/FibroScan®. 
2. Continuous 
attenuation 
parameter 
(CAP) 
as 
measured 
by 
transient 
elastography/FibroScan. 
3. Fasting lipid and lipoprotein profiles (lipoprofiles) at Week 4, Week 8, Week 12 
and Week 16 of treatment. 
4. Insulin resistance and glycemic control at Week 8 and Week 16 of treatment. 


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3. 
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1 
Overview 
This is a randomized, double-blind, placebo-controlled study in up to 104 patients with a 
diagnosis of NAFLD and/or NASH. The study will be conducted over a period of up to 22 weeks 
and will include an optional Pre-screening, a 5-week Screening and a 16-week Treatment Phase 
following randomization on Day 1 to either Saroglitazar Magnesium (1 mg, 2 mg or 4 mg) or 
placebo orally once daily in the morning before breakfast. Please refer to the Schedule of 
Assessments (Table 4) for a detailed schedule of procedures performed on each study day/visit.   
Pre-screening 
The study sites may identify potential subjects by conducting a laboratory evaluation of the ALT 
levels. This optional pre-screening can be conducted before the actual study screening. A subject 
with an ALT ≥50 U/L may be considered for the actual study screening. 
Also, along with the evaluation of the ALT levels, in those potential subjects who do not have a 
documented diagnosis of NAFLD through any imaging method, an optional abdominal 
ultrasound may be performed during the pre-screening. 
The evaluation of the ALT levels during the pre-screening will be done at the local laboratory, 
whereas the laboratory evaluations during the Screening and the Treatment Phase will be done at 
the central laboratory. 
An informed consent has to be obtained from the potential subjects before any pre-screening 
evaluations. 
Screening 
Visit 1 (Day -35): Patient eligibility for participation in the study will be assessed. Medical 
history will be obtained, physical examination, electrocardiogram (ECG) and laboratory 
evaluations (including serology, clinical chemistry, hematology, liver enzymes and urinalysis) 
will be performed. Female patients will undergo a serum pregnancy test. Serum ALT must be 
≥50 U/L to proceed further in the study. In addition, PI will instruct the patient to maintain his or 
her current diet and physical activity at each visit. 
Visit 2 (Day -14 to -7): Liver enzymes (AST, ALT, ALP and total bilirubin [TB]) will be 
re-measured approximately 3 weeks from Day -35 to determine eligibility. Elevated ALT ≥50 
U/L on 2 occasions in the Screening is necessary for study entry. The variance in the levels of 


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the repeat measures of serum ALT and TB at Day -14 (Visit 2) must be ≤30%, compared to the 
Day -35 (Visit 1) levels to be eligible for study entry. 
(Calculation of the variance and round of laboratory values will be done as following; 
Rounding up of the values will be done according to the following method: 
For e.g. 31.1, 31.2, 31.3, 31.4 will be rounded off to 31. 
31.5, 31.6, 31.7, 31.8, 31.9 will be rounded off to 32. 
0.21, 0.22, 0.23, 0.24 will be rounded off to 0.2 
0.25, 0.26, 0.27, 0.28, 0.29 will be rounded off to 0.3 
1. An example with ALT values 
If the ALT values of subject xx at visit 1 is 73 U/L 
Calculate the 30% of 73 which is 21.9 
+ 30% is 73 + 21.9 which is 94.9 U/L (rounded off to 95) 
- 30% is 73 – 21.9 which is 51.1 U/L (rounded off to 51) 
The ALT value of the same subject at visit 2 has to be not ≤51U/L and not ≥95 U/L. However, 
please keep in mind that the ALT at visit 2 also needs to be ≥50 U/L).  
The liver function test (LFT) values at Day -14 to -7 (Visit 2) will be considered as baseline for 
the efficacy assessment. 
Randomization & Treatment Phase 
The Randomization & Treatment Phase will include 5 additional outpatient visits over a period 
of 16 weeks including the randomization visit. Efficacy assessments will be conducted on these 
5 visits by measuring liver enzymes, CK-18 fragments, ELF, fasting glucose, serum insulin 
levels, lipoprofile, homeostasis model assessment (insulin resistance [HOMA-IR]) and 
homeostasis model assessment (β cell function [HOMA-β], liver stiffness and CAP by transient 
elastography/FibroScan, liver fat content with MRI-PDFF and QoL. In addition, safety 
assessments will be conducted and there will be no clinically significant changes in dietary, 
physical activity or alcohol consumption. 


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Visit 3 (Day 1): Patients will be randomly assigned to receive Saroglitazar Magnesium (1 mg, 
2 mg or 4 mg) or placebo orally once daily, starting on Day 1 of a 16-week outpatient treatment 
period. Patients will commence with a once daily oral dosing regimen.  
Visits 4, 5 and 6: Patients will visit the study site at Week 4 (Visit 4), Week 8 (Visit 5) and Week 
12 (Visit 6) for clinical assessment, dispensation and reconciliation of study drug, measurements 
of efficacy endpoints and assessment of AEs.  
End-of-Treatment Visit (Visit 7): An End-of-treatment Visit will occur at Week 16 for clinical 
assessment, reconciliation of study drug and measurements of efficacy and AEs.  
Telephone follow-up will occur 7 days (± 3 days) after the End-of-treatment Visit for safety 
monitoring. 
3.2 
Endpoints 
The study involves primary and secondary efficacy endpoints and safety assessments. The 
specific endpoints are listed below.   
3.2.1 
Primary Efficacy Endpoint 
 Percentage change from baseline in serum ALT levels at Week 16  in the Saroglitazar 
Magnesium groups as compared to the placebo group  
3.2.2 
Secondary Efficacy Endpoints 
1 Change in liver fat at Week 16 as measured by magnetic resonance imaging-derived 
proton density-fat fraction (MRI-PDFF). 
2 Percentage change from baseline and absolute change from baseline in serum ALT levels 
at Week 4, Week 8 and Week 12 of treatment in the Saroglitazar Magnesium groups as 
compared to the placebo group. 
3 Proportion of patients who sustain a decrease in ALT observed at Week 4, Week 8, Week 
12 and Week 16 in the Saroglitazar Magnesium groups as compared to the placebo 
group. 
4 Proportions of patients with ≥25% and ≥50% reduction from baseline in ALT levels at 
Week 4, Week 8, Week 12 and Week 16 in the Saroglitazar Magnesium groups as 
compared to the placebo group. 


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5 Percentage change from baseline and absolute change from baseline in CK-18 fragments, 
ELF score and APRI at Week 8 and Week 16 after treatment in the Saroglitazar 
Magnesium groups as compared to the placebo group. 
6 Absolute change from baseline in AST/ALT ratio at Week 4, Week 8, Week 12 and 
Week 16 after treatment in the Saroglitazar Magnesium groups as compared to the 
placebo group. 
7 Pharmacokinetics of Saroglitazar Magnesium following first dose and last dose in 
patients with NAFLD/NASH. 
8 Absolute change from baseline in the Short-Form 36 Health Survey Version 2.0 (SF 36) 
8 domain scores and 2 component scores (separate analyses) change from baseline in 
QoL scores at Week 16 after treatment in the Saroglitazar Magnesium groups as 
compared to the placebo group. 
3.2.3 
Exploratory Efficacy Endpoints 
1. Changes in liver stiffness/CAP as measured by transient elastography/FibroScan in the 
Saroglitazar Magnesium groups as compared to the placebo group.  
2. Absolute changes in fasting lipid and lipoprofiles at Week 4, Week 8, Weeks 12 and 
Week 16 after treatment in the Saroglitazar Magnesium groups as compared to the 
placebo group. 
3. Absolute changes in insulin resistance and glycemic control (adiponectin, fasting insulin, 
fasting blood glucose, C peptide, HOMA-IR and HOMA-ß, free fatty acids) at Week 8 
and Week 16 after treatment in the Saroglitazar Magnesium groups as compared to the 
placebo group. Absolute change in HbA1c will be assessed at Week 16. 
3.2.4 
Safety Endpoints  
 Frequency and severity of AEs and serious AEs 
 Clinical laboratory testing (hematology, clinical chemistry and urinalysis) 
 Twelve-lead ECG 
 Vital signs. 
3.3 
Justification of the Study Design 
The present study was designed in accordance with the recommendations set out by the 
American Association for the Study of Liver Diseases, the American Gastroenterological 


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Association and the American College of Gastroenterology Multisociety Practice Guidelines, 
including “Endpoints and Clinical Trial Design for Nonalcoholic Steatohepatitis” authored by 
Sanyal et al and published by the National Institute of Health (Sanyal et al., 2011).  
Recommendations regarding the diagnosis of NAFLD, disease activity and disease staging are 
incorporated into the inclusion/exclusion criteria of the study and the inclusion and exclusion 
criteria is designed to accurately identify patients with NAFLD. During the Treatment Phase, 
patients will be monitored at appropriate intervals for AEs and changes in laboratory parameters. 


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4. 
STUDY POPULATION 
The study population will consist of patients with NAFLD and/or NASH who have elevated 
ALT (defined as ≥50 U/L at the Screening Visits). Patients will be eligible for the study if they 
meet all of the inclusion criteria and none of the exclusion criteria. 
4.1 
Number of Patients 
One-hundred-four patients will be enrolled in the clinical study according to the 
inclusion/exclusion criteria outlined below. Patients will be randomly assigned to receive 
Saroglitazar Magnesium (1 mg, 2 mg or 4 mg) or placebo in a 1:1:1:1 ratio.  
Total ~32 patients (~8 patients from each treatment arm i.e. Saroglitazar Magnesium 1 mg, 2 mg 
or 4 mg, and placebo) will participate in pharmacokinetic assessment.  
4.2 
Inclusion Criteria 
Patients who meet the following criteria will be considered eligible to participate in the clinical 
study: 
1. Males or females, 18 to 75 years of age, with body mass index (BMI) ≥25 kg/m2. 
2. Documented diagnosis of NAFLD established either by imaging (ultrasound, CT scan or 
MRI) or liver biopsy showing NASH or simple steatosis, within the 24 months preceding 
Visit 1. The diagnosis of NAFLD is made according to the American Association for the 
Study of Liver Diseases (AASLD) criteria (Chalasani et al. Hepatology 2012; 
55:2005-2023). 
3. ALT level of ≥50 U/L at Screening Visit 1 and Visit 2 with ≤30% variance in the levels at 
Visit 1 and Visit 2.  
4. Patient’s demonstration of understanding of study requirements and treatment procedures, 
willingness to comply with all protocol-required evaluations; provision of written informed 
consent before any study specific tests or procedures are performed. 
4.3 
Exclusion Criteria 
1. Consumption of >3 units of alcohol per day (>21 units per week) if male and >2 units of 
alcohol per day (>14 units per week) if female for at least 3 consecutive months in the 
5 years preceding Visit 1 (Note: 1 unit = 12 ounces of beer, 4 ounces of wine or 1 ounce of 
spirits/hard liquor). 


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2. Presence of alternative causes of fatty liver, including: 
a. Weight change >5% within the 3 months preceding Visit 1 
b. Total parenteral nutrition, starvation or protein-calorie malnutrition within the 
90 days preceding Visit 1 
c. Use of drugs associated with NAFLD for more than 12 consecutive weeks in the 
1 year before Screening Visit 1, including amiodarone, tamoxifen, methotrexate, 
systemic glucocorticoids, anabolic steroids, tetracycline, estrogens in doses 
higher than used in oral contraceptives, vitamin A, L asparaginase, valproate, 
chloroquine or antiretroviral drugs. 
3. Initiation of vitamin E at doses >100 IU/day, or multivitamins containing >100 IU/day of 
vitamin E in the 3 months preceding Visit 1.  
4. Use of drugs with potential effect on NASH such as ursodeoxycholic acid, 
S-adenosylmethionine (SAM-e), betaine, pentoxifylline, obeticholic acid or milk thistle in 
the 3 months prior to Visit 1.  
5. Changing doses of statins (simvastatin, pitavastatin, pravastatin, atorvastatin, fluvastatin, 
lovastatin, rosuvastatin) or fibrates (clofibrate, fenofibrate) in the 3 months preceding Visit 1.  
6. Use of thiazolidinediones (pioglitazone, rosiglitazone). 
7. Use of drugs that are known CYP2C8 inhibitors/substrate (please refer Section 5.8.1.1 
Excluded Concomitant Medications). 
8. History of bowel surgery (gastrointestinal (bariatric) surgery or undergoing evaluation for 
bariatric surgery for obesity, extensive small-bowel resection or orthotopic liver transplant 
(OLT) or listed for OLT. 
9. History of other chronic liver disease (chronic hepatitis C, (HCV) infection, irrespective of 
their mRNA HCV assay status, or active hepatitis B infection, (i.e., serum positive for 
hepatitis B surface antigen) or autoimmune hepatitis, cholestatic and metabolic liver 
diseases) or hemochromatosis. 
10. Patient has known cirrhosis, either based on clinical criteria or liver histology. 
11.  Patient with INR >1.3.  
12.  Type 1 diabetes mellitus. 
13. Poorly controlled type 2 diabetes mellitus, i.e., glycosylated hemoglobin (HbA1c) >9%. 


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14. Unstable cardiovascular disease, including: 
a. unstable angina, (i.e., new or worsening symptoms of coronary heart disease 
within the 3 months preceding Visit 1), acute coronary syndrome within the 
6 months preceding Visit 1, acute myocardial infarction within the 3 months 
preceding Visit 1 or heart failure of New York Heart Association class (III – IV) 
or worsening congestive heart failure, or coronary artery intervention, within the 
6 months preceding Visit 1 
b. history of (within 3 months preceding Visit 1) or current unstable cardiac 
dysrhythmias  
c. uncontrolled hypertension (systolic blood pressure [BP] >160 mmHg and/or 
diastolic BP >100 mmHg) 
d. stroke or transient ischemic attack within the 6 months preceding Visit 1. 
15. History of myopathies or evidence of active muscle disease. 
16. History of malignancy in the 5 years preceding Visit 1 and/or active neoplasm with the 
exception of resolved superficial nonmelanoma skin cancer. 
17. Any of the following laboratory values: 
a. Hemoglobin <9 g/dL 
b. White blood cell count <2.5 × 103/µL 
c. Neutrophil count <1.5 × 103/µL 
d. Platelets <100 × 103/µL 
e. Total Serum bilirubin >1.5 mg/dL (except in patient with known Gilbert bilirubin 
where TB up to 2.5 mg/dL is allowed), if it is <1.5 mg/dL at screening and >30% 
variance in the levels at Visit 1 and Visit 2. 
f. Albumin <3.2 g/dL 
g. Serum creatinine >1.5 mg/dL 
h. Serum ALT or AST >250 U/L at Visit 1 or Visit 2. 
18. Contraindications to Saroglitazar Magnesium or has any conditions affecting the ability to 
evaluate the effects of Saroglitazar Magnesium.  


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19.  Known allergy, sensitivity or intolerance to the study drug, placebo or formulation 
ingredients. 
20. Participation in any other therapeutic clinical study within the 3 months preceding Visit 1, 
including participation in any other NAFLD/NASH clinical trials. 
21. History of bladder disease and/or hematuria or has current hematuria except due to a urinary 
tract infection. 
22. Illicit substance abuse within the 12 months preceding Visit 1. 
23. Pregnancy-related exclusions, including: 
a. Pregnant/lactating female (including a positive serum pregnancy test at Visit 1) 
b. A male patient has to use a condom with spermicide, and the female partner of the 
male patient has to use an intrauterine device OR a diaphragm with spermicide 
OR oral contraceptive pills. 
c. If a male patient has undergone a vasectomy, the female partner does not have to 
use any contraception. 
d. A female patient has to use either an intrauterine device OR a diaphragm with 
spermicide OR oral contraceptive pills. The male partner of the female patient has 
to use a condom with spermicide. 
e. If the female patient is surgically sterilized for at least the 6 months preceding 
Visit 1 or postmenopausal, defined as at least 12 months with no menses and 
without an alternative cause, the male partner of the female patient does not have 
to use any contraception. 
24. History or other evidence of severe illness or any other conditions that would make the 
patient, in the opinion of the investigator, unsuitable for the study (such as poorly controlled 
psychiatric disease, HIV, coronary artery disease or active gastrointestinal conditions that 
might interfere with drug absorption). 
4.3.1 
Screen Failures 
If a subject is termed as a screen failure for not meeting the inclusion/exclusion criteria, the 
subject may be rescreened only after obtaining sponsor approval. The sponsor may approve for 
rescreening those cases in which subjects failed the screening parameters within a narrow 


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margin. Screening laboratory tests may be repeated following the approval of Sponsor or its 
designee if the laboratory test results seem implausible or inaccurate. 
At least 35 days from the date of the subject’s initial screening will need to elapse prior to 
rescreening a subject. 
The subject will need to be rescreened under a new screening number and a new informed 
consent has to be obtained. 
A screen failure occurs when a patient who has signed the informed consent form (ICF) does not 
meet all the entry criteria outlined in this protocol and has not been randomized or received study 
drug. No study procedures (including End-of-treatment procedures) will be performed for these 
patients. For patients who fail to meet the inclusion criteria or who meet 1 or more of the 
exclusion criteria, the Principal Investigator (PI) (or designee) will document on a screening log 
the reason for the screening failure.   
4.3.2 
Patient Withdrawal 
Patients may withdraw from the entire study at any time without penalty and for any reason 
without prejudice to his or her future medical care. Although a patient is not obliged to give 
his/her reason for withdrawing prematurely, the PI will make a reasonable effort to obtain the 
reason while fully respecting the patient’s rights. If there is a medical reason for withdrawal, the 
patient will remain under the supervision of the PI for follow-up of AE(s) as detailed in Section 
6.1.2.8. Every effort will be made to continue clinical and/or laboratory follow-up, as 
appropriate, in patients who wish to withdraw from the study drug (active drug or placebo) and 
reasonable efforts will be made to contact a patient who fails to attend any follow-up 
appointments, in order to ensure that he/she is in satisfactory health. A patient’s withdrawal of 
consent and agreement to undergo a final examination will be documented on the case report 
form (CRF) and on the PI’s copy of the ICF, which will be countersigned and dated by the 
patient.  
As far as possible, all assessments scheduled for End-of-treatment must be performed on all 
patients who receive the study drug but do not complete the study according to protocol.   
4.3.3 
Discontinuation of Patients from the Study or Study Drug 
A patient may be discontinued from the study for any of the following reasons: 
 Occurrence of a deviation/noncompliance with the protocol 


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 Occurrence of a serious or intolerable AE 
 The Sponsor or PI terminates the study (Section 4.5) 
 Either the PI or the Sponsor decides that discontinuing the study or discontinuing the 
patient is in the patient’s best interest 
 For reasons related to safety as specified in Section 4.4  
 The patient is lost to follow-up.  
A patient may also be discontinued from study drug/study by the Regulatory Authorities or IRB. 
A study completion CRF, which includes the reason for discontinuation, must be completed for 
all patients who are discontinued from the study. If the patient is discontinued prematurely, the 
study completion CRF should clearly indicate the reason for discontinuation. If the patient 
discontinues due to an AE, an AE CRF must be completed. The AE must be followed by medical 
attention to satisfactory resolution and all study data related to the patient will be reported. 
Every effort will be made to continue clinical and laboratory follow-up, as appropriate, in 
patients who are withdrawn or in whom the study drug is stopped by the PI or per individual 
stopping rules (Section 4.4). 
4.3.4 
Patients Lost to Follow-up 
Every attempt must be made to have all patients complete the visit schedule. A patient will not 
be considered lost-to-follow-up unless all efforts to obtain compliance are unsuccessful. Study 
sites should attempt to contact these patients in order to maintain study visit compliance and all 
contact attempts should be documented in both the patient’s medical records and on the study 
CRFs. At a minimum, the site should make 2 attempts (at least 3 to 5 days apart and during both 
business and nonbusiness hours) to contact the patient; once by phone and once by certified mail. 
4.4 
Stopping Criteria for Individual Patients 
The following clinical events warrant discontinuation of study drug; however, the patient will 
continue to be followed for safety, liver function tests and lipid levels until the event has 
resolved, i.e., clinical laboratory value(s) has/have returned to baseline or is/are no longer of 
clinical significance. Discontinuation of study drug will only occur if mandated by safety events 
as defined below: 


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 Discontinue any patient with a Common Terminology Criteria for Adverse Event 
(CTCAE) of grade 3 or higher that is possible or likely drug related and discontinue any 
patient with a CTCAE of grade 4 regardless of attribution to drug. 
 Serious AE (SAE) that may be related to the drug and warrant discontinuation as per 
discretion of the PI; 
 In the opinion of the PI, continuation of study drug poses a health risk to the patient. 
 Evidence of drug induced liver injury requiring study drug discontinuation as shown in 
the algorithm below. 
 The second LFT values during the Screening (those obtained at Visit 2) will be 
considered as baseline for the efficacy assessment. 
o If patients with abnormal baseline liver indices develop elevations of AST or ALT 
greater than 2 times baseline or total bilirubin greater than 1.5 X baseline values 
(BL) while on study, testing should be repeated within 48-72 hours. If there are 
persistent elevations in ALT or AST greater than 2 X baseline or TB greater than 
1.5 X baseline values, then close observation (see DILI Guidance for definition, 
testing and physical examination 2-3 times per week) should be initiated or drug 
should be discontinued. 
o A decision to discontinue or temporarily interrupt a study drug should be 
considered based on factors that include how much higher baseline ALT and AST 
were relative to the upper limit of normal (ULN) and how much the on study ALT 
and AST levels have increased relative to baseline, in addition to whether there is 
concomitant elevation of bilirubin or INR.  
o The criteria for discontinuing or temporarily interrupting study drug are as 
follows:  
 When the baseline values were ≥50 U/L but <5 X ULN, discontinue if 
ALT or AST increases to >3 X BL 
 Discontinue if ALT or AST increase >2 X BL AND the increase is 
accompanied by a concomitant TBL increase to >2 X BL OR the INR 
concomitantly increases by >0.2 
 Discontinue and evaluate any patient with elevations of ALT/AST if sign 
or symptoms of right upper quadrant pain (RUQ), abdominal pain, 
anorexia, nausea, vomiting fever, eosinophilia and/or rash are present 






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5.2 
Supply, Packaging, Labeling and Storage 
Study drug will be packaged by the Sponsor according to all local legal requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Until dispensed to the patients, the study drug will be stored at room temperature (20°C to 25°C 
or 68°F to 77°F) in a dry place at the study site or pharmacy that can be securely locked and that 
is accessible to authorized personnel only. If the IP temperature extends outside the 20-25°C 
range, a temperature excursion must be documented, and sent to the Sponsor and CRO. If the 
excursion is within 15-30°C, quarantine is not required, and the IP is acceptable for use. If the 
excursion is outside of the 15-30°C range, the IP must be quarantined until a decision on the 
stability of the IP is made by the Sponsor. If the excursion go beyond the range of 15-300 C will 
be consider protocol deviation. 
5.3 
Dispensing and Administration 
The PI or designated study personnel will assign the box with the lowest available randomization 
ID to the first patient to randomize, followed by the next lowest randomization ID to the second 
patient to randomize and so on 
. The process will 
begin again using the next outer carton of IP available. One bottle from each inner carton will be 
dispensed to cover the 4-week interval between study visits (Schedule of Assessments [Table 4]). 
Patients will be instructed to store study drug in a dry place at room temperature (20°C to 25°C 
or 68°F to 77°F). 


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Patients will take 1 tablet of Saroglitazar Magnesium (1 mg, 2 mg or 4 mg) or placebo for a 
period of 112 days. The tablet should be taken at approximately the same time each day. Specific 
written instructions will be provided on the label and will include directions to take the tablet.   
5.4 
Drug Accountability 
Receipt and dispensing of study drug must be recorded by an authorized person at the study site.  
The PI will maintain an accurate record of the receipt of the study drug as shipped by the 
Sponsor, including the date received. Study drug supply management will be processed and 
maintained in the CRFs and on Drug Accountability forms, which will be monitored and 
reconciled by the study monitor assigned to the site. This inventory record must be available for 
inspection at any time. Copies of this record will be provided to the Sponsor at the conclusion of 
the study. 
The PI will not be allowed to store study drug at any site other than those listed on Form 
FDA 1572 or Investigator’s Agreement or to dispense the study drug from sites not listed on this 
form. The PI will also agree that study drug will be dispensed by the PI or Sub-investigator 
named on Form FDA 1572 or Investigator’s Agreement, or their qualified designees. The PI, 
Sub-investigators and qualified designees also agree that study drug will be dispensed only to 
study patients who have provided written informed consent and have met all entry criteria. Study 
drug may not be used for any purpose other than that stated in the protocol. 
After the study has been completed, the PI must account for all study drug used, unused and 
partially used. All study drug will be adequately destroyed at the site (per site’s SOPs) or 
returned to the Sponsor (or designee).  No study drug will be destroyed or returned until drug 
accountability has been performed by the study monitor. 
5.5 
Patient Identification and Randomization 
5.5.1 
Screening Numbers 
Patients will be assigned a unique site-specific (e.g., site number 101, 102, etc.,) and patient 
number (a 3-digit site identification and 3-digit number, e.g., 101-001, 101-002, etc.) that will be 
used to identify the patient on all data collection forms from Visit 1 until the end of the 
Treatment Phase. 


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5.5.2 
Randomization Scheme, Randomization Numbers and Allocation of Patients to 
Treatment 
Block Randomization of patients to treatment (placebo, saroglitazar magnesium 1 mg, 2 mg or 
4 mg) will occur in 1:1:1:1 ratio. The block randomization will be generated following 
biostatistics procedure for generation of randomization lists. Each block will contain 
investigational medicinal products; Saroglitazar Magnesium 1 mg, 2 mg, 4 mg and placebo. 
 
    
On Day 1 of the Treatment (Visit 3), the first eligible patient will be assigned the lowest 
available randomization ID. The second eligible patient will receive the next lowest available 
randomization ID 
 
5.5.3 
Patient Replacements 
If patients fail to complete for reasons unrelated to the safety of the study drug, then replacement 
patients may be enrolled to ensure that each study arm is adequately filled and approximately 
104 patients (approximately 26 per treatment arm) complete the study.  
5.6 
Compliance 
At each treatment period visit, study coordinators will log all study drug dispensed to a study 
patient and returned to the site by the study patient into the CRF for the purpose of drug supply 
management and accountability. Although 100% compliance to study drug is desired and should 
be encouraged throughout the treatment phase, a compliance of ≥80% and ≤120% will be 
considered as acceptable.   
5.7 
Blinding and Breaking the Blind 
The study will be performed in a double-blind manner. All study drugs will be supplied in 
identical packages and study drug kits and the tablets will be similar in color, smell, taste and 
appearance, thereby enabling double-blind conditions.  
The study blind should not be broken except in a medical emergency where knowledge of the 
study drug received would affect the treatment of the emergency.  
The blind must only be broken following discussion on a case-by-case basis, at the discretion of 
the Sponsor/Medical Monitor. 
If an emergency unblinding becomes necessary, the PI should notify the Sponsor/Medical 
Monitor, if possible, before unblinding. If it is determined that unblinding is necessary, an 


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envelope matching the randomization ID will be opened to reveal the treatment received by the 
patient. All cases resulting in an unblinding event will be documented and reported to the 
Medical Monitor and the Sponsor. If the blind is broken, the date, time and reason must be 
recorded in the patient’s CRF and any associated AE report completed.  
The overall randomization code will be broken only for reporting purposes. This will occur once 
all final clinical data have been entered into the database and all data queries have been resolved, 
and the assignment of patients to the analysis sets has been completed.    
5.8 
Previous and Concomitant Medications and Other Restrictions 
5.8.1 
Previous and Concomitant Medications 
Any medication the patient takes other than the study drug, including herbal and other 
nontraditional remedies, is considered a concomitant medication. All concomitant medications 
and any changes in the dosage or regimen of a concomitant medication for the 30 days preceding 
Visit 1 until the end of the study (i.e., the safety telephone call) must be recorded in the CRF. 
5.8.1.1 
Excluded Concomitant Medications 
Patients are not permitted to take Zileuton, unstable dose of vitamin E or other drugs with 
potential effect on NAFLD such as ursodeoxycholic acid, S-adenosylmethionine (SAM-e), 
betaine, pentoxifylline, obeticholic acid or milk thistle.  In addition, patients are not permitted to 
take drugs associated with NAFLD during the study period including amiodarone, tamoxifen, 
methotrexate, systemic glucocorticoids, anabolic steroids, tetracycline, estrogens in doses higher 
than used in oral contraceptives, vitamin A, L asparaginase, valproate, chloroquine or 
antiretroviral drugs. The doses of statins (simvastatin, pravastatin, atorvastatin, fluvastatin, 
lovastatin, rosuvastatin) or fibrates (clofibrate, fenofibrate) should remain stable throughout the 
study period as much as possible. Patients are not permitted to thiazolidinediones (pioglitazone, 
rosiglitazone), chemotherapy or other investigational medications during the study duration.   
The known CYP2C8 inhibitors/substrates are not permitted during the study (Appendix 2: List of 
Known CYP2C8 Inhibitors/Substrates).  
Patients also should not take any non-allowed over-the-counter medications or complementary 
and/or alternative medications believed to have a potential impact that would affect the ability to 
evaluate the study data. 


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5.8.1.2 
Permitted Concomitant Medications 
With the exception of excluded concomitant medications, other medications that patients have 
been taking at stable dosages for at least 3 months preceding Visit 1, i.e., statins and drugs for 
glycemic control, will be permitted as concomitant medications, including antidiabetic drugs 
such as metformin, sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors and insulin.  To the 
extent possible, patients should continue with their current regimen of medication without any 
change throughout the study. 
Allowed over-the-counter medications include acetaminophen (maximum 1 gram/day), 
ibuprofen (maximum 800 mg/day) or naproxen (maximum 440 mg/day) or antacids such as H2 
receptor blockers or proton-pump inhibitors for shorter duration as per investigator discretion.  
The PI should be alerted if, during the course of the study, a patient requires a new medicine or 
therapy or a change to an established dosing regimen. All medications that target NAFLD or 
NASH, or have been suggested to target the underlying causes of NAFLD or NASH, should be 
reviewed and agreed on by the PI, Medical Monitor and Sponsor before being taken by the 
patient.   
5.8.2 
Other Restrictions 
5.8.2.1 
Alcohol 
Patients are encouraged to stop alcohol consumption entirely during the trial. They are not 
permitted to consume >1 unit of alcohol per day (>7 units per week) during the study. Alcohol 
consumption will be recorded throughout the study period.  
5.8.2.2 
Diet and Exercise 
Patients must maintain lifestyle modifications, including diet and exercise, previously undertaken 
according to AASLD guidelines for the duration of the study.  Patients should make no major 
changes in the type or amount of exercise in which they partake during the study. 
5.9 
Overdose and Drug Interaction 
No incidence of overdose with saroglitazar magnesium has been reported. In case of overdose 
with saroglitazar magnesium, general supportive care of the patient is indicated, including 
monitoring of vital signs and observation of clinical status. 
 
 


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6. 
VARIABLES AND METHODS OF ASSESSMENT 
6.1 
Safety Variables 
There will be a designated safety officer for data and safety monitoring. The safety officer will 
be an experienced hepatologist with no direct involvement with the study (Please refer Section 
7.2 Data Monitoring Committee).  
6.1.1 
Medical History, Demographic and Other Baseline Information 
The medical history comprises: 
 General medical history 
 Medication history 
 Reproductive history. 
The following demographic information will be recorded: 
 Gender 
 Age 
 Ethnic origin (Hispanic/Latino or not Hispanic/not Latino) 
 Race (White, American Indian/Alaska Native, Asian, Native Hawaiian or other Pacific 
Islander, Black/African American) 
 Height, without shoes 
 Body weight, without shoes 
 Body mass index. 
Other baseline characteristics will be recorded as follows: 
 History of drug abuse 
 History of alcohol abuse 
 Smoking history 
 History of caffeine use (or other stimulating beverages) 
 Diet 
 History of blood or plasma donation. 


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6.1.2 
Adverse Events 
Adverse event reporting will begin after the informed consent has been signed and will continue 
until end of the study (i.e., the safety telephone call). The Common Terminology Criteria for 
Adverse Event (CTCAE) (Version 4.03 or higher) system will be used for reporting and grading 
AEs. 
6.1.2.1 
Definitions 
An AE is any unfavorable or unintended sign, symptom or disease temporally associated with 
the use of study drug whether or not considered related to study drug. Adverse events may 
include: 
 Objective signs observed by the PI or study personnel 
 Subjective or objective signs/symptoms 
 Concomitant disease or accidents 
 Clinically relevant adverse changes in laboratory parameters observed in a patient in the 
course of a clinical study 
 Pre-existing conditions that worsen in severity or frequency or have new signs/symptoms 
associated with them 
Findings related to abnormal laboratory values, ECGs and vital signs, which are not considered 
clinically significant, are not to be recorded on the AE reporting page; such events should instead 
be entered in the relevant CRF page. 
6.1.2.2 
Serious Adverse Events 
Serious Adverse Events 
An SAE is an event that: 
 Results in death 
 Is an immediate threat to life 
 Requires hospitalization, or prolongation of existing hospitalization 
 Results in persistent disability/incapacity 
 Is a congenital anomaly or birth defect 


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Serious AEs also include events that are medically significant in the PI’s judgment, including 
medically significant laboratory abnormalities, such as those that warrant stopping study drug for 
individual patients as specified in Section 4.4 of the protocol. In general, medically significant 
events require medical/surgical intervention to prevent one of the outcomes listed above. 
6.1.2.3 
Treatment-emergent Adverse Events 
Treatment-emergent AEs are defined as any AE that started after the first dose of study drug or 
started before the first dose but increased in severity or frequency after administration of the 
initial dose of study drug. 
6.1.2.4 
Collection of Adverse Events 
It is the responsibility of the PI to collect all AEs (both serious and nonserious) derived by 
spontaneous, unsolicited reports of patients, by observation and by routine open questionings, 
e.g., "How have you felt since I last saw you?" 
6.1.2.5 
Assessment of Adverse Events 
Each AE will be assessed by the PI with regard to the following categories: 
Severity 
The PI will provide an assessment of the severity of each AE by recording a severity rating on 
the appropriate AE reporting page of the patient’s CRF. Severity will be assessed according to 
the following scale: 
Mild: Event is usually transient and easily tolerated, requiring no special treatment and causing 
no disruption of the patient’s normal daily activities. 
Moderate: Event introduces a low level of inconvenience or concern to the patient and may 
interfere with daily activities, but is usually improved by simple therapeutic measures. Moderate 
experiences may cause some interference with functioning. 
Severe: Event interrupts the patient’s normal daily activities and generally requires systemic drug 
therapy or other treatment. Severe events are usually incapacitating. 
Causality 
For all AEs, the PI will provide an assessment of causal relationship to study drug. The causality 
assessment must be recorded on the appropriate AE reporting page of the patient’s CRF. 


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Causal relationship will be classified according to the following criteria: 
 Unrelated 
 Possibly related: Suggests that the association of the AE with the study drug is unknown.  
However, the AE is not reasonably supported by other conditions 
 Probably related: Suggests that a reasonable temporal sequence of the AE with study 
drug administration exists and, based upon the PI’s clinical experience, the association of 
the AE with study drug seems likely 
 Definitely related: Suggests that a causal relationship exists between the study drug and 
the AE, and other conditions (concomitant illness, progression or expression of the 
disease state, reaction to concomitant medication) do not appear to explain the AE 
 Unknown. 
Outcome 
Outcome of AEs will be defined according to the International Council for Harmonisation (ICH) 
Topic E2B, ICH Guideline, as follows: 
 Recovered/Resolved 
 Recovered/Resolved with sequelae 
 Recovering/Resolving 
 Not Recovered/Not Resolved 
 Fatal 
 Unknown. 
6.1.2.6 
Recording Adverse Events 
All AEs must be recorded on the appropriate AE CRF for the patient. All AEs must be reported 
whether or not considered causally related to study drug. For every AE, the PI will provide an 
assessment of the severity and causal relationship to study drug, will document all actions taken 
with regard to study drug, and will document any other treatment measures for the AE. If an 
outcome for an AE is not available at the time of the initial report, follow-up will proceed until 
an outcome is known. 


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6.1.2.7 
Reporting Serious Adverse Events 
The PI must report any SAEs
 Clinical Studies Safety Center within 24 hours of 
becoming aware of the event.  
When calling to report an SAE, state that you are reporting an SAE and give the PI’s name, your 
name, the telephone number where you can be reached and the protocol number and title. 
The PI and the Sponsor (or Sponsor’s designated agent) will review each SAE report and the 
Sponsor
 will evaluate the seriousness and the causal relationship of the event to 
study drug. In addition, the Sponsor (or Sponsor’s designated agent) will evaluate the 
expectedness according to the reference document (Investigator Brochure or Summary of 
Product Characteristics). Based on the PI and Sponsor’s assessment of the event, a decision will 
be made concerning the need for further action. 
All SAEs will be recorded from signing of informed consent until the end of the study (i.e., the 
safety telephone call). Serious AEs occurring after the end of the study and coming to the 
attention of the PI must be reported only if they are considered (in the opinion of the PI) 
causally-related to the investigational drug. 
6.1.2.8 
Follow-up of Adverse Events 
All AEs experienced by a patient, irrespective of the suspected causality, will be monitored until 
the AE has resolved, any abnormal laboratory values have returned to baseline or stabilized at a 


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level acceptable to the Investigator and Medical Monitor, until there is a satisfactory explanation 
for the changes observed, until the patient is lost to follow-up or until the patient has died. 
6.1.2.9 
Pregnancy 
Women are advised not to become pregnant during the trial and for at least 3 days after the end 
of the trial period. A pregnancy which occurs during the trial is a reason for study withdrawal. 
Although a pregnancy is not considered as an adverse event, it is the responsibility of 
investigators or their designees to report any pregnancy that occurs during the trial or within 
3 days of completing the trial. All subjects who become pregnant must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage 
and stillbirth must be reported as serious adverse events (Important Medical Events). If the 
pregnancy continues to term, the outcome (health of infant) must also be reported. The 
investigator should fax or email the Pregnancy Form to 
 Safety within 24 hours of 
being notified. 
6.1.3 
Clinical Laboratory Assessments 
6.1.3.1 
Sample Collection 
Blood samples will be collected for clinical laboratory testing at the time points indicated in the 
Schedule of Assessments (Table 4). Safety laboratory variables are listed in Table 3. 
Table 3 
Safety Laboratory Assessments 
Hematology 
 
erythrocytes 
MCV 
MCH 
neutrophils 
eosinophils 
basophils 
lymphocytes 
monocytes 
platelets 
leukocytes 
hemoglobin 
hematocrit 
PT 
INR 
Clinical chemistry 
 
Albumin  
BUN 
creatinine 
CPK 
hs-CRP 
triglycerides 
urea 
uric acid 
cholesterol 
 
Electrolytes: 
sodium 
potassium 
Liver Enzymes: 
ALT 
AST 
ALP 
bilirubin 
GGT  
serum proteins 
Urinalysis 
appearance 
color 
leukocytes 
blood 


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bilirubin 
pH 
protein 
glucose 
ketones 
nitrite 
specific gravity 
urobilinogen 
Serology 
 
HIV type 1 and type 2 
HAV IgM 
HBsAg 
HCV  
Pregnancy test 
For women of childbearing potential only at the first Screening Visit 
Drugs of Abuse 
Screen (urine) 
amphetamines 
benzodiazepines 
marijuana 
cocaine 
opioids 
AST = aminotransferase; ALT = alanine aminotransferase; ALP = alkaline phosphatase; BUN = blood urea 
nitrogen; CPK = creatinine phosphokinase; GGT = γ-glutamyl transferase; HAV IgM= anti hepatitis A virus; 
HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; hs-CRP = 
high-sensitive c-reactive protein; INR = international normalized ratio; MCH = mean corpuscular hemoglobin; 
MCV = mean corpuscular volume; PT =  prothrombin time  
6.1.3.2 
Sample Storage and Shipping 
Except where noted, all samples for laboratory assessments will be shipped to and processed by a 
central laboratory. All details regarding laboratory sample preparation and shipment will be 
provided by the central laboratory and all other blood and urine samples will be collected 
according to the laboratory manual provided by the central laboratory and according to the 
Schedule of Assessments (Table 4). 
The laboratory evaluations that are to be performed locally at the study site (e.g., urinalysis and 
pregnancy testing by means of serum human chorionic gonadotropin [hCG] and urine hCG) 
should be performed according to the site’s local laboratory protocol. 
6.1.3.3 
Results of Laboratory Assessments 
The central laboratory will provide the results of the testing to the study site to allow for the PI to 
confirm patient eligibility, manage enrolled patients and assess the clinical significance of each 
laboratory value/result. In the event of abnormal clinical laboratory values, the PI will make a 
judgment as to whether or not the abnormality is clinically significant.   
Approximately 1 week after Visit 2, the results of the laboratory tests will be returned to the site 
for verification of patient eligibility.  
6.1.3.4 
Urine Tests 
Urine tests will be processed either centrally or locally, as noted below: 


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 Urine hCG (women of childbearing potential only at Visits 3, 4, 5, 6 and 7) will be 
processed by a local laboratory   
 Urinalysis will be processed by a local laboratory  
 Urine drugs of abuse screening will be processed at a central laboratory.  
6.1.4 
Vital Signs 
The following vital signs will be assessed at time points described in the Schedule of 
Assessments (Table 4): 
 Sitting blood pressure (systolic and diastolic; mmHg) (measured in triplicate at Visit 1 
and a single measurement at all other visits) 
 Pulse (beats per minute) (measured in triplicate at Visit 1 and a single measurement at all 
other visits) 
 Oral body temperature (°F)  
 Respiratory rate (breaths per minute). 
Vitals signs will be measured before any blood draw that occurs at the same visit and after the 
patient has been resting for at least 5 minutes. A 5-minute rest period in between vital signs and 
ECG measurements is recommended.    
6.1.5 
Twelve-lead Electrocardiograms 
Electrocardiograms will be performed locally at the study site in accordance with the Schedule of 
Assessments (Table 4). The 12-lead ECG equipment will be set to 25 mm/sec and 10 mm/mV 
and ECGs will be recorded with patients in the recumbent position and resting. Patients should 
be in this resting position for 5 minutes before ECG recording and performed before any blood 
draw that occurs at the same visit.  
Measures will be taken to eliminate baseline tremor, as it may interfere significantly with the 
quality of the interpretation. Before electrode placement, the 10 anatomical sites will be prepared 
to allow for proper skin/electrode interface. Patients with excessive hair will be dry shaven, as 
needed. 
Electrocardiogram recordings will be taken in triplicate at the Screening Visit and as a single 
recording at all other visits.  


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6.1.6 
Physical Examinations 
Physical examinations will be performed in accordance with the Schedule of Assessments 
(Table 4). Patients’ body weight will be recorded during all physical examinations. Height will 
be recorded at Screening Visit only). 
6.2 
Efficacy Variables 
6.2.1 
Blood Samples  
Multiple venipunctures should be avoided to collect blood samples. It is recommended to collect 
only 1 blood sample for efficacy and safety measurement at a given visit. 
For the primary efficacy variable, blood samples for measurement of ALT will be collected at 
the time-points specified in the Schedule of Assessments (Table 4). Refer to Section 6.1.3 for 
information about sample collection, shipping and storage and results of sample collection for 
ALT. 
Samples for secondary and exploratory efficacy variables will be collected as follows: 
Insulin resistance and glycemic control: includes fasting (at least 8 hours) insulin, fasting 
plasma glucose, HbA1c, C-peptide, HOMA-IR and HOMA-ß. The results of the fasting plasma 
glucose, HbA1c, HOMA-IR and HOMA-ß will be blinded to site. Results of Insulin and C-
Peptide will not be blinded.  
Lipoprofile: includes fasting (at least 8 hours) LDL, VLDL, HDL, total cholesterol, non-HDL 
cholesterol, apo A and apo B. The results of the lipoprofile (except total cholesterol) will be 
blinded to site. Serum triglyceride results will not be blinded. 
CK-18 and APRI: includes CK-18, AST and platelet count   
ELF score: serum samples. Enhanced liver fibroses score is an extracellular matrix marker set 
consisting of tissue inhibitor of metalloproteinases 1 (TIMP-1), amino-terminal propeptide of 
type III procollagen (PIIINP) and hyaluronic acid (HA) showing good correlations with fibrosis 
stages in chronic liver disease. 
Full details regarding laboratory sample preparation and shipment will be provided by the central 
laboratory.   


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6.2.2 
Quality of Life  
Subjective QoL assessments will be measured using the SF-36 version 2.0 (See Appendix 1: 
Quality of Life Assessment Questionnaire), which is a 36-item patient response questionnaire 
that measures QoL across 8 domains, both physically and emotionally based. The 8 domains are 
physical functioning, role limitations due to physical health, role limitations due to emotional 
problems, energy/fatigue, emotional well-being, social functioning, pain and general health.    
6.2.3 
Transient Elastography/FibroScan 
Liver stiffness measurements will be performed by transient elastography using the FibroScan 
(Echosens, Paris, France). The appropriate FibroScan measurement probe should be used (i.e., M 
or XL) based on the manufacturer’s recommendation for probe choice according to chest 
circumference and age. FibroScan is optional and performed only sites with machines available 
at sites. 
Patients will fast for 3 hours before the transient elastography/FibroScan procedure. For the liver 
stiffness measurements, patients will be in dorsal decubitus position with the right arm in 
maximal abduction. The exam begins with placement of the probe along the intercostal space to 
obtain a view of the right lobe of the liver. Once an area of at least 6 cm thick and free of large 
vascular structures or gallbladder is identified, 10 measurements should be obtained. A 
FibroScan exam will only be considered acceptable if it results in 10 measurements with a 70% 
success rate, and the interquartile range is less than 30% of the value of the median or controlled 
attenuation parameter (CAP) will be simultaneously measured with liver stiffness using the same 
probe. 
6.2.4 
Magnetic Resonance Imaging-Derived Proton Density-Fat Fraction (MRI PDFF) 
The magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) is a novel 
imaging-based biomarker that allows fat mapping of the entire liver. Liver fat content will be 
measured using MRI-PDFF. Proton-density-fat-fraction technique is an MRI protocol that 
improves on the conventional Dixon in- and out-of phase method.  PDFF uses a low flip angle to 
reduce T1 bias (Bydder M et al. 2008; Liu et al. 2007).  Multiple echoes per excitation are used 
to correct T2* decay (Bydder M et al. 2008; Yokoo et al. 2009; Yu et al. 2007).  As a result, the 
expected loss of signal with longer echo times, particularly in the presence of iron, is corrected. 
In head-to-head comparisons, PDFF quantified liver fat more accurately than conventional two-
point Dixon MRI (Yokoo et al. 2011; Mashhood et al. 2013).  In addition, PDFF minimizes the 
multifrequency interference effects of fat protons (Yokoo et al. 2009).  PDFF has been shown to 


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have high reproducibility at 1.5 T and 3.0 T (Kang et al. 2011).  Studies assessing liver fat have 
confirmed the accuracy of PDFF using hydrogen-1 MR spectroscopy (H1-MRS) (Yokoo et al. 
2009; Yokoo et al. 2011; Kang et al. 2011; Noureddin et al. 2013) or liver histology (Idilman et 
al. 2013; Tang et al. 2013) as gold standard. In addition, PDFF MRI technique allows fat 
mapping for the entire liver, whereas longitudinal segmental changes of liver fat may be 
accurately determined and small differences can be detected (Noureddin et al. 2013).  On the 
other hand, H1-MRS only measures liver fat content in a small region of interest.  Another 
benefit of PDFF over H1-MRS is that the former may be performed in a few seconds as a 
breath-hold scan.  H1-MRS, together with the shimming time required prior to the scan, takes at 
least 30 minutes to complete. 
6.3 
Pharmacokinetics Assessment 
Pharmacokinetics of Saroglitazar Magnesium following first dose and last dose in patients with 
NAFLD/NASH will be performed. The samples will be collected at Pre-dose (0.0), 0.5, 1.0, 2.0, 
3.0, 4.0, 6.0, 8.0, 10.0 and 24 hours post-dose.  In addition pre-dose sample will be collected at 
Visits 4, 5 and 6. The pharmacokinetics sampling will only be collected in the approximately 32 
subjects participating in the PK evaluation.  
The following pharmacokinetic parameters will be evaluated for first and last dose: 
i. 
Peak Plasma concentration (Cmax) 
ii. 
Time to reach peak Plasma concentration (Tmax) 
iii. 
Area under Plasma concentration vs. time curve till the last time-point (AUC0-t) 
iv. 
Area under Plasma concentration vs. time curve extrapolated to the infinity (AUC0-∞) 
after first dose 
v. 
Area under plasma concentration vs. time curve in a 24 h dosing interval (AUCtau) 
vi. 
Elimination rate constant (λz) 
vii. 
Elimination half-life (t1/2) 
viii. 
Apparent Volume of distribution (Vd/F) 
ix. 
Apparent Clearance (CL/F) 
x. 
Minimal or Trough plasma concentration (Cmin) -for last dose only  
xi. 
Accumulation index calculated as a ratio of AUCtau(last dose)/AUCtau(first dose) 
xii. 
Fluctuation index.  


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6.4 
Biobanking Samples for Exploratory Analyses 
At each visit, approximately 3.5 mL of whole blood (1 mL of serum) will be collected for 
biobanking. It means a total of 24.5 mL of whole blood will be collected at Visits 1 through 7 for 
biobanking and exploratory analyses.   
6.5 
Total Amount of Blood 
The total amount of blood drawn for each patient over the study will be less than 500 mL. 


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7. 
STUDY CONDUCT 
7.1 
Schedule of Assessments 
The study consists of an optional Pre-screening, a 35-day Screening Period, a Treatment Period 
(Day 1 through Day 112) and a telephone follow-up.  Therefore, the maximal study duration for 
an individual patient will be up to 154 days or 22 weeks.   
Please Table 4 for the Schedule of Assessments.   
 
 


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Table 4 Schedule of Assessments 


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7.2 
Data Monitoring Committee 
Safety data will be reviewed regularly by a Data Monitoring Committee (DMC). The Data 
Monitoring Committee comprised of an unblinded independent statistician and hepatologist who 
will review period reports from the EDC. The formal structure and conduct of DMC will be 
according to a previously agreed upon remit.  
7.3 
Adjudication 
An external independent Central Adjudication Committee (CAC) will adjudicate serious adverse 
events (SAEs), including all deaths, that are known or suspected to be a Major Adverse Cardiac 
Events (MACE) or heart failure hospitalizations. The CAC members will be independent of the 
Sponsor, the Data Monitoring Committee (DMC), and the clinical study sites and Investigators. 
The blinded medical review of known or suspected MACE will primarily focus on CV death, 
myocardial infarction, cerebrovascular accident (stroke), and hospitalization for heart failure.   
A detailed CAC Charter and adjudication process will be described in a separate document. 
 
 


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8. 
STATISTICAL METHODS 
Before database lock, a statistical analysis plan (SAP) will be issued as a separate document, 
providing detailed methods for the analyses summarized below. Any deviations from the planned 
analyses will be described and justified in the final clinical study report. 
8.1 
Study Population 
8.1.1 
Disposition of Patients 
The number of patients who will be enrolled into the study, patients included in each analysis set, 
and subjects who completed/prematurely discontinued the study, as well as the reason for 
discontinuation, will be presented by treatment and overall using frequency counts and 
percentages. Percentages will be based on the number of patients randomized. In addition listings 
will be provided for study discontinuation, subject disposition and subject populations. 
8.1.2 
Patient Characteristics 
Patient characteristics will include a summary and listing of the following: 
 Demographics (including gender, age, race, ethnicity) 
 Baseline characteristics (including height, weight, BMI) 
 Medical history 
 Prior and concomitant medications. 
8.1.3 
Protocol Deviations 
Protocol deviations will be listed by patient.   
8.1.4 
Analysis Populations 
Randomized Set: The Randomized Set will consist of all subjects randomized into the study. 
Safety Analysis Set: The Safety Analysis Set will consist of all patients who are known to have 
received at least 1 dose of study treatment, with patients grouped according to the actual 
treatment received. 
Full Analysis Set (FAS): The FAS will consist of all patients who have been randomized, taken 
at least 1 dose of the study treatment and have provided efficacy data for at least 1 endpoint.  


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Patients who receive study drug different from that to which they are randomized will be 
included in the group to which they are randomized. 
Per Protocol (PP) analysis set: The PP Analysis Set will consist of all patients in the FAS who 
have additionally completed the double-blind treatment phase and have not deviated from or 
violated the protocol in such a way that could affect efficacy outcome. The PP Analysis Set will 
be defined before unblinding the study. 
Enrolled Set: The Enrolled Set will consist of all patients who are enrolled. 
8.2 
General Considerations 
All analyses will be performed using SAS® version 9.2 or later (SAS Institute, Cary, NC, USA). 
Data may be summarized by treatment group, and in addition, may be summarized by time 
(nominal). 
It is planned that at least 104 subjects will be enrolled at multiple clinical centers in USA. The 
data from different centers will be pooled. The data summaries and statistical analyses will not 
be performed by center. 
Continuous data will be summarized by treatment group using descriptive statistics (number of 
patients, mean, median, standard deviation, minimum and maximum). Categorical data will be 
summarized by patient counts and percentages. 
If not otherwise stated, Baseline will be the last available pre-dose value or, if missing, the 
Screening value. Measurement specific baseline values will be defined in the SAP. 
8.3 
Safety Analyses 
All safety parameters will be listed by treatment group and patient. 
All study drug administration information will be listed. 
Review of alcohol consumption will be listed.   
8.3.1 
Adverse Events 
Adverse events will be listed. The number and percent of patients experiencing an event will be 
tabulated for each system-organ class and preferred term. Adverse events will also be tabulated 
according to intensity and causality. The Adverse Events leading to discontinuation and SAEs 
will also be summarized by treatment group. 


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Adverse Events leading to discontinuation and SAEs will be listed separately.   
8.3.2 
Clinical Laboratory Tests 
Individual data listings of laboratory results will be presented for each patient. Clinically 
significant laboratory test abnormalities that were considered AEs by the Investigator will be 
presented in the AE listings.   
Observed results and changes from baseline in laboratory data will be tabulated by treatment 
group. Laboratory values will be categorized as normal, high or low in relation to the normal 
range values. Change from the Baseline value and each post-treatment assessment will be 
presented in shift tables for categorized laboratory results (normal, low and high). Values outside 
the reference range will be flagged in the listings. The normal range values will be reported.   
Additional laboratory tests (including pregnancy tests) will be listed. 
8.3.3 
Vital Signs 
Individual data listings of vital signs (observed and change from baseline) will be presented for 
each patient. Individual clinically significant vital sign findings that were considered AEs by the 
Investigator will be presented in the AE listings.    
Observed values as well as change from baseline data will be summarized descriptively by vital 
sign variables will be presented by treatment group in tabular format.  
8.3.4 
Electrocardiogram 
Twelve-lead ECG data (observed and change from baseline) will be listed for each patient and 
time-point. Observed values will be summarized descriptively in tabular format by treatment 
group.   
8.3.5 
Physical Examination 
Abnormal physical exam findings will be listed.   
8.4 
Efficacy Analyses 
All efficacy analyses will be based primarily on the FAS, and analyses based on the PP Analysis 
Set will be secondary to this, as required.  


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8.4.1 
Primary Efficacy Analyses 
The primary analysis for the primary efficacy endpoint will be based on the FAS. The primary 
efficacy endpoint in this study is percent change from baseline to Week 16 in serum ALT levels 
and will be analyzed using an analysis of covariance (ANCOVA) model with treatment as factor 
and baseline ALT levels as covariate. The comparison of interest is Saroglitazar Magnesium 
1 mg, 2 mg and 4 mg versus placebo at Week 16.   
The statistical null-hypothesis regarding the primary endpoint is as follows: 
H0:   -µSaroglitazar Magnesium ≤  -µplacebo 
and 
H1: -µSaroglitazar Magnesium > -µplacebo 
where µtreatment group is the mean percent change from baseline to Week 16 in serum ALT levels 
with Saroglitazar Magnesium (1 mg, 2 mg and 4 mg) and placebo. Note: Improvement in percent 
change from baseline to Week 16 in ALT levels is indicated by µtreatment group < 0. Hypotheses 
will be tested at a 1-sided nominal significance level-alpha of 0.05. 
Least squares (LS) means for each treatment group and associated standard errors will be 
derived. Differences in LS means will be calculated and associated 2-sided 90% confidence 
intervals will be provided. These will be derived from the calculation of Type III LS Means from 
ANCOVA and presented. One-tailed P value will also be presented to test the alternative 
hypothesis that Saroglitazar Magnesium is superior to placebo. 
Missing values will be imputed by carrying forward the last observation value after baseline. 
Secondary analyses (of the primary endpoint) will be analyzed using a similar analysis in the 
PP Analysis Set.  
Residual analysis will be used to check assumptions for the ANCOVA model. Should any of the 
assumptions of the analysis method not be adequately met, an alternative procedure will be used 
and fully documented. 
8.4.2 
Secondary Efficacy Analyses 
Due to this being a proof-of-concept (PoC) study, no adjustment of any P values will be made to 
account for inflation of the Type 1 error rate arising from testing multiple endpoints, or testing 


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the same endpoint at different times. For each endpoint, the comparison will be conducted using 
a significance level (alpha) set at 0.1 (2-sided) or equivalently 0.05 (1-sided). 
Each secondary efficacy endpoint will be summarized by treatment group at each time-point, as 
appropriate. 
The following endpoints will be analyzed similar to primary analysis: 
 Change in liver fat at Week 16 as measured by magnetic resonance imaging-derived proton 
density-fat fraction (MRI-PDFF) 
 Percentage change from baseline and absolute change from baseline in serum ALT levels at 
Week 4, week 8 and  Week 12 of treatment  
 Percentage change from baseline and absolute change from baseline in CK-18 fragment, ELF 
score and APRI at Week 8, and Week 16 after treatment   
 Absolute change from baseline in AST/ALT ratio at Week 4,Week 8, Week 12 and Week 16 
after treatment 
 Pharmacokinetics of Saroglitazar following first dose and last dose in approximately 
32 patients (approximately 8 from each dose arm) with NAFLD/NASH 
 Absolute Change from baseline in the SF-36 8 domain scores and 2 component scores 
(separate analyses) at Week 16 after treatment. 
Above analyses will also be supported by simple summaries (n, mean, standard deviation, 
median, minimum and maximum) at each visit, without covariate adjustment.   
Proportions of patients with percentage reductions of ≥25% and ≥50% from baseline in ALT 
levels at Week 4, Week 8, Week 12 and Week 16 will be analyzed using logistic regression 
including terms for baseline ALT levels and treatment. Endpoints based on proportion of patients 
will be summarized. For the categorical data, descriptive summary statistics will be, 
summarizing the number and percentage of patients in each category at each visit. 
Descriptive statistics will be provided for each Pharmacokinetic parameter (as detailed in Section 
6.3). 


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8.4.3 
Exploratory Efficacy Analyses 
The individual values of the exploratory endpoints will be listed and summary statistics will be 
calculated for each treatment group. The exploratory analyses will be based primarily on the 
FAS, and analyses based on the PP Analysis Set will be secondary to this, as required.   
8.5 
Interim Analyses 
No interim analysis is planned.     
8.6 
Determination of Sample Size 
The endpoint that determines the sample size for this trial is the percentage change from baseline 
to Week 16 in serum ALT levels.  
Descriptive statistics was calculated for the percentage change from baseline to Week 12 in 
serum ALT levels from a clinical study on Saroglitazar Magnesium in NASH patients (Protocol 
No.: ZYH1.09.004.01. PROT). The mean percentage change from baseline to Week 12 in ALT 
(U/L) with Saroglitazar Magnesium 4 mg was -49.36 and standard deviation was 24.03. 
Sample size is based on a 1-sided t-test (2 independent samples) at the 5% significance level for 
the percentage change from baseline between Saroglitazar Magnesium (1 mg, 2 mg 4 mg) and 
placebo at Week 16 (a 1 sided test ignores the small probability of a significant result in the 
“wrong” direction [i.e., superiority of placebo over Saroglitazar Magnesium]. Because this is a 
PoC study, this approach is acceptable).  
A sample size of 23 patients in each arm will provide 95% power to detect a difference in mean 
of 25% of ALT (U/L) levels between Saroglitazar Magnesium 4 mg and placebo assuming a 
common standard deviation of 25% approximately. Therefore, allowing for 10% attrition 
between randomization and inclusion in the full analysis set, 104 patients will be required in the 
study (26 randomly assigned to placebo and 26 randomly assigned to each Saroglitazar group i.e. 
1 mg, 2 mg and 4 mg).   


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9. 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
9.1 
Data Quality Assurance 
The Sponsor or Sponsor’s designee will conduct a site visit to verify the qualifications of each 
Investigator, inspect the site facilities, and inform the Investigator of responsibilities and the 
procedures for ensuring adequate and correct documentation. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. All information recorded on the CRF for this study must be consistent with the 
patients’ source documentation (i.e., medical records).   
9.1.1 
Database Management and Quality Control 
All data generated by the site personnel will be captured electronically at each study center using 
CRFs. Data from external sources (such as laboratory data) will be imported into the database.  
Once the CRF clinical data have been submitted to the central server at the independent data 
center, corrections to the data fields will be captured in an audit trail. The reason for change, the 
name of the person who performed the change, together with the time and date will be logged to 
provide an audit trail.  
If additional corrections are needed, the responsible monitor or data manger will raise a query in 
the electronic data capture (EDC) application. The appropriate staff at the study site will answer 
queries sent to the investigator. The name of the staff member responding to the query, and time 
and date stamp will be captured to provide an audit trail. Once all source data verification is 
complete and all queries are closed, the monitor will freeze the CRF page. 
The specific procedures to be used for data entry and query resolution using the CRF will be 
provided to study sites in a training manual. In addition, site personnel will receive training on 
the CRF. 
9.2 
Case Report Forms and Source Documentation 
All data obtained during this study should be entered in the CRFs promptly. All source 
documents from which CRF entries are derived should be placed in the patient’s medical 
records. Measurements for which source documents are usually available include laboratory 
assessments and ECG recordings. 


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Data that will be entered directly into the CRF (i.e., for which there is no prior written or 
electronic record of data, such as QoL assessments) are considered to be source data. 
The original CRF entries for each patient may be checked against source documents at the study 
site by the
 site monitor.  
The specific procedures to be used for data entry and query resolution using the CRF will be 
provided to study sites in a training manual. In addition, site personnel will receive training on 
the CRF. 
9.2.1 
Data Collection  
The Investigators (and appropriately authorized staff) will be given access to an online web-
based EDC) system which is 21 CFR Part 11 compliant. This system is specifically designed for 
the collection of the clinical data in electronic format. Access and right to the EDC system will 
be carefully controlled and configured according to each individual’s role throughout the study. 
In general, only the investigator and authorized staff will be able to enter data and make 
corrections in the CRFs. 
The CRF should be completed for each patient included in the study and should reflect the latest 
observations on the patients participating in the study. Therefore, the CRFs are to be completed 
as soon as possible during or immediately after the patient’s visit or assessment. The investigator 
must verify that all data entries in the CRF are accurate and correct. If some assessments cannot 
be done, or if certain information is unavailable, not applicable or unknown, the Investigator 
should indicate this in the CRF.  
Computerized data-check programs and manual checks will identify any clinical data 
discrepancies for resolution. Corresponding queries will be loaded into the system and the site 
will be informed about new issues to be resolved on-line. All discrepancies will be solved on-line 
directly by the Investigator or by authorized staff. Off-line edit checks will be done to examine 
relationships over time and across panels to facilitate quality data. 
After completion, the investigator will be required to electronically sign off the clinical data. 
Data about all study drug dispensed to the patient and any dosage changes will be tracked on the 
CRF. 


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9.3 
Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare CRF 
entries and individual patient’s medical records, assess drug accountability and ensure that the 
study is being conducted according to pertinent regulatory requirements. Case report form entries 
will be verified with source documentation. The review of medical records will be performed in 
a manner to ensure that patient confidentiality is maintained. 
Checking of the CRF entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study. Moreover, Regulatory 
Authorities of certain countries, IRBs, IECs and/or the Sponsor’s Clinical Quality Assurance 
Group may wish to carry out such source data checks and/or on-site audit inspections. Direct 
access to source data will be required for these inspections and audits; they will be carried out 
giving due consideration to data protection and medical confidentiality. The Investigator assures 
 and the Sponsor of the necessary support at all times. 
9.4 
Data Processing 
All data will be entered by site personnel into the CRF (as detailed in Section 9.2.1).  
The data-review and data-handling document, to be developed during the initiation phase of the 
study, will include specifications for consistency and plausibility checks on data and will also 
include data-handling rules for obvious data errors. Query/correction sheets for unresolved 
queries will be sent to the study monitors for resolution with the Investigator. The database will 
be updated on the basis of signed corrections.  
Previous and concomitant medications will be coded using the World Health Organization Drug 
Reference List, which employs the Anatomical Therapeutic Classification system. Medical 
history/current medical conditions and AEs will be coded using the Medical dictionary for 
regulatory activities (MedDRA) terminology. 
Previous and concomitant diseases as well as AEs will be coded using MedDRA. 
The version of the coding dictionaries will be provided in the Clinical Study Report. 
9.5 
Archiving Study Documents 
According to ICH guidelines, essential documents should be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 


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the formal discontinuation of clinical development of the investigational product. However, these 
documents should be retained for a longer period if required by the applicable legal 
requirements. 
9.6 
Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the Sponsor and 
Investigator abide by the principles of the Good Clinical Practice guidelines. The study also will 
be carried out in keeping with local legal requirements. 
9.7 
Informed Consent 
Before each patient is admitted to the study, informed consent will be obtained from the patient 
(or his/her legally authorized representative) according to the regulatory and legal requirements 
of the participating country. This consent form must be dated and retained by the Investigator as 
part of the study records. The Investigator will not undertake any investigation specifically 
required only for the clinical study until valid consent has been obtained. The terms of the 
consent and when it was obtained must also be documented in the CRF. 
If a protocol amendment is required, the informed consent form may need to be revised to reflect 
the changes to the protocol. If the consent form is revised, it must be reviewed and approved by 
the appropriate IRB, and signed by all patients subsequently enrolled in the study as well as 
those currently enrolled in the study. 
9.8 
Protocol Approval and Amendment(s) 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IRB, in accordance with local legal requirements. The Sponsor must ensure that all ethical 
and legal requirements have been met before the first patient is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB approval before 
implementation (if appropriate). Following approval, the protocol amendment(s) will be 
submitted to the Investigational New Drug under which the study is being conducted.  
Administrative changes (not affecting the patient benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 


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9.9 
Confidentiality Data Protection 
All study findings and documents will be regarded as confidential. The Investigator and 
members of his/her research team must not disclose such information without prior written 
approval from the Sponsor. 
The anonymity of participating patients must be maintained. Patients will be identified on CRF 
and other documents submitted to 
 by their patient number, initials and/or birth date, 
not by name. Documents not to be submitted to 
 that identify the patient (e.g., the 
signed informed consent) must be maintained in confidence by the Investigator. 
9.10 Other Ethical and Regulatory Issues  
If a significant safety issue is identified, either from an individual case report or review of 
aggregate data, then the Sponsor will issue prompt notification to all parties – Regulatory 
Authorities, Investigators and the IRB. 
A significant safety issue is one that has a significant impact on the course of the clinical study or 
program (including the potential for suspension of the development program or amendments to 
protocols) or warrants immediate update of informed consent. 
9.11 Publication Policy 
By signing the clinical study protocol, the Investigator agrees with the use of results of the 
clinical study for the purposes of national and international registration, publication and 
information for medical and pharmaceutical professionals. If necessary, the competent 
authorities will be notified of the Investigator’s name, address, qualifications and extent of 
involvement. 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having consulted 
with the Sponsor in advance. 


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10. 
REFERENCE LIST 
Angulo P, Bugianesi E, Bjornsson ES, Charatcharoenwitthaya P, Mills PR, Barrera F, 
Haflidadottir S, Day CP, George J. Simple noninvasive systems predict long-term outcomes of 
patients with nonalcoholic fatty liver disease. Gastroenterology 2013; 145(4):782-9. 
Bellentani S, Dalle Grave R, Suppini A, Marchesini G, Fatty Liver Italian Network. Behavior 
therapy for nonalcoholic fatty liver disease: The need for a multidisciplinary approach. 
Hepatology 2008; 47(2):746-54.  
Brunt EM, Tiniakos DG. Pathological features of NASH. Frontiers in bioscience: a journal and 
virtual library. 2005;10:1475-84.  
Bydder M, Yokoo T, Hamilton G, et al. Relaxation effects in the quantification of fat using 
gradient echo imaging. Magn Reson Imaging. 2008;26(3):347-59. 
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty 
liver disease: practice Guideline by the American Association for the Study of Liver Diseases, 
American College of Gastroenterology, and the American Gastroenterological Association. 
Hepatology. 2012; 55(6):2005-23. 
Hu FB. Globalization of Diabetes: The role of diet, lifestyle, and genes. Diabetes Care. Published 
online. 2011;34(6):1249–1257.  
Idilman IS, Aniktar H, Idilman R, et al. Hepatic steatosis: quantification by proton density fat 
fraction with MR imaging versus liver biopsy. Radiology. 2013;267(3):767-75. 
Kang GH, Cruite I, Shiehmorteza M, et al. Reproducibility of MRI-determined proton density fat 
fraction across two different MR scanner platforms. J Magn Reson Imaging. 2011;34(4):928-34. 
Liu CY, McKenzie CA, Yu H, Brittain JH, Reeder SB. Fat quantification with IDEAL gradient 
echo imaging: correction of bias from T(1) and noise. Magn Reson Med. 2007;58(2):354-64. 
Mashhood A, Railkar R, Yokoo T, et al. Reproducibility of hepatic fat fraction measurement by 
magnetic resonance imaging. J Magn Reson Imaging. 2013;37(6):1359-70. 
Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic 
fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 
116(6):1413-9. 


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McCullough AJ. The clinical features, diagnosis and natural history of nonalcoholic fatty liver 
disease. Clin Liver Dis 2004; 8(3):521-33. 
Musso G1, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic 
fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease 
severity. Ann Med 2011; 43(8):617-49. 
Noureddin M, Lam J, Peterson MR, et al. Utility of magnetic resonance imaging versus histology 
for quantifying changes in liver fat in nonalcoholic fatty liver disease trials. Hepatology. 
2013;58(6):1930-40. 
Sanyal AJ, Brunt EM, Kleiner DE, Kowdley K, Chalasani N, Lavine J, Ratziu V, McCullough 
A. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 2011; 54(1): 
344–353. 
Tang A, Tan J, Sun M, et al. Nonalcoholic fatty liver disease: MR imaging of liver proton 
density fat fraction to assess hepatic steatosis. Radiology. 2013;267(2):422-31.  
Yokoo T, Bydder M, Hamilton G, et al. Nonalcoholic fatty liver disease: diagnostic and fat-
grading accuracy of low-flip-angle multiecho gradient-recalled-echo MR imaging at 1.5 T. 
Radiology. 2009;251(1):67-76. 
Yokoo T, Shiehmorteza M, Hamilton G, et al. Estimation of hepatic proton-density fat fraction 
by using MR imaging at 3.0 T. Radiology. 2011;258(3):749-59. 
Yu H, McKenzie CA, Shimakawa A, et al. Multiecho reconstruction for simultaneous water-fat 
decomposition and T2* estimation. J Magn Reson Imaging. 2007;26(4):1153-61. 
Wieckowska A1, Feldstein AE. Nonalcoholic fatty liver disease in the pediatric population: a 
review. Curr Opin Pediatr 2005; 17(5):636-41.   
 
 


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11. 
APPENDICES 
11.1 Appendix 1: Quality of Life Assessment Questionnaire 
For information about the quality of life assessment, SF-36, version 2, refer to the SF-36.org 
Community at http://www.sf-36.org/tools/sf36.shtml  


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11.2 Appendix 2: List of Known CYP2C8 Inhibitors/Substrates 
Selected inducers, inhibitors and substrates of CYP2C8 
Substrates 
Inhibitors 
Inducers 
 
amodiaquinea (antimalarial, 
anti-inflammatory) 
 
cerivastatina (statin) 
 
enzalutamide 
(antiandrogen) 
 
paclitaxela 
(chemotherapeutic) 
 
repaglinidea (antidiabetic) 
 
torasemidea (loop diuretic) 
 
sorafeniba (tyrosine kinase 
inhibitor) 
 
rosiglitazone (antidiabetic) 
- converted to active 
metabolitesb 
 
buprenorphine 
(semisynthetic opioid) 
 
polyunsaturated fatty acids 
 
montelukast (leukotriene 
receptor antagonist) 
Strong 
 
gemfibrozila 
(hypolipidemic) 
Moderate 
 
trimethoprima (antibiotic) 
Unspecified potency 
 
thiazolidinedionesa 
(antidiabetic) 
 
montelukasta (leukotriene 
receptor antagonist) 
 
quercetina 
(antiinflammatory) 
Unspecified potency 
 
rifampicina 
(antibiotic) 
a Flockhart DA (2007). "Drug Interactions: Cytochrome P450 Drug Interaction Table". Indiana University School of Medicine. 
Retrieved on July 2011 
b Chapter 26 in: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. 
Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
SARO.16.005.03.PROT 
A Phase 2, Prospective, Multicenter, Double-blind, Randomized Study of Saroglitazar 
Magnesium 1 mg, 2 mg or 4 mg Versus Placebo in Patients with Nonalcoholic Fatty Liver 
Disease and/or Nonalcoholic Steatohepatitis 
Version:  Final 1.0 
Date: 19/Oct/2018 
NCT03061721


Statistical Analysis Plan 
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Statistical Analysis Plan 
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SIGNATURE PAGE – ZYDUS DISCOVERY DMCC 
Declaration 
The undersigned has/have reviewed and agree to the statistical analyses and procedures of this 
clinical study, as presented in this document. 
 
 
 
Dr. Deven Parmar MD 
 
Date (DD/MM/YY) 
Head  - Clinical R & D   
 
 
 
 
 
 
 
 
 
26/10/18




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TABLE OF CONTENTS 
REVISION HISTORY .................................................................................................................... 2 
SIGNATURE PAGE – ZYDUS DISCOVERY DMCC ................................................................. 3 
TABLE OF CONTENTS ................................................................................................................ 5 
LIST OF TABLES .......................................................................................................................... 7 
ABBREVIATION AND ACRONYM LIST .................................................................................. 8 
STATISTICAL ANALYSIS PLAN ............................................................................................. 10 
1. 
STUDY OBJECTIVES .................................................................................................... 10 
1.1 
Primary Objective ............................................................................................... 10 
1.2 
Secondary Objective ........................................................................................... 10 
1.3 
Exploratory Objective ......................................................................................... 11 
2. 
STUDY DESIGN ............................................................................................................. 11 
3. 
STUDY POPULATION .................................................................................................. 17 
4. 
STATISTICAL BASIS FOR SAMPLE SIZE ................................................................. 17 
5. 
RANDOMIZATION ........................................................................................................ 18 
5.1 
Screening Numbers ............................................................................................. 18 
5.2 
Randomization Scheme, Randomization Numbers and Allocation of Patients 
to Treatment ........................................................................................................ 18 
5.3 
Patient Replacements .......................................................................................... 18 
6. 
STATISTICAL ANALYSIS CONVENTIONS .............................................................. 18 
6.1 
Analysis Variables .............................................................................................. 18 
6.1.1 
Medial History, Demographic and other Baseline Variables .......................... 18 
6.1.2 
Safety Variables .............................................................................................. 19 
6.1.2.1 
Adverse Events ................................................................................ 19 
6.1.2.2 
Clinical Laboratory Tests ................................................................ 22 
6.1.2.3 
Vital Signs ....................................................................................... 23 
6.1.2.4 
Electrocardiograms .......................................................................... 23 
6.1.2.5 
Physical Examination ...................................................................... 24 
6.1.2.6 
Prior and Concomitant Medication .................................................. 24 
6.1.3 
Pharmacokinetic Variables .............................................................................. 25 
6.1.4 
Pharmacodynamic Variables ........................................................................... 25 
6.1.5 
Efficacy Variables ........................................................................................... 25 
6.1.5.1 
Blood Samples ................................................................................. 25 
6.1.5.2 
Quality of Life ................................................................................. 25 
6.1.5.3 
Transient Elastography/FibroScan ................................................... 26 
6.1.5.4 
Magnetic 
Resonance 
Imaging-Derived 
Proton 
Density-Fat 
Fraction (MRI PDFF) ...................................................................... 26 


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6.2 
Analysis Populations ........................................................................................... 26 
6.2.1 
Randomized Set .............................................................................................. 26 
6.2.2 
Safety Analysis Set ......................................................................................... 26 
6.2.3 
Full Analysis Set (FAS) .................................................................................. 26 
6.2.4 
Per Protocol (PP) Analysis Set ........................................................................ 27 
6.2.5 
Enrolled Set ..................................................................................................... 27 
6.2.6 
Pharmacokinetic Population ............................................................................ 27 
6.2.7 
Treatment misallocations ................................................................................ 27 
6.3 
Statistical Analysis Methods ............................................................................... 27 
6.3.1 
Listings and Descriptive Statistics .................................................................. 27 
6.3.2 
Statistical Significance Level .......................................................................... 28 
6.3.3 
Software .......................................................................................................... 28 
6.3.4 
Missing Data ................................................................................................... 28 
6.3.5 
Interim Analysis .............................................................................................. 29 
6.3.6 
Patient Disposition .......................................................................................... 29 
6.3.7 
Protocol Deviations ......................................................................................... 29 
6.3.8 
Demographic Data and other baseline characteristics ..................................... 29 
6.3.9 
Prior and Concomitant Medication ................................................................. 30 
6.3.10 
Exposure to the study drug and compliance.................................................... 30 
6.3.11 
Pharmacokinetic Concentrations and Variables .............................................. 31 
6.3.12 
Safety Analysis ............................................................................................... 31 
6.3.12.1 Adverse Events ................................................................................ 31 
6.3.12.2 Clinical Safety Laboratory Tests (hematology, biochemistry and 
urinalysis) ........................................................................................ 31 
6.3.12.3 Vital Signs ....................................................................................... 32 
6.3.12.4 Twelve-Lead Electrocardiogram ..................................................... 32 
6.3.12.5 Physical Examination ...................................................................... 32 
6.3.13 
Efficacy Analysis ............................................................................................ 33 
Magnetic Resonance Imaging-Derived Proton Density-Fat Fraction (MRI 
PDFF) .............................................................................................. 34 
6.3.13.1 Primary Efficacy Analyses .............................................................. 34 
6.3.13.2 Secondary Efficacy Analyses .......................................................... 36 
6.3.13.3 Exploratory Efficacy Analyses ........................................................ 37 
7. 
REFERENCES ................................................................................................................. 38 
8. 
TABLES AND LISTINGS TO BE INCLUDED IN SECTION 14 OF THE 
CLINICAL STUDY REPORT ........................................................................................ 39 
9. 
FIGURES ......................................................................................................................... 44 
10. 
LISTINGS TO BE INCLUDED IN SECTION 16 OF THE CLINICAL STUDY 
REPORT .......................................................................................................................... 45 
11. 
DOCUMENTATION OF STATISTICAL METHODS .................................................. 48 
 
 


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LIST OF TABLES 
TABLE 1 SCHEDULE OF ASSESSMENTS 
 
 






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STATISTICAL ANALYSIS PLAN 
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing 
study data and outlines the statistical programming specifications for the Tables, Listings and 
Figures (TLFs). It describes the variables, populations, anticipated data transformations and other 
details of the analyses not provided in the Clinical Study Protocol (CSP). 
The analyses described are based on the final 3.0 CSP, dated, 26/Mar/2018.The SAP will be 
finalized prior to database lock and describes the statistical analysis as it is foreseen when the study 
is being planned. If circumstances should arise during the study rendering this analysis 
inappropriate, or if improved methods of analysis should arise, updates to the analyses may be 
made. Any deviations from the SAP after database lock, reasons for such deviations and all 
alternative or additional statistical analyses that may be performed, will be described in a SAP 
Addendum. 
1. 
STUDY OBJECTIVES 
1.1 
Primary Objective 
 To investigate the effect of a 16-week treatment regimen of Saroglitazar Magnesium 1 mg, 
2 mg or 4 mg on serum alanine aminotransferase (ALT) levels in patients with nonalcoholic 
fatty liver disease (NAFLD) and/or nonalcoholic steatohepatitis (NASH). 
1.2 
Secondary Objective 
 To assess the effect of a 16-week treatment regimen of Saroglitazar Magnesium 1 mg, 2 mg 
or 4 mg on the following parameters in patients with NAFLD and/or NASH:  
o Change in liver fat content at Week 16 as measured by magnetic resonance 
imaging-derived proton density-fat fraction (MRI-PDFF). 
o Proportion of patients who sustain a decrease in serum ALT levels observed at 
Week 4, Week 8, Week 12 and Week 16 of therapy. 
o Changes in serum-based predictors of liver injury and fibrosis [cytokeratin-18 (CK-
18), Enhanced liver fibrosis (ELF) and aspartate aminotransferase-to-platelet ratio 
index (APRI)], at Week 8 and Week 16 of therapy. 


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o Pharmacokinetics of Saroglitazar Magnesium following first dose and last dose. 
o Quality of life (QoL) 
o Safety and tolerability of repeat dosing of 1 mg, 2 mg or 4 mg Saroglitazar 
Magnesium. 
1.3 
Exploratory Objective 
 To explore the effect of a 16-week treatment regimen of Saroglitazar Magnesium 1 mg, 2 
mg or 4 mg on the following parameters in patients with NAFLD: 
o Liver stiffness as measured by transient elastography/FibroScan®. 
o Continuous 
attenuation 
parameter 
(CAP) 
as 
measured 
by 
transient 
elastography/FibroScan. 
o Fasting lipid and lipoprotein profiles (lipoprofiles) at Week 4, Week 8, Week 12 and 
Week 16 of treatment. 
o Insulin resistance and glycemic control at Week 8 and Week 16 of treatment. 
2. 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled study in up to 104 patients with a diagnosis 
of NAFLD and/or NASH. The study will be conducted over a period of up to 22 weeks and will 
include an optional Pre-screening, a Screening Phase (Days -35 to -7), a 16-week Treatment Phase 
following randomization on Day 1 to either Saroglitazar Magnesium (1 mg, 2 mg or 4 mg) or 
placebo orally once daily in the morning before breakfast.  
Pre-screening 
The study sites may identify potential subjects by conducting a laboratory evaluation of the ALT 
levels. This optional pre-screening can be conducted before the actual study screening. A subject 
with an ALT ≥50 U/L may be considered for the actual study screening.  
Also, along with the evaluation of the ALT levels, in those potential subjects who do not have a 
documented diagnosis of NAFLD through any imaging method, an optional abdominal ultrasound 
may be performed during the pre-screening. 


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The evaluation of the ALT levels during the pre-screening will be done at the local laboratory, 
whereas the laboratory evaluations during the Screening and the Treatment Phase will be done at 
the central laboratory. 
An informed consent has to be obtained from the potential subjects before any pre-screening 
evaluations. 
Screening Phase: 
Visit 1 (Day -35): Patient eligibility for participation in the study will be assessed. Medical history 
will be obtained; physical examination, electrocardiogram (ECG) and laboratory evaluations 
(including serology, clinical chemistry, hematology, liver enzymes and urinalysis) will be 
performed. Female patients will undergo a serum pregnancy test. Serum ALT must be ≥50 U/L to 
proceed further in the study. In addition, Investigator will instruct the patient to maintain their 
current diet and physical activity at each visit.  
Visit 2 (Day -14 to -7): Liver enzymes (AST, ALT, ALP and total bilirubin (TB) will be re-
measured approximately 3 weeks from Day -35 to determine eligibility. Elevated ALT ≥50 U/L on 
2 occasions in the Screening is necessary for study entry. The variance in the levels of the repeat 
measures of serum ALT and total bilirubin (TB) at Day -14 (Visit 2) must be ≤30%, compared to 
the Day -35 (Visit 1) levels to be eligible for study entry.  
The liver function test values at Day -14 to -7 (Visit 2) will be considered as baseline for the 
efficacy assessment.  
Treatments:  
 Treatment A= Saroglitazar Magnesium 1 mg  
 Treatment B = Saroglitazar Magnesium 2 mg 
 Treatment C = Saroglitazar Magnesium 4 mg 
 Placebo = Placebo 
Randomization & Treatment Phase: 
 
The Randomization & Treatment Phase will include 5 additional outpatient visits over a period of 
16 weeks including the randomization visit. Efficacy assessments will be conducted on these 5 
visits by measuring liver enzymes (AST, ALT, ALP and TB), CK-18 fragments, ELF, fasting 
glucose, serum insulin levels, lipoprofile, homeostasis model assessment (insulin resistance 


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[HOMA-IR]) and homeostasis model assessment (β cell function [HOMA-β], liver stiffness and 
CAP by transient elastography/FibroScan, liver fat content with MRI-PDFF and QoL. In addition, 
safety assessments will be conducted and there will be no clinically significant changes in dietary, 
physical activity or alcohol consumption. 
 
Visit 3 (Day 1): Patients will be randomly assigned to receive Saroglitazar Magnesium (1 mg, 2 
mg or 4 mg) or placebo orally once daily, starting on Day 1 of a 16-week outpatient treatment 
period. Patients will commence with a once daily oral dosing regimen. 
 
Visits 4, 5 and 6: Patients will visit the study site at Week 4 (Visit 4), Week 8 (Visit 5) and Week 
12 (Visit 6) for clinical assessment, dispensation and reconciliation of study drug, measurements of 
efficacy endpoints and assessment of adverse events (AEs). 
 
End-of-Treatment Visit (Visit 7): An End-of-treatment Visit will occur at Week 16 for clinical 
assessment, reconciliation of study drug and measurements of efficacy and AEs. 
 
Telephone follow-up will occur 7 days (± 3 days) after the End-of-treatment Visit for safety 
monitoring. 
 


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Table 1 Schedule of Assessments 


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3. 
STUDY POPULATION 
The study population will consist of 104 patients (with NAFLD and/or NASH who have elevated 
ALT (defined as ≥50 U/L at the Screening Visits)). Patients will be eligible for the study if they 
meet all of the inclusion criteria and none of the exclusion criteria. Detailed lists of inclusion and 
exclusion criteria are shown in Sections 4.2 and 4.3 of the CSP. 
4. 
STATISTICAL BASIS FOR SAMPLE SIZE 
The endpoint that determines the sample size for this trial is the percentage change from baseline to 
Week 16 in serum ALT levels. 
Descriptive statistics was calculated for the percentage change from baseline to Week 12 in serum 
ALT levels from a clinical study on Saroglitazar Magnesium in NASH patients 
 
 
 
 
Sample size is based on a 1-sided t-test (2 independent samples) at the 5% significance level for the 
percentage change from baseline between Saroglitazar Magnesium (1 mg, 2 mg and 4 mg) and 
placebo at Week 12 (a 1 sided test ignores the small probability of a significant result in the 
“wrong” direction [i.e., superiority of placebo over Saroglitazar Magnesium]. Because this is a 
proof-of-concept (PoC) study, this approach is acceptable). 
A sample size of 23 patients in each arm will provide 95% power to detect a difference in mean of 
25% of ALT (U/L) levels between Saroglitazar Magnesium 4 mg and placebo assuming a common 
standard deviation of 25% approximately. Therefore, allowing for 10% attrition between 
randomization and inclusion in the full analysis set (FAS), 104 patients will be required in the 
study (26 randomized to placebo and 26 patients randomized to each Saroglitazar Magnesium arm, 
i.e. 1 mg, 2 mg or 4 mg). 


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5. 
RANDOMIZATION 
5.1 
Screening Numbers 
Patients are assigned a unique site-specific (e.g., site number 101, 102, etc.) and patient number (a 
3-digit site identification and 3-digit number, e.g., 101-001, 101-002, etc.) that were used to 
identify the patient on all data collection forms from Visit 1 until the end of the Treatment Phase. 
5.2 
Randomization Scheme, Randomization Numbers and Allocation of Patients to 
Treatment 
Block randomization of patients to treatment (Placebo, Saroglitazar Magnesium 1 mg, 2 mg or 4 
mg) will occur in 1:1:1:1 ratio. The block randomization was generated following biostatistics 
procedure for generation of randomization lists. Each block contained investigational medicinal 
products; Saroglitazar Magnesium 1 mg, 2 mg, 4 mg and placebo. Each block (outer carton) 
contain 4 boxes (inner cartons) of study drug (enough for 4 patients). 
On Day 1 of the Treatment (Visit 3), the first eligible patient will be assigned the lowest available 
randomization ID. The second eligible patient will receive the next lowest available randomization 
ID
 
5.3 
Patient Replacements 
If patients fail to complete for reasons unrelated to the safety of the study drug, then replacement 
patients may be enrolled to ensure that each study arm is adequately filled and approximately 104 
patients (approximately 26 per treatment arm) complete the study. 
6. 
STATISTICAL ANALYSIS CONVENTIONS 
6.1 
Analysis Variables 
6.1.1 
Medial History, Demographic and other Baseline Variables 
The medical history comprises:  
Medical history (including start and stop date or whether the condition is ongoing) 
 Medical history 
 Medication history 


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 Reproductive history 
The following demographic and baseline information will be recorded: 
 Date of informed consent 
 Age (yrs) 
 Gender 
 Ethnic origin (Hispanic/Latino, Not Hispanic/not Latino, Not Reported, Unknown). 
 Race (White, American Indian/Alaska Native, Asian, Native Hawaiian or other Pacific 
Islander, Black/African American, Other) 
 Height (cm) (without shoes) 
 Weight (kg) (without shoes) 
 BMI  
Other baseline characteristics will be recorded as follows: 
 History of drug abuse 
 History of alcohol abuse 
 Smoking history 
 History of caffeine use (or other stimulating beverages) 
 Diet 
 History of blood or plasma donation. 
All medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 19.1  or later. 
6.1.2 
Safety Variables 
6.1.2.1 
Adverse Events 
An AE is any unfavorable or unintended sign, symptom or disease temporally associated with the 
use of study drug whether or not considered related to study drug.  


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Adverse event reporting will begin after the informed consent has been signed and will continue 
until end of the study (i.e., the safety telephone call). The Common Terminology Criteria for 
Adverse Event (CTCAE) (Version 4.03 or higher) system will be used for reporting and grading 
AEs.  
Treatment Emergent Adverse Event 
Treatment-emergent AEs are defined as any AE that started after the first dose of study drug or 
started before the first dose but increased in severity or frequency after administration of the initial 
dose of study drug. 
Severity and Relationship to Study Medication 
All AEs must be recorded on the appropriate AE CRF for the patient. All AEs must be reported 
whether or not considered causally related to study drug. For every AE, the PI will provide an 
assessment of the severity and causal relationship to study drug, will document all actions taken 
with regard to study drug, and will document any other treatment measures for the AE. 
Serious adverse events (SAEs) 
All SAEs will be recorded from signing of informed consent until the end of the study (i.e., the 
safety telephone call). Serious AEs occurring after the end of the study and coming to the attention 
of the PI must be reported only if they are considered (in the opinion of the PI) causally-related to 
the investigational drug. 
TEAE leading to discontinuation 
If the patient discontinued due to an AE, as indicated by the investigator from the Study 
Conclusion page of the eCRF where primary reason for withdrawal is “Adverse Event” then the 
TEAE is considered as TEAE led to discontinuation of study. All adverse events will be coded 
according to the Medical Dictionary for Regulatory Activities (MedDRA, last version available 
before database lock).  
If the relationship is unknown the relationship will be imputed with “Related”. Any AE recorded 
with an unknown seriousness will be regarded as a SAE for the tabulations. 
There will be no imputation of missing or partial AE date and it will be shown as NK for the 
listings. 


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AEs with missing start dates/times will be handled as follows for the treatment-emergent based 
tabulations: 
 Missing start date: 
 If the start date is completely missing but the end date is known and shows that the AE 
ended on or after the dosing date in a specific treatment group, then the start date will be 
imputed as the day of dosing in that treatment group  
 If the end date is known and shows that the AE ended before the first dosing date then the 
screening date will be used for the start date  
 Missing start day: 
 If only the start day is missing the day will be imputed as the first day on which a dose was 
given in that month unless the end date is known and shows that the AE ended before a 
dose was given in that month; in which case the date will be imputed as 01  
 If the end date is non-informative (i.e., is missing or does not contain enough information), 
the start date will be imputed as the first date of dosing in the known month. If the month is 
not a dosing month the date will be imputed as 01 
 Missing start day and month: 
 If the start day and month are missing the date will be imputed as the first day of dosing in 
the known year unless the end date is known and shows that the AE ended before a dose 
was given in that year; in which case the start day and month will be imputed as 01Jan or 
with the date of screening if this is later. If the end date is non-informative (i.e., is missing 
or does not contain enough information), the start date will be imputed as the first date of 
dosing in the known year. If the year is not a year of dosing then the date will be imputed as 
01Jan or with the date of screening if this is later 
 Missing times 
 Missing times will be imputed as 00:00 h or with the time of dosing for events starting on a 
dosing day. 
 
Adverse events with completely unknown start dates will be considered as treatment-emergent for 
the tabulations. Adverse events with missing start/ stop date will be considered as treatment-


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emergent unless the partial date excludes that possibility, e.g. the AE month is prior to the month in 
which treatment started. Otherwise, the first day of the month will be used to impute missing start 
days and January will be used to impute missing start months.  
Start and stop dates for prior/ concomitant medication will also be treated similarly for tabulations 
as mentioned above for treatment-emergent AEs. 
6.1.2.2 
Clinical Laboratory Tests 
Laboratory tests will be performed at the following time points (unless otherwise stated below): 
 Pre-screening 
 Screening (Visit 1 and Visit 2) 
 Week 0 (Visit 3), Week 4 (Visit 4), Week 8 (Visit 5), Week 12 (Visit 6)  
 End of Treatment (Week 16/Visit 7) 
The following safety laboratory parameters will be measured: 
Hematology: 
Erythrocytes, Mean Corpuscular Volume (MCV),  
Mean 
Corpuscular 
Hemoglobin 
(MCH), 
Neutrophils, 
Eosinophils, 
Basophils, Lymphocytes, Monocytes, Platelets, Leukocytes, Hemoglobin, 
Hematocrit, Prothrombin Time (PT), International Normalized Ratio (INR). 
Clinical 
chemistry: 
Albumin, 
Blood 
Urea 
Nitrogen 
(BUN), 
Creatinine, 
Creatinine 
Phosphokinase (CPK), high-sensitive C-Reactive Protein (hs-CRP), 
Triglycerides, Urea, Uric Acid, Cholesterol 
Electrolytes: Sodium, Potassium 
Liver Enzymes: Alanine Aminotransferase (ALT), Aminotransferase 
(AST), Alkaline Phosphatase (ALP), Bilirubin, γ-Glutamyl Transferase 
(GGT), Serum proteins 
Urinalysis: 
Appearance, color, Bilirubin, pH, Protein, Glucose, Ketones, leukocytes, 
Blood, Nitrite, Specific Gravity, Urobilinogen  
Serology: 
Human Immunodeficiency Virus (HIV) type 1 and type 2,  
Anti-Hepatitis A virus (HAV IgM), Hepatitis B Virus Surface Antigen 
(HBsAg), Hepatitis C Virus Antibody (HCV) 
Pregnancy test: For women of childbearing potential only at the first Screening Visit: 
Serum Pregnancy test at screening (Visit 1/Day -35) and urine Pregnancy 
test at week 0 (Visit 3), week 4 (Visit 4), week 8 (Visit 5), week 12 (Visit 6) 
and week 16 (Visit 7) (end of treatment). 


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Drugs-of-abuse 
Screening 
(Urine) 
Screening Phase [Day -35]: Amphetamines, Benzodiazepines, Marijuana, 
Cocaine, Opioids 
 
6.1.2.3 
Vital Signs 
Measurement of vital signs will be performed at the following time points (unless otherwise stated 
below): 
 Screening (Visit 1/Day -35) 
 Week 0 (Visit 3), Week 4 (Visit 4), Week 8 (Visit 5), Week 12 (Visit 6) 
 End of Treatment (Week 16/Visit 7) 
The following vital signs measurements will be obtained: 
 Sitting blood pressure (Systolic (SBP) and diastolic (DBP); mmHg) (measured in triplicate, 
approximately 2 minutes apart at the Screening Visit and a single measurement at all other 
visits) 
 Pulse (beats per minute) (measured in triplicate, approximately 2 minutes apart at the 
Screening Visit and a single measurement at all other visits) 
 Oral body temperature [°F or °C] (single measurement at all visits) 
 Respiratory rate (breaths per minute) (single measurement at all visits) 
Vitals signs will be measured before any blood draw that occurs at the same visit and after the 
patient has been resting for at least 5 minutes. 
6.1.2.4 
Electrocardiograms  
Measurement of 12-lead ECGs will be performed at the following time points: 
 Screening (Visit 1/Day -35) 
 Week 0 (Visit 3), Week 4 (Visit 4), Week 8 (Visit 5), Week 12 (Visit 6) 
 End of Treatment (Week 16/Visit 7) 
 


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The following ECG parameters will be recorded: 
 PR interval (msec) 
 QRS interval (msec) 
 QT interval (msec) 
 corrected QT interval (QTc) 
 Heart rate (bpm) 
Electrocardiogram recordings will be taken in triplicate at the Screening Visit and as a single 
recording at all other visits. 
The ECG will be evaluated by the Investigator as ‘Normal’, ‘Abnormal, NCS’ or ‘Abnormal, CS’. 
6.1.2.5 
Physical Examination 
Physical examination will be performed at the following time points: 
 Screening (Visit 1/Day -35) 
 Week 0 (Visit 3), Week 4 (Visit 4), Week 8 (Visit 5), Week 12 (Visit 6) 
 End of Treatment (Week 16/Visit 7) 
The physical examination will include the following: General appearance, Eyes, Ears/Nose/Throat, 
cardiovascular, respiratory, abdominal, genitourinary, skin/mucosa, musculoskeletal, neurological, 
and lymphatic system. 
Patients’ body weight will be recorded during all physical examinations. Height will be recorded at 
the Screening Visit only. 
The Investigator will mark the physical findings as normal, abnormal or not done and the 
Investigator will assess abnormal results as ‘Normal’, ‘Abnormal, NCS’ or ‘Abnormal, CS’ in the 
CRF, including details of any abnormality. 
6.1.2.6 
Prior and Concomitant Medication 
Prior medications and concomitant treatments (if any) will be coded according to the World Health 
Organization Drug Dictionary (WHO Drug Dictionary, latest version before database lock). These 


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will be classified by Anatomical Therapeutic Chemical (ATC) categories and listed separately for 
each patient. 
6.1.3 
Pharmacokinetic Variables 
Not applicable in this plan.  
6.1.4 
Pharmacodynamic Variables 
Not applicable. 
6.1.5 
Efficacy Variables 
6.1.5.1 
Blood Samples 
Samples for primary, secondary and exploratory efficacy variables will be collected as follows: 
Serum alanine aminotransferase (ALT) levels. 
Insulin resistance and glycemic control: includes fasting (at least 8 hours) insulin, fasting plasma 
glucose, HbA1c, C-peptide, HOMA-IR and HOMA-ß. The results of the fasting plasma glucose, 
HbA1c, HOMA-IR and HOMA-ß will be blinded to site. Results of Insulin and C-Peptide will not 
be blinded. 
Lipoprofile: includes fasting (at least 8 hours) LDL, VLDL, HDL, total cholesterol, non-HDL 
cholesterol, apo A1 and apo B. The results of the lipoprofile (except total cholesterol) will be 
blinded to site. Serum triglyceride results will not be blinded.  
 
CK-18 and APRI: includes CK-18, AST and platelet count 
ELF score: serum samples. Enhanced liver fibroses score is an extracellular matrix marker set 
consisting of tissue inhibitor of metalloproteinases 1 (TIMP-1), amino-terminal propeptide of type 
III procollagen (PIIINP) and hyaluronic acid (HA) showing good correlations with fibrosis stages 
in chronic liver disease. 
6.1.5.2 
Quality of Life 
Subjective QoL assessments will be measured using the SF-36 version 2.0, which is a 36-item 
patient response questionnaire that measures QoL across 8 domains, both physically and 
emotionally based. The 8 domains are physical functioning, role limitations due to physical health, 


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role limitations due to emotional problems, energy/fatigue, emotional well-being, social 
functioning, pain and general health. 
The two component scores will include: 
Physical Component Summary: Summarizes the physical components of the SF-36V2: Physical 
Functioning, Role-Physical, Bodily Pain and General Health.  
Mental Component Summary: Summarizes the mental component of the SF-36V2: Vitality, Social 
Functioning, Role Emotional and Mental Health. 
6.1.5.3 
Transient Elastography/FibroScan 
Liver stiffness measurements will be performed by transient elastography using the FibroScan 
(Echosens, Paris, France). The appropriate FibroScan measurement probe should be used (i.e., M 
or XL) based on the manufacturer’s recommendation for probe choice according to chest 
circumference and age. FibroScan is optional and performed only with machines available at sites. 
6.1.5.4 
Magnetic Resonance Imaging-Derived Proton Density-Fat Fraction (MRI PDFF) 
The magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) is a novel 
imaging-based biomarker that allows fat mapping of the entire liver. Liver fat content will be 
measured using MRI-PDFF. PDFF technique is an MRI protocol that improves on the conventional 
Dixon in- and out-of-phase method. 
6.2 
Analysis Populations 
6.2.1 
Randomized Set 
The Randomized Set will consist of all patients randomized into the study. 
6.2.2 
Safety Analysis Set 
The Safety Analysis Set will consist of all patients who are known to have received at least 1 dose 
of study treatment, with patients grouped according to the actual treatment received. 
6.2.3 
Full Analysis Set (FAS) 
The FAS will consist of all patients who have been randomized, taken at least 1 dose of the study 
treatment and have provided efficacy data for at least 1 endpoint. Patients who receive study drug 


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different from that to which they are randomized will be included in the group to which they are 
randomized.   
The primary analysis population for this study is defined by the full analysis set of patients. 
6.2.4 
Per Protocol (PP) Analysis Set 
The PP Analysis Set will consist of all patients in the FAS who have additionally completed the 
double-blind treatment phase and have not deviated from or violated the protocol in such a way 
that could affect efficacy outcome. Patients will be grouped according to the actual treatment 
received. The PP Analysis Set will be defined before un-blinding the study.  
6.2.5 
Enrolled Set 
The Enrolled Set will consist of all patients who are enrolled. 
6.2.6 
Pharmacokinetic Population 
Pharmacokinetic population will include randomized patients with evaluable concentration profiles 
and do not have any major protocol deviations that could affect the PK profile of the treatment. 
6.2.7 
Treatment misallocations 
If a patient was, 
 Randomized but not treated: patient will appear on the patient evaluation table as 
randomized but not treated; this is the extent of how much the patient will be reported. 
 
randomized but took at least one dose of incorrect treatment, then the patient will be 
reported under the randomized treatment group for all efficacy and safety analyses as part 
of the FAS and Safety analyses, but omitted from PP analyses.  
6.3 
Statistical Analysis Methods 
6.3.1 
Listings and Descriptive Statistics 
All original and derived parameters as well as demographic and disposition data will be listed and 
described using summary statistics, unless stated otherwise. 


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Frequency counts (number of subjects [n] and percentages) will be presented for each qualitative 
variable. Descriptive statistics (n, mean, SD, median, minimum and maximum) will be calculated 
for each quantitative variable (unless otherwise stated). Descriptive statistics will only be presented 
if n ≥3. 
The following rules will apply to any repeated safety measurements: 
 If the repeated measurement occurs prior to IMP administration in each treatment group, 
then the last obtained value prior to dosing will be used in the descriptive statistics and in 
the calculation of changes from baseline; 
 If the repeated measurement occurs after IMP administration in each treatment group, then 
the first (non-missing) value of any repeated measurements will be used in descriptive 
statistics and in the calculation of changes from baseline. 
All descriptive statistics will be presented by treatment for measurements obtained during each 
treatment group. The baseline for all measurements (where applicable) will be the last pre-dose 
measurement within each treatment group while values at Day -14 to -7 (Visit 2) will be considered 
as baseline for the efficacy assessment of liver function tests. Descriptive statistics for all data 
obtained at Screening and follow-up will be presented separately. 
6.3.2 
Statistical Significance Level 
All statistical tests will be one-sided and will be performed at the 5% level of significance, unless 
otherwise stated. 
6.3.3 
Software 
All statistical analyses will be performed using Statistical Analysis Software (SAS®) Version 9.2 or 
later. The PK analysis will be performed using Phoenix® WinNonlin® professional software 
(Version 6.4 or higher). 
6.3.4 
Missing Data 
Last observation carried forward (LOCF) method will be used to impute missing values for the 
efficacy variables for the FAS population. Only post-baseline values will be carried forward. If no 
post-baseline value is present then no imputation will be done and baseline value will not be 
carried forward. 


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No imputation method will be employed for drug concentration or PK parameters. Data from any 
subject with missing concentration values (missed blood samples, lost samples, samples unable to 
be quantitated) may be used if pharmacokinetic parameters can be adequately estimated using the 
remaining data points, otherwise that subject will be excluded from specific pharmacokinetic 
parameter that cannot be estimated. 
6.3.5 
Interim Analysis 
Not applicable 
6.3.6 
Patient Disposition  
The number of patients who will be enrolled into the study, patients included in each analysis set, 
and subjects who completed/prematurely discontinued the study, as well as the reason for 
discontinuation, will be presented by treatment and overall using counts and percentages [Table 
14.1.1, Table 14.1.2].  
Patient disposition will be listed by treatment group and patient number. It will include whether 
study was completed as per protocol, date of discontinuation, reason for discontinuation and 
comment on discontinuation [Listing 16.2.1.1].  
Patient assignment to analysis populations will be listed by patient number [Listing 16.2.3.1]. 
6.3.7 
Protocol Deviations 
All protocol deviations as recorded in the protocol deviations log will be listed by patient number 
and will include a category of deviation, description of the deviation, the date/time of the deviation, 
study day of the deviation, time point, classification (Major/Minor) and led to exclusion of 
population if any [Listing 16.2.2.1] and will be summarized by treatment group [Table 14.2.2]. 
6.3.8 
Demographic Data and other baseline characteristics 
Demographic variables (gender, race, ethnicity, age, height, weight, BMI) will be listed by 
treatment group and patient number [Listing 16.2.4.1]. Demographic variables will be summarized 
by treatment group for each for Safety, FAS, PP and PK [Table 14.1.2.1 (Safety), Table 14.1.2.2 
(FAS), Table 14.1.2.3 (PP), Table 14.1.2.4 (PK)]. 


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Medical history will be listed by patient number and medical history term. It will include the 
following: condition/disease, start date and stop date (or ongoing if applicable) [Listing 16.2.4.2]. 
Reproductive history will be listed by patient number [Listing 16.2.4.4]. 
Informed consent history will be listed by patient number and will include the date of consent and 
whether consent was obtained [Listing 16.2.1.2]. 
Study visits will be listed by treatment and patient number [Listing 16.2.1.3]. 
Failed Inclusion and exclusion criteria will be listed by patient number which will include screen 
failures as well [Listing 16.2.1.4]. 
Randomization of patients will be listed by patient number and will include randomization number, 
planned treatment, actual treatment received and replacement patient number if any [Listing 
16.2.1.5].  
Other baseline characteristics data will be listed by treatment group and patient number as follows: 
 Alcohol, tobacco history and caffeine usage history [Listing 16.2.4.3] 
 Diet, Physical activity and alcohol [Listing 16.2.4.4] 
6.3.9 
Prior and Concomitant Medication 
Prior and concomitant medication will be listed by treatment group, patient number and will 
include the following information: medication name, start date/time of medication, stop date/time 
of medication, whether the medication is ongoing, dose per intake, unit, route, frequency, 
indication. If the date/time cannot be used to determine whether the medication is prior or 
concomitant, 
then 
the 
information 
would 
be 
missing 
for 
category 
of 
medication 
(Prior/Concomitant) in the concomitant medication listing [Listing 16.2.4.5] and will be 
summarized by treatment group [Table 14.3.4.1]. 
6.3.10 
Exposure to the study drug and compliance 
Exposure to study drug and compliance information will be recorded and will be listed by 
treatment group and patient number [Listing 16.2.5.1 and Listing 16.2.5.2] and will be summarized 
by treatment group [Table 14.3.4.2 and Table 14.3.4.3]. 


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6.3.11 
Pharmacokinetic Concentrations and Variables 
Not applicable in this plan.  
6.3.12 
Safety Analysis 
The analysis of the safety variables will be based on the safety population. All safety parameters 
will be listed by treatment group and patient number.  
6.3.12.1 
Adverse Events 
Adverse events will be listed by patient number [Listing 16.2.7.1]. The number and percent of 
patients experiencing an event will be tabulated for each system-organ class, preferred term by 
treatment group [Table 14.3.1.1].  
Adverse events will also be tabulated according to causality [Table 14.3.1.2] and severity by 
treatment group [Table 14.3.1.3].  
The Adverse Events leading to discontinuation and SAEs will also be summarized by treatment 
group [Table 14.3.1.4].  
Adverse Events leading to discontinuation [Listing 14.3.2.1] and SAEs will be listed [Listing 
14.3.2.2] by patient number. 
6.3.12.2 
Clinical Safety Laboratory Tests (hematology, biochemistry and urinalysis) 
Individual data listings of laboratory results for observed and change from baseline (biochemistry 
[Listing 16.2.8.1], hematology [Listing 16.2.8.2] and urinalysis [Listing 16.2.8.3]) will be listed by 
treatment group, patient number, laboratory parameter and study visit/time point.  
All values outside the clinical reference ranges will be flagged in the data listings. The abnormal 
values will be flagged with ‘L’ for values below the lower limit of the clinical reference range and 
‘H’ for values above the upper limit of the clinical reference range and included in the listings. The 
All the laboratory abnormal results will be assessed by the Investigator and will be reported as 
abnormal not clinically significant (NCS) or abnormal clinically significant (CS) by the 
Investigator. Clinically significant laboratory values will be recorded by the Investigator as AEs. 


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Descriptive statistics (biochemistry [Table 14.3.5.1] and hematology [Table 14.3.5.2]) will be 
presented for observed results and change from baseline by treatment group (n, mean, SD, median, 
minimum, maximum). 
Each post-treatment assessment will be presented in shift tables (biochemistry [Table 14.3.5.3] and 
hematology [Table 14.3.5.4]) for categorized laboratory results (normal, low and high). Shift table 
for qualitative variables (Urinalysis) will be presented in Table 14.3.5.5 for laboratory results 
(abnormal and normal). 
Additional individual data listings will be presented by patient number as following: 
 Childbearing potential and Pregnancy [Listing 16.2.8.4]. 
 Serology [Listing 16.2.8.5] 
6.3.12.3 
Vital Signs 
Individual data listings of vital signs (observed and change from baseline) will be presented by 
treatment group, parameter and patient number [Listing 16.2.9.1]. Individual clinically significant 
vital sign findings that were considered AEs by the Investigator will be presented in the AE 
listings. 
Descriptive statistics (n, mean, SD, median, minimum, maximum) for observed values as well as 
change from baseline data values will be presented by treatment group and parameter [Table 
14.3.6.1]. 
6.3.12.4 
Twelve-Lead Electrocardiogram 
Twelve-lead ECG data (observed and change from baseline) will be listed [Listing 16.2.9.2] by 
treatment group, parameter, patient number and visit/time point.  
Descriptive statistics (n, mean, SD, median, minimum, maximum) for observed values will be 
presented by treatment group and parameter [Table 14.3.6.2]. 
6.3.12.5 
Physical Examination 
The abnormal physical exam findings will be listed by treatment group, parameter, patient number 
and visit/time-point [Listing 16.2.9.3]. 


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6.3.13 
Efficacy Analysis 
All efficacy analyses will be based primarily on the FAS, and analyses based on the PP Analysis 
Set will be secondary to this. 
Individual data listings of efficacy variables (observed, absolute change from baseline, percentage 
change from baseline) will be presented by treatment group, efficacy parameter, patient number 
and visit/time point. Observed, absolute change, percentage change from baseline values will be 
summarized (n, mean, standard deviation, median, minimum and maximum) for each efficacy 
parameter by treatment group and at each visit/time point without covariate adjustment. 
Primary Efficacy Variable: serum ALT levels [Listing 16.2.6.1 and Table 14.2.1.1, Table 14.2.1.2] 
Secondary and exploratory efficacy variables: 
 Insulin resistance and glycemic control: includes fasting (at least 8 hours) insulin, fasting 
plasma glucose, HbA1c, C-peptide, HOMA-IR and HOMA-ß [Listing 16.2.6.9 and Table 
14.2.4.7, Table 14.2.4.8]. Graphical representation of mean absolute, mean change and 
mean percent change from baseline of insulin resistance (IR) by treatment will be presented 
[Figure 14.2.1.10, Figure 14.2.1.11, Figure 14.2.1.12]. Graphical representation of mean 
absolute, mean change and mean percent change from baseline of glycemic control by 
treatment will be presented [Figure 14.2.1.13, Figure 14.2.1.14, Figure 14.2.1.15]. 
 Lipoprofile: includes fasting (at least 8 hours) LDL, VLDL, HDL, total cholesterol, non-
HDL cholesterol, apo A and apo B [Listing 16.2.6.8 and Table 14.2.4.5, Table 14.2.4.6]. 
Graphical representation of mean absolute, mean change and mean percent change from 
baseline lipids and lipoprofiles by treatment will be presented [Figure 14.2.1.7, Figure 
14.2.1.8, Figure 14.2.1.9]. 
 CK-18 and APRI: includes CK-18, AST and platelet count [Listing 16.2.6.3, Listing 
16.2.6.5 and Table 14.2.3.3, Table 14.2.3.4, Table 14.2.3.7, Table 14.2.3.8].  
 ELF score: serum samples. Enhanced liver fibroses score is an extracellular matrix marker 
set consisting of tissue inhibitor of metalloproteinases 1 (TIMP-1), amino-terminal 
propeptide of type III procollagen (PIIINP) and hyaluronic acid (HA) showing good 
correlations with fibrosis stages in chronic liver disease [Listing 16.2.6.4 and Table 
14.2.3.5, Table 14.2.3.6]. 


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Quality of life:  
 Subjective QoL assessments will be measured using the SF-36 version 2.0, which is a 36-item 
patient response questionnaire that measures QoL across 8 domains, both physically and 
emotionally based. The 8 domains are physical functioning, role limitations due to physical health, 
role limitations due to emotional problems, energy/fatigue, emotional well-being, social 
functioning, pain and general health [Listing 16.2.6.10, Listing 16.2.6.11 and Table 14.2.5.1, Table 
14.2.5.2]. 
Transient Elastography/FibroScan 
Liver stiffness measurements will be performed by transient elastography using the FibroScan 
(Echosens, Paris, France). The appropriate FibroScan measurement probe should be used (i.e., M 
or XL) based on the manufacturer’s recommendation for probe choice according to chest 
circumference and age. FibroScan is optional and performed only sites with machines available at 
sites [Listing 16.2.6.7 and Table 14.2.4.3, Table 14.2.4.4]. 
Magnetic Resonance Imaging-Derived Proton Density-Fat Fraction (MRI PDFF) 
The magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) is a novel 
imaging-based biomarker that allows fat mapping of the entire liver. Liver fat content will be 
measured using MRI-PDFF. Proton-density-fat-fraction technique is an MRI protocol that 
improves on the conventional Dixon in- and out-of-phase method. Graphical representation of 
mean absolute, mean change and mean percent change from baseline of liver fat content by 
treatment will be presented [Listing 16.2.6.2 and Table 14.2.1.3, Table 14.2.1.4 and Figure 
14.2.1.4, Figure 14.2.1.5, Figure 14.2.1.6]. 
6.3.13.1 
Primary Efficacy Analyses 
The primary analysis for the primary efficacy endpoint will be based on the FAS.  
The primary efficacy endpoint in this study is percent change from baseline to Week 16 in serum 
ALT levels and will be analyzed using an analysis of covariance (ANCOVA) model with treatment 
as factor and baseline ALT levels as covariate. The comparison of interest is Saroglitazar 
Magnesium 1 mg, 2 mg and 4 mg versus placebo at Week 16. 
The statistical null hypothesis regarding the primary endpoint is as follows: 


 
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H0: -µSaroglitazar Magnesium ≤ -µplacebo 
and 
H1: -µSaroglitazar Magnesium > -µplacebo 
where µtreatment group is the mean percent change from baseline to Week 16 in serum ALT levels with 
Saroglitazar Magnesium (1 mg, 2 mg and 4 mg) or placebo.  
Note: Improvement in percent change from baseline to Week 16 in ALT levels is indicated by 
µtreatment group < 0. 
Hypotheses will be tested at a 1-sided nominal significance level-alpha of 0.05. 
Least squares (LS) means for each treatment group and associated standard errors will be derived. 
Differences in LS means and associated 2-sided 90% confidence intervals will be obtained using 
ANCOVA and tabulated [Table 14.2.1.1]. One-tailed p-value will be presented to test the 
alternative hypothesis that Saroglitazar Magnesium is superior to placebo. 
Graphical representation of mean absolute, mean change and mean percent change from baseline at 
Week 16 in for liver enzymes levels for different treatment groups will be presented [Figure 
14.2.1.1, Figure 14.2.1.2 and Figure 14.2.1.3] 
Missing values will be imputed by carrying forward the post-baseline last observation value . 
Due to this being a proof-of-concept (PoC) study, no adjustment of any p-values will be presented 
to account for inflation of the Type 1 error rate. 
Secondary analyses (of the primary endpoint) will be analyzed using a similar analysis in the PP 
Analysis Set [Table 14.2.1.2]. 
The following SAS code will be used for analyses of primary endpoint:  
Proc Mixed data= eff (where= (visit=’Week 16’)); 
Class treatment subject; 
model Percent =treatment baseline; 
Lsmeans treatment / alpha=0.10 cl pdiff; 
Estimate “Treatment A – Placebo” treatment 1 0 0 -1/ cl alpha=0.10; 
Estimate “Treatment B – Placebo” treatment 0 1 0 -1/ cl alpha=0.10; 
Estimate “Treatment C – Placebo” treatment 0 0 1 -1/ cl alpha=0.10; 
ods output estimates=estim lsmeans=ls_means; 
run; 
 


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Similar set of SAS statements will be used for estimating significance of change from baseline 
between the treatment arms. 
Residual analysis will be used to check assumptions for the ANCOVA model. Normality of 
residuals will be performed by using Shapiro-Wilk test. Should any of the assumptions of the 
analysis method not be adequately met, an alternative procedure will be used and fully 
documented. 
6.3.13.2 
Secondary Efficacy Analyses 
For each endpoint, the comparison will be conducted using a significance level (alpha) set at 0.10 
(2-sided) or equivalently 0.05 (1-sided). 
 Change in liver fat at Week 16 as measured by magnetic resonance imaging-derived proton 
density-fat fraction (MRI-PDFF) 
 Percentage change from baseline and absolute change from baseline in serum ALT levels at 
Week 4, week 8 and Week 12 of treatment 
 Percentage change from baseline and absolute change from baseline in CK-18 fragment, 
ELF score and APRI at Week 8, and Week 16 after treatment 
 Absolute change from baseline in AST/ALT ratio at Week 4, Week 8, Week 12 and Week 
16 after treatment 
 Pharmacokinetics of Saroglitazar following first dose and last dose in approximately 32 
patients (approximately 8 from each dose arm) with NAFLD/NASH 
 Absolute Change from baseline in the SF-36 8 domain scores and 2 component scores 
(separate analyses) at Week 16 after treatment.  
 Proportions of patients with percentage reductions of ≥ 25% and ≥ 50% from baseline in 
ALT levels at Week 4, Week 8, Week 12 and Week 16 will be analyzed using Chi-square 
test/ Fisher exact test by comparing treatment group to placebo group. The results will be 
tabulated with Chi-square coefficient, p-value and 90% confidence interval.  
 
The following SAS code will be used for secondary analyses except for proportions:  


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Proc Mixed data= eff;  
by visit; 
Class treatment subject; 
model Percent =treatment baseline; 
Lsmeans treatment / alpha=0.10 cl pdiff; 
Estimate “Treatment A – Placebo” treatment 1 0 0 -1/ cl alpha=0.10; 
Estimate “Treatment B – Placebo” treatment 0 1 0 -1/ cl alpha=0.10; 
Estimate “Treatment C – Placebo” treatment 0 0 1 -1/ cl alpha=0.10; 
ods output estimates=estim lsmeans=ls_means; 
run; 
Similar set of SAS statements will be used for estimating significance of change from baseline 
between the treatment arms. 
The following SAS code will be used for secondary analyses for proportions:  
Proc freq data=eff;  
by visit; 
Table param*trt/ nocum nopercent chisq; 
output out=ChiSqData n nmiss pchi; 
run; 
 
6.3.13.3 
Exploratory Efficacy Analyses 
The exploratory analyses will be done for the following end points using an analysis of 
covariance (ANCOVA) model with treatment as factor and baseline as covariate. The 
comparison of interest is Saroglitazar Magnesium 1 mg, 2 mg and 4 mg versus placebo. 
 
 Changes in liver stiffness/CAP as measured by transient elastography/FibroScan in the 
Saroglitazar Magnesium groups as compared to the placebo group. 
 
 Absolute changes in fasting lipid and lipo profiles at Week 4, Week 8, Weeks 12 and Week 
16 after treatment in the Saroglitazar Magnesium groups as compared to the placebo group. 
 
 Absolute changes in insulin resistance and glycemic control (adiponectin, fasting insulin, 
fasting blood glucose, C peptide, HOMA-IR and HOMA-ß, free fatty acids) at Week 8 and 
Week 16 after treatment in the Saroglitazar Magnesium groups as compared to the placebo 
group. Absolute change in HbA1c will be assessed at Week 16. 
 
The exploratory analyses will be based primarily on the FAS, and analyses based on the PP 
Analysis Set will be secondary to this. The same sas code as given in section 6.3.13.1 will be 


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considered for this exploratory analysis. The individual values of the exploratory endpoints will be 
listed by treatment group, patient number and summary statistics will be tabulated for each 
treatment group. 
7. 
REFERENCES 
1. SAS® Version 9.3 of the SAS System for Personal Computers. Copyright © 2002-2003. SAS 
Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered 
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA. 
2. WinNonlin Professional Software Version 6.3. https://www.certara.com/  
3. Guidance for Industry. E9 Statistical Principles for Clinical Trials. CDER. September 1998  
 
 


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8. 
TABLES AND LISTINGS TO BE INCLUDED IN SECTION 14 OF THE 
CLINICAL STUDY REPORT 
Baseline and Demographic Data 
Table 14.1.1 
Patient Disposition (Randomized set) 
Table 14.1.2 
Summary of screen failures (Enrolled set) 
Table 14.1.2.1 
Patient Demographics (Safety Population) 
Table 14.1.2.2 
Patient Demographics (FAS Population) 
Table 14.1.2.3 
Patient Demographics (PP Population) 
Table 14.1.2.4 
Patient Demographics (PK Population) 
Pharmacokinetic Data 
Not applicable in this analysis plan.  
Efficacy Data 
Table 14.2.1.1 
Statistical Analysis of ALT percentage change from baseline to week 16 
(FAS Population) 
Table 14.2.1.2 
Statistical Analysis of ALT percentage change from baseline to week 16 
(PP Population) 
Table 14.2.1.3 
Statistical Analysis of change in liver fat from baseline to week 16 (FAS 
Population) 
Table 14.2.1.4 
Statistical Analysis of change in liver fat from baseline to week 16 (PP 
Population) 
Table 14.2.1.5 
Statistical Analysis of ALT change from baseline to week 4, Week 8, 
Week 12 & Week 16 (FAS Population) 
Table 14.2.1.6 
Statistical Analysis of ALT change from baseline to week 4, Week 8, 
Week 12 & Week 16 (PP Population) 


 
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Table 14.2.1.7 
Statistical Analysis of proportion of patients who sustain a decrease in 
ALT from baseline to week 4, Week 8, Week 12 & Week 16 (FAS 
Population) 
Table 14.2.1.8 
Statistical Analysis of proportion of patients who sustain a decrease in 
ALT from baseline to week 4, Week 8, Week 12 & Week 16 (PP 
Population) 
Table 14.2.1.9 
Statistical Analysis of proportion of patients with ≥ 25% and ≥ 50% 
reduction in ALT from baseline to week 4, Week 8, Week 12 & Week 16 
(FAS Population) 
Table 14.2.1.10 
Statistical Analysis of proportion of patients with ≥ 25% and ≥ 50% 
reduction in ALT from baseline to week 4, Week 8, Week 12 & Week 16 
(PP Population) 
Table 14.2.1.11 
Statistical Analysis of change in CK-18 fragments from baseline to Week 
8 and Week 16 (FAS Population) 
Table 14.2.1.12 
Statistical Analysis of change in CK-18 fragments from baseline to Week 
8 and Week 16 (PP Population) 
Table 14.2.1.13 
Statistical Analysis of change in ELF score from baseline to Week 8 and 
Week 16 (FAS Population) 
Table 14.2.1.14 
Statistical Analysis of change in ELF score from baseline to Week 8 and 
Week 16 (PP Population) 
Table 14.2.1.15 
Statistical Analysis of change in APRI from baseline to Week 8 and Week 
16 (FAS Population) 
Table 14.2.1.16 
Statistical Analysis of change in APRI from baseline to Week 8 and Week 
16 (PP Population) 
Table 14.2.1.17 
Statistical Analysis of absolute change in AST/ALT ratio from baseline to 
week 4, Week 8, Week 12 & Week 16 (FAS Population) 
Table 14.2.1.18 
Statistical Analysis of absolute change in AST/ALT ratio from baseline to 


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week 4, Week 8, Week 12 & Week 16 (PP Population) 
Table 14.2.1.19 
Statistical Analysis of absolute change in QOL scores from baseline to 
Week 16 (FAS Population) 
Table 14.2.1.20 
Statistical Analysis of absolute change in QOL scores from baseline to 
Week 16 (PP Population) 
Table 14.2.1.21 
Statistical Analysis of change in liver stiffness/CAP from baseline to 
Week 16 (FAS Population) 
Table 14.2.1.22 
Statistical Analysis of change in liver stiffness/CAP from baseline to 
Week 16 (PP Population) 
Table 14.2.1.23 
Statistical Analysis of absolute change in fasting lipid and lipoprofiles 
from baseline to week 4, Week 8, Week 12 & Week 16 (FAS Population) 
Table 14.2.1.24 
Statistical Analysis of absolute change in fasting lipid and lipoprofiles 
from baseline to week 4, Week 8, Week 12 & Week 16 (PP Population) 
Table 14.2.1.25 
Statistical Analysis of absolute change in insulin resistance and glycemic 
control from baseline to Week 8 & Week 16 (FAS Population) 
Table 14.2.1.26 
Statistical Analysis of absolute change in insulin resistance and glycemic 
control from baseline to Week 8 & Week 16 (PP Population) 
Table 14.2.2 
Summary of Protocol deviation 
Table 14.2.3.1 
Summary of ALT levels (FAS Population) 
Table 14.2.3.2 
Summary of liver fat content measured by MRI-PDFF (FAS Population) 
Table 14.2.3.3 
Summary of CK-18 fragments (FAS Population) 
Table 14.2.3.4 
Summary of APRI (FAS Population) 
Table 14.2.3.5 
Summary of ELF Score (FAS Population) 
Table 14.2.3.6 
Summary of AST/ALT ratio (FAS Population) 


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Table 14.2.3.7 
Summary of Insulin resistance and glycemic control (FAS Population) 
Table 14.2.3.8 
Summary of Lipids and Lipoprofile (FAS Population) 
Table 14.2.3.9 
Summary of Quality of Life - SF-36 domain and 2 components scores 
(FAS Population) 
Safety Data 
 
Table 14.3.1.1 
Number and percent of patients with Adverse Events by System Organ 
Class, Preferred Term and Treatment (Safety Population) 
Table 14.3.1.2 
Number and percent of patients with Adverse Events by Treatment, 
System Organ Class, Preferred Term and Causality (Safety Population) 
Table 14.3.1.3 
Number and percent of patients with Adverse Events by Treatment, 
System Organ Class, Preferred Term and Severity (Safety Population) 
Table 14.3.1.4 
Summary of Adverse Events by Treatment (Safety Population) 
Table 14.3.2.1 
Adverse Events Leading to Discontinuation (Safety Population) 
Table 14.3.2.2 
Serious Adverse Events 
Table 14.3.5.1 
Summary of Biochemistry (Safety Population) 
Table 14.3.5.2 
Summary of Hematology (Safety Population) 
Table 14.3.5.3 
Summary of Biochemistry Shift Table (Safety Population) 
Table 14.3.5.4 
Summary of Hematology Shift Table (Safety Population) 
Table 14.3.5.5 
Summary of Qualitative parameters Shift Table (Safety Population) 
Table 14.3.6.1 
Summary of Vital Signs (Safety Population) 
Table 14.3.6.2 
Summary of Electrocardiogram (Safety Population) 
Table 14.3.4.1 
Summary of Concomitant Medication 
Table 14.3.4.2 
Summary of Exposure to study drug 


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Table 14.3.4.3 
Summary of Compliance to study drug 
 
 
 


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9. 
FIGURES 
Figure 14.2.1.1 
Mean liver enzymes vs visit by treatment  
Figure 14.2.1.2 
Mean absolute change from baseline of liver enzymes vs visit by treatment  
Figure 14.2.1.3 
Mean percentage change from baseline of liver enzymes vs visit by treatment  
Figure 14.2.1.4 
Mean liver fat content vs visit by treatment  
Figure 14.2.1.5 
Mean absolute change from baseline of liver fat content vs visit by treatment  
Figure 14.2.1.6 
Mean percentage change from baseline of liver fat content vs visit by treatment  
Figure 14.2.1.7 
Mean lipids and lipoprofiles vs visit by treatment 
Figure 14.2.1.8 
Mean absolute change from baseline of lipids and lipoprofiles vs visit by 
treatment  
Figure 14.2.1.9 
Mean percentage change from baseline of lipids and lipoprofiles vs visit by 
treatment  
Figure 14.2.1.10 
Mean IR vs visit by treatment  
Figure 14.2.1.11 
Mean absolute change from baseline of IR vs visit by treatment  
Figure 14.2.1.12 
Mean percentage change from baseline of IR vs visit by treatment  
Figure 14.2.1.13 
Mean glycemic control vs visit by treatment  
Figure 14.2.1.14 
Mean absolute change from baseline of glycemic control vs visit by treatment  
Figure 14.2.1.15 
Mean percentage change from baseline of glycemic control vs visit by treatment  


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10. 
LISTINGS TO BE INCLUDED IN SECTION 16 OF THE CLINICAL 
STUDY REPORT 
Patient Disposition 
 
Listing 16.2.1.1 
Patient Disposition 
Listing 16.2.1.2 
Informed Consent 
Listing 16.2.1.3 
Study Visits 
Listing 16.2.1.4 
Failed Inclusion and Exclusion Criteria 
Listing 16.2.1.5 
Patient Randomization 
Listing 16.2.2.1 
Protocol Deviations 
Listing 16.2.3.1 
Assignment to Analysis Populations 
 
Baseline and Demographic Data 
 
Listing 16.2.4.1 
Demographics  
Listing 16.2.4.2 
Medical History 
Listing 16.2.4.3 
Alcohol, smoking and caffeine usage history 
Listing 16.2.4.4 
Diet Physical Activity and Alcohol (DPA) 
 
Concomitant Medication 
 
Listing 16.2.4.5 
Prior and Concomitant medication 
 
Exposure 
 
Listing 16.2.5.1 
Exposure to study drug  
 
Listing 16.2.5.2 
Compliance  
 
 


 
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Pharmacokinetic Data 
Not applicable in this analysis plan.  
 
Pharmacodynamic Data 
Not Applicable 
 
 
Efficacy Data 
 
Listing 16.2.6.1 
Serum ALT levels 
Listing 16.2.6.2 
Liver Fat measured by magnetic resonance imaging-derived proton density-fat 
fraction (MRI-PDFF) 
Listing 16.2.6.3 
Cytokeratin-18 [CK-18] 
Listing 16.2.6.4 
Enhanced liver fibrosis [ELF] score 
Listing 16.2.6.5 
Aspartate aminotransferase-to-platelet ratio index [APRI]) 
Listing 16.2.6.6 
Serum AST/ALT ratio 
Listing 16.2.6.7 
Liver stiffness/CAP results measured by transient elastography/FibroScan® 
Listing 16.2.6.8 
Lipids and Lipoprofile parameters 
Listing 16.2.6.9 
Insulin resistance and glycemic control parameters 
Listing 16.2.6.10 
Individual Questions of QOL data 
Listing 16.2.6.11 
QOL data 
 
Safety Variables 
 
Listing 16.2.7.1 
Adverse Events  
Listing 14.3.2.1 
Adverse Events leading to discontinuation 
Listing 14.3.2.2 
SAEs 
Listing 16.2.8.1 
Biochemistry 
Listing 16.2.8.2 
Hematology 
Listing 16.2.8.3 
Urinalysis 


 
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Listing 16.2.8.4 
Pregnancy Test 
Listing 16.2.8.5 
Serology 
Listing 16.2.9.1 
Vital Signs 
Listing 16.2.9.2 
Electrocardiogram Parameters 
Listing 16.2.9.3 
Physical Examination 
Listing 16.2.9.4 
Electrocardiogram Parameters 
 
 


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11. 
DOCUMENTATION OF STATISTICAL METHODS 
Appendix 16.1.9.1.1 
Raw SAS output of: Table 14.2.1.1 Statistical Analysis of ALT 
percentage change from baseline to week 16 - (FAS Population) 
Appendix 16.1.9.1.2 
Raw SAS output of: Table 14.2.1.2 Statistical Analysis of ALT 
percentage change from baseline to week 16 - (PP Population) 
Appendix 16.1.9.2.1 
Raw SAS output of: Table 14.2.1.3 Statistical Analysis of change in 
liver fat from baseline to week 16 - (FAS Population) 
Appendix 16.1.9.2.2 
Raw SAS output of: Table 14.2.1.4 Statistical Analysis of change in 
liver fat from baseline to week 16 - (PP Population) 
Appendix 16.1.9.3.1 
Raw SAS output of: Table 14.2.1.5 Statistical Analysis of ALT 
change from baseline to week 4, Week 8, Week 12 & Week 16 - 
(FAS Population) 
Appendix 16.1.9.3.2 
Raw SAS output of: Table 14.2.1.6 Statistical Analysis of ALT 
change from baseline to week 4, Week 8, Week 12 & Week 16 - (PP 
Population) 
Appendix 16.1.9.4.1 
Raw SAS output of: Table 14.2.1.7 Statistical Analysis of 
proportion of patients who sustain a decrease in ALT from baseline 
to week 4, Week 8, Week 12 & Week 16 - (FAS Population) 
Appendix 16.1.9.4.2 
Raw SAS output of: Table 14.2.1.8 Statistical Analysis of 
proportion of patients who sustain a decrease in ALT from baseline 
to week 4, Week 8, Week 12 & Week 16 - (PP Population) 
Appendix 16.1.9.5.1 
Raw SAS output of: Table 14.2.3.1 Statistical Analysis of 
proportion of patients with ≥ 25% and ≥ 50% reduction in ALT 
from baseline to week 4, Week 8, Week 12 & Week 16 - (FAS 
Population) 
Appendix 16.1.9.5.2 
Raw SAS output of: Table 14.2.3.2 Statistical Analysis of 
proportion of patients with ≥ 25% and ≥ 50% reduction in ALT 
from baseline to week 4, Week 8, Week 12 & Week 16 - (PP 


 
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Population) 
Appendix 16.1.9.6.1 
Raw SAS output of: Table 14.2.3.3 Statistical Analysis of change in 
CK-18 fragments from baseline to Week 8 and Week 16 - (FAS 
Population) 
Appendix 16.1.9.6.2 
Raw SAS output of: Table 14.2.3.4 Statistical Analysis of change in 
CK-18 fragments from baseline to Week 8 and Week 16 - (PP 
Population) 
Appendix 16.1.9.7.1 
Raw SAS output of: Table 14.2.3.5 Statistical Analysis of change in 
ELF score from baseline to Week 8 and Week 16 - (FAS 
Population) 
Appendix 16.1.9.7.2 
Raw SAS output of: Table 14.2.3.6 Statistical Analysis of change in 
ELF score from baseline to Week 8 and Week 16 - (PP Population) 
Appendix 16.1.9.8.1 
Raw SAS output of: Table 14.2.3.7 Statistical Analysis of change in 
APRI from baseline to Week 8 and Week 16 - (FAS Population) 
Appendix 16.1.9.8.2 
Raw SAS output of: Table 14.2.3.8 Statistical Analysis of change in 
APRI from baseline to Week 8 and Week 16 - (PP Population) 
Appendix 16.1.9.9.1 
Raw SAS output of: Table 14.2.4.1 Statistical Analysis of absolute 
change in AST/ALT ratio from baseline to week 4, Week 8, Week 
12 & Week 16 - (FAS Population) 
Appendix 16.1.9.9.2 
Raw SAS output of: Table 14.2.4.2 Statistical Analysis of absolute 
change in AST/ALT ratio from baseline to week 4, Week 8, Week 
12 & Week 16 - (PP Population) 
Appendix 16.1.9.10.1 
Raw SAS output of: Table 14.2.4.3 Statistical Analysis of change in 
liver stiffness/CAP from baseline to Week 16 - (FAS Population) 
Appendix 16.1.9.10.2 
Raw SAS output of: Table 14.2.4.4 Statistical Analysis of change in 
liver stiffness/CAP from baseline to Week 16 - (PP Population) 
Appendix 16.1.9.11.1 
Raw SAS output of: Table 14.2.4.5 Statistical Analysis of absolute 


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change in fasting lipid and lipoprofiles from baseline to week 4, 
Week 8, Week 12 & Week 16 - (FAS Population) 
Appendix 16.1.9.11.2 
Raw SAS output of: Table 14.2.4.6 Statistical Analysis of absolute 
change in fasting lipid and lipoprofiles from baseline to week 4, 
Week 8, Week 12 & Week 16 - (PP Population) 
Appendix 16.1.9.12.1 
Raw SAS output of: Table 14.2.4.7 Statistical Analysis of absolute 
change in insulin resistance and glycemic control from baseline to 
Week 8 & Week 16 - (FAS Population) 
Appendix 16.1.9.12.2 
Raw SAS output of: Table 14.2.4.8 Statistical Analysis of absolute 
change in insulin resistance and glycemic control from baseline to 
Week 8 & Week 16 - (PP Population)