A Phase 2A, Single Center, Open-label, Single-arm, 24-week Study to Evaluate the Safety, Tolerability and Efficacy of Saroglitazar Magnesium 4 mg in Liver Transplant Recipients With Nonalcoholic Fatty Liver Disease (EVIDENCES VIII)
Phase: PHASE2
Conditions: Liver Transplant; Complications, NAFLD
Sponsor: Zydus Therapeutics Inc.



 
 
Zydus Discovery DMCC 
CLINICAL TRIAL PROTOCOL  
Saroglitazar Magnesium – Phase 2A 
SARO.17.010 
 
Confidential 
Page 3 of 80 
 
Approved by: 
 Dr Deven V Parmar 
Protocol No.: SARO.17.010 
Version No.: 7.0 
 
STUDY PROTOCOL SUMMARY 
Name of Sponsor 
Zydus Discovery DMCC 
Unit No 909, Armada 2 
Plot No: JLT-PH2-P2A, 
Jumeirah Lakes Towers 
Dubai UAE 
P.O Box 113536 
Name of the test product 
Saroglitazar magnesium  
Name of active ingredient of test product 
Saroglitazar magnesium 4 mg 
Name of the reference drug 
Not Applicable 
Name of active ingredient of reference product 
Not Applicable 
Potential Indication 
Nonalcoholic fatty liver disease (NAFLD) 
in liver transplant recipients 
Study Subjects 
Liver transplant recipients with NAFLD 
Number of Subjects 
15 subjects 
Clinical phase 
2A 
Trial Number 
SARO.17.010 
Date of Protocol 
01 August 2019 
Study Duration 
33 Weeks 
Treatment Duration 
24 weeks  
Study Title: A Phase 2A, single-center, open-label, single-arm, 24-week study to evaluate the 
safety, tolerability and efficacy of Saroglitazar magnesium 4 mg in liver transplant recipients with 
nonalcoholic fatty liver disease. 
 
Objective: The objective of this study is to evaluate the safety, tolerability and efficacy of 
Saroglitazar magnesium in liver transplant recipients with nonalcoholic fatty liver disease 
(NAFLD). 
 
Primary Endpoint: 
 
 
To assess the safety of Saroglitazar magnesium 4 mg tablets in liver transplant recipients 
with NAFLD over 24 weeks of treatment. 
 
Secondary Endpoints: 
 
1 
Changes in hepatic fat as determined by MRI-PDFF and MRE from baseline to End of 
treatment (EOT). 
2 
Changes in metabolic flexibility from baseline to EOT. 
3 
Changes in markers of insulin resistance [frequently sampled intravenous glucose 
tolerance test  (FSIVGTT), glycosylated hemoglobin (HbA1c) and fructosamine] from 
baseline to EOT.  
4 
Changes in serum liver enzymes from baseline to EOT.  
5 
Changes in serum lipids from baseline to EOT. 
6 
Changes in atherogenic lipoprotein which includes small dense low-density lipoprotein 
(sdLDL), LDL size and concentration, subtypes of very low-density lipoprotein (VLDL) 
and high-density lipoprotein (HDL) from baseline to EOT 
7 
Change in Quality of life (QoL) score from baseline to EOT  

 
 
Zydus Discovery DMCC 
CLINICAL TRIAL PROTOCOL  
Saroglitazar Magnesium – Phase 2A 
SARO.17.010 
 
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Approved by: 
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Protocol No.: SARO.17.010 
Version No.: 7.0 
 
8 
Pharmacokinetics of Saroglitazar following first dose and last dose. 
9 
Body composition assessment via change in adipose tissue and skeletal muscle volume 
from baseline to EOT by whole body MRI. 
 
Criteria for Safety: 
1. 
Vitals: blood pressure (BP), pulse rate, oral temperature, respiratory rate.  
2. 
The physical examination will consist of an evaluation of the head, neck, eyes, ears, nose, 
throat, chest, heart, lungs, abdomen, skin, extremities, and the neurological and 
musculoskeletal systems. 
3. 
Body weight. 
4. 
Laboratory assessment 
o Hematology: hematocrit, hemoglobin, mean corpuscular hemoglobin concentration 
(MCHC), mean corpuscular volume (MCV), platelet count, mean platelet volume 
(MPV), RBC count, white blood cell (WBC) count, differential WBC count. 
o Lipid profile: total cholesterol (TC), triglycerides (TG), high-density lipoprotein 
(HDL), low-density lipoprotein (LDL), VLDL and non-HDL. 
o Liver function tests (LFTs): aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (with Conjugated 
bilirubin), gamma-glutamyltransferase (GGT), total protein and albumin. 
o Amylase and lipase  
o Renal function tests (RFTs): blood urea nitrogen (BUN), serum creatinine and 
estimated glomerular filtration rate (eGFR).  
o Coagulation panel: activated partial thromboplastin time (APTT), prothrombin 
time/international normalized ratio (PT/INR), thrombin time (TT). 
o Immunosuppression level (tacrolimus, cyclosporine or sirolimus). 
o Gut hormones: Ghrelin, glucagon like peptide, leptin, resistin, and adiponectin 
o Glycemic control: HbA1c and fasting plasma glucose. 
o Urinalysis: urine examination: physical examination (appearance, color, specific 
gravity and pH); microscopy (epithelial cells, red blood cells, pus or white blood cells, 
casts and crystals) and chemical examination (protein, glucose, bilirubin, 
urobilinogen, ketone bodies, nitrite and blood); urine drug test (at screening). 
o Creatine phosphokinase (CPK), CK-MB, troponin 1 and NT-proBNP 
o Serum electrolytes: sodium, potassium, calcium, bicarbonate and chloride. 
o Serology: human immunodeficiency virus (HIV) type 1 and type 2, HAV IgM, 
hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), CMV (IgG), and EBV 
VCAIgG 
o Pregnancy test: Serum pregnancy test and urine pregnacy test for women of 
childbearing potential. 
5. 
Cardiac function: standard 12-lead electrocardiogram (ECG) and 2D echocardiogram (2D 
ECHO).  
6. 
Adverse event(s): Frequency and severity of adverse events (AEs) /serious adverse events 
(SAEs), drop-outs due to AEs/SAEs for all subjects enrolled will be recorded. AE’s will be 
assessed, and reported as appropriate, in accordance with applicable sections of the U.S. Code 
of Federal Regulations, Title 21 Part 312 for:  
 
Causality (relatedness) 
 
Severity 
 
Seriousness 
 
Expectedness 

 
 
Zydus Discovery DMCC 
CLINICAL TRIAL PROTOCOL  
Saroglitazar Magnesium – Phase 2A 
SARO.17.010 
 
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Approved by: 
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Protocol No.: SARO.17.010 
Version No.: 7.0 
 
Inclusion Criteria: 
Must meet all of the following conditions: 
1. Able and willing to give written informed consent and comply with the requirements of 
the study protocol. 
2. Male or female, 18 to 75 years of age, both inclusive. 
3. Patients who are at least 6 months post liver-transplant with evidence of NAFLD in the 
liver graft. 
4. Presence of NAFLD determined by Transient Elastography (TE) with a controlled 
attenuation parameter (CAP) score cut-off at 263 dB/m prior to enrollment. 
5. Patients with ≤20% variation in the levels of ALT, AST, ALP and total bilirubin between 
Visit 1 and Visit 1.1, if either Visit 1 or Visit 1.1 laboratory results are elevated above the 
reference range. 
6. History of medical compliance with immunosuppression. 
7. Female subjects of non-child bearing potential or on highly effective contraception. For 
male subjects with female partners of childbearing potential, willing to follow highly 
effective contraception measures during the study, either by the male participant or his 
female partner or both. 
Exclusion Criteria: 
1. Pregnant or lactating females. 
2. Patient with abnormal transaminases due to secondary intercurrent illness (should be 
determined over a period within last 12 months prior to screening). 
3. Patients with clinically significant bile duct strictures as assessed with MRI and elevated 
liver enzymes during screening. 
4. Recurrence of non-NASH causes of chronic liver disease after liver transplantation 
including autoimmune, viral, medications associated with steatosis and steatohepatitis 
(e.g., amiodarone and doxycycline) and alcoholic liver disease that are clinically active.  
5. Graft cirrhosis as defined by:  
I. 
Cirrhosis on historical liver biopsy. 
II. 
Evidence of cirrhosis on imaging including portal venous collaterals.  
III. 
Prior history of decompensated liver disease including ascites, hepatic 
encephalopathy or variceal bleeding. 
IV. 
Evidence of esophageal varices on prior endoscopy.  
6. Body mass index (BMI) <18 kg/m2. 
7. Subjects with change in body weight >5% in the 3 months prior to enrollment. 
8. Subjects requiring corticosteroid or anticoagulation therapy. 
9. History of myopathies or evidence of active muscle diseases. 
10. Unstable cardiovascular disease, including: 
i. Unstable angina (i.e., new or worsening symptoms of coronary heart disease within the 
past 3 months), acute coronary syndrome within the past 6 months, acute myocardial 
infarction in the past 3 months or heart failure of New York Heart Association class 
(III-IV) or worsening congestive heart failure, or coronary artery intervention, within 
the past 6 months. 
ii. History of (within prior 3 months) or current unstable cardiac dysrhythmias. 
iii. Uncontrolled hypertension (systolic blood pressure >160 mmHg and/or diastolic blood 
pressure >100 mmHg. 
iv. Stroke or transient ischemic attack within the prior 6 months. 
11. History of bladder disease and/or hematuria or has current hematuria unless due to a urinary 
tract infection. 
12. Active malignancy post-liver transplantation. 

 
 
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CLINICAL TRIAL PROTOCOL  
Saroglitazar Magnesium – Phase 2A 
SARO.17.010 
 
Confidential 
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Approved by: 
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Protocol No.: SARO.17.010 
Version No.: 7.0 
 
13. History of malignancy in the past 5 years and/or active neoplasm with the exception of 
resolved superficial non-melanoma skin cancer. 
14. History of chronic rejection of liver transplant graft.  
15. Acute cellular rejection of liver transplant graft within the past 6 months.  
16. Evidence of Acute cellular rejection (ACR) or chronic rejection (CR) or alternative 
etiologies to NAFLD must be ruled out within 4-6 weeks prior to enrollment into the 
study by either a liver biopsy or at the discretion (clinical judgement and according to 
local standard of care) of the treating hepatologist.  
17. Any of the following laboratory values: 
a. White blood cell count <2.5 x 103/uL 
b. Neutrophil count <1.5 x 103/uL 
c. Serum bilirubin >1.5 mg/dL 
d. Serum ALT >3X ULN  
e. INR >1.2 
f. Renal impairment as demonstrated by baseline estimated glomerular filtration rate 
(eGFR) <60 mL/min/1.73m2 
g. Abnormal screening total creatine kinase 
h. Abnormal screening lipase or amylase 
18. Poorly controlled diabetes as defined by an HbA1c >8.5% within the past 6 months. 
19. Subjects with history of excessive alcohol intake, defined by ≥21 units of alcohol per 
week in males and ≥14 units of alcohol per week in females for two years prior to 
enrollment, where a “unit” of alcohol is equivalent to a 12 ounce (oz.) beer, 4 oz. glass of 
wine, or 1 oz. shot of hard liquor. 
20. Subject tests positive for a urine drug screen. 
21. Subject has a history of chronic (uncontrolled) pain. 
 
Methodology  
 
 
This is a phase 2A, single-center, open-label, single-arm study evaluating the safety, 
tolerability and efficacy of Saroglitazar magnesium 4 mg tablets in liver transplant recipients 
with NAFLD. 
 
This study will be initiated only after obtaining the approval of Independent Ethics 
Committee/Institutional Review Board (IEC/IRB), clinical trial permission from the 
applicable regulatory agencies and after registering the trial with clinicaltrials.gov. 
 
It is the responsibility of the Principal Investigator (PI) to ensure that the study is conducted 
in accordance with the protocol, with International Council for Harmonisation Good Clinical 
Practice (ICH-GCP), and with all other applicable regulatory requirements. Informed 
consent must be obtained from each study subjects before the start of any trial-related 
procedures. 
 
All laboratory reports should be reviewed by the PI and/or his/her designee and any 
abnormal findings should be addressed. 
 
All protocol deviations/violations occurring in the study shall be documented and informed 
to the Sponsor and to the IEC/IRB in accordance with their standard procedures. 
 
Participation in this study will last 33 weeks, which includes a 5-week Screening Period, a 24-
week Treatment Period during which study drug will be administered and a 4-week Follow-
up Period. The Screening Period may be extended under special circumstances with the 
explicit approval of the Sponsors’ Medical Expert(s). 
 
 

 
 
Zydus Discovery DMCC 
CLINICAL TRIAL PROTOCOL  
Saroglitazar Magnesium – Phase 2A 
SARO.17.010 
 
Confidential 
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Approved by: 
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Protocol No.: SARO.17.010 
Version No.: 7.0 
 
Study Schedules: 
 
After signing the informed consent form (ICF), subjects will complete a screening visit which will 
include the following assessments: Demographic assessment, complete medical history, prior 
medications history, physical examination, vital signs, body weight and height measurement, 
laboratory assessments (i.e., hematology, lipid profile and lipoprotein, liver function test, renal 
function test, coagulation panel, HbA1c), viral serology, pregnancy test (for females of child-
bearing potential), standard 12-lead ECG, AE assessment, urine analysis and urine drug (substance 
abuse) test. MRI (Whole Body and PDFF) and MRE will be performed at any point during 
screening but only after the assessment of Visit 1 laboratory results. 
 
Liver enzymes (AST, ALT, ALP and total bilirubin) will be re-measured at least 4-week from Day 
-35 (Visit 1) to determine eligibility. The variation in the levels of the repeat measures of serum 
ALT, AST, ALP and total bilirubin at Day -7 (Visit 1.1) must be ≤20%, compared to the Day -35 
(Visit 1) levels to be eligible for study entry, unless they are within the reference range.  
 
After the Screening Period, the enrolment visit will occur at Day 1, study visits will occur on week 
1, 4, 8, 12, 16, 20 and 24 with a Follow-up visit 4-week after the last dose of the study drug. Vital 
signs, targeted physical examination (lab results/signs/symptom driven), safety laboratory tests 
(i.e. hematology, coagulation panel, and immunosuppression levels, serum electrolytes, creatine 
phosphokinase, urine pregnancy test, fructosamine), dietary assessment, review of concomitant 
medications, AEs and glucometer assessment will be done as per table 1 (Schedule of Events). In 
addition, all the study assessments will be performed as per table 1 (Schedule of Events). 
 
Eligible subjects will be enrolled. Prior to initial dosing, required Day 1 assessments will be 
performed and will include QoL assessment, targeted physical examination (lab 
results/signs/symptom driven), vital signs, laboratory assessments, pregnancy tests (for females of 
child-bearing potential), urine and blood collection for biomarker assessments and 
pharmacokinetic analyses, FSIVGTT, review of concomitant medications and AEs. A window of 
±3 days will be given to perform all baseline assessments. 
 
Pharmacokinetics of Saroglitazar will be assessed following first dose and last dose in liver 
transplant recipients with NAFLD. 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 3, 4, 5, 6 and 7. 
 
At the End of Treatment visit, all required parameters and assessments will be performed again. 
 
Subjects will return for their final visit, the Follow-up visit, 4-week after the last dose of the study 
drug. At this visit assessments include a targeted physical examination (lab results/signs/symptom 
driven), vital signs, safety laboratory tests, a review of concomitant medications and AEs. A urine 
pregnancy test will be performed for females of child bearing potential only. All the study related 
procedures will be performed as per table 1 (Schedule of Events).  
 
Unscheduled visits – Permitted at any time during the study for assessment and management of 
AEs and any concurrent clinical conditions. To be captured in the electronic case report form 
(eCRF). 
 
If further investigations are required in case of any AEs, PI will assess the AE and take 
necessary action, if required.  
 

 
 
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CLINICAL TRIAL PROTOCOL  
Saroglitazar Magnesium – Phase 2A 
SARO.17.010 
 
Confidential 
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Approved by: 
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Protocol No.: SARO.17.010 
Version No.: 7.0 
 
Protocol Deviations: 
Protocol deviations/ will include but are not limited to the following; 
 
Subjects that did not meet entry criteria but are enrolled into the study. 
 
Subjects that received the wrong treatment or incorrect dose. 
 
Subjects that received an excluded medication. 
 
Subjects that met the discontinuation criteria but continued in the study. 
 
Failure to report within specified timelines of the planned visits. 
 
Failure to perform a study procedure/assessment. 
 
IP non-compliance (80% or >120%). 
 
Subject withdrawal criteria: 
 
Subject who reports an SAE and if considered in PI or Medical Expert’s opinion it is not in 
the subject’s best interest to continue. 
 
Any subject found to have entered the study in violation of the protocol 
 
Termination of study by Sponsor or PI or the regulatory authorities or IEC/IRB. 
 
The subject is lost to follow-up. 
 
Any subject who wishes to withdraw his/her consent for participation in the study.  
 
In case a subject becomes pregnant, then she will be withdrawn from the study. 
 
Discontinuation of patients from the Study Drug 
1 
Discontinue any patient with an AE of Common Terminology Criteria for Adverse Events 
(CTCAE) grade 3 or higher that is possible or probably drug related and discontinue any 
patient with an AE of CTCAE grade 4 regardless of attribution to study drug. 
2 
If any of the following criteria are met, the patient shall be immediately discontinued from 
drug and followed until resolution of adverse events and laboratory values shall be returned to 
baseline. 
a. Total bilirubin ≥3.0 mg/dL. 
b. Total CK >5 X ULN. 
c. Amylase or lipase >ULN. 
d. eGFR <60 mL/min/1.73 m2 and where the value is reconfirmed after 24 hours repeat. 
Additionally, any subject who requires renal replacement therapy should also be 
discontinued from drug. 
e. Hemoglobin <10 mg/dL or hematocrit <30%; platelets <100,000/µL; WBC <4 x 
103/uL. 
f. If troponin and CK-MB exceed the 99th percentile of the upper reference limit of the 
particular assay, serial labs should be obtained along with serial 12-lead ECGs, and 
cardiology should be consulted. If a patient has symptoms of dyspnea, edema, or a 
presumptive diagnosis of heart failure, NT-proBNP should be measured as close to 
the event as possible. 
3 
The criteria for discontinuing or temporarily interrupting study drug with close monitoring are 
as follows:  
a. When baseline measure (BLM) are <2x ULN, discontinue if ALT or AST increases 
>5x BLM.  
b. When the BLM ≥2X ULN but <5X ULN, discontinue if ALT or AST increases >3X 
BLM. 
c. When BLM ≥5X ULN, discontinue if ALT or AST increases >2X BLM.  
d. For ALT or AST increase >2X BLM accompanied by a concomitant total bilirubin 
increase to >2X BLM OR an INR increase by >0.2. 

 
 
Zydus Discovery DMCC 
CLINICAL TRIAL PROTOCOL  
Saroglitazar Magnesium – Phase 2A 
SARO.17.010 
 
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Approved by: 
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Protocol No.: SARO.17.010 
Version No.: 7.0 
 
e. For elevations of liver enzymes accompanied by symptoms consistent with hepatic 
injury [e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, and/or eosinophilia (>5%)].  
f. Temporarily interrupted treatment should be permanently discontinued for recurrence 
of laboratory abnormalities or symptoms following re-challenge. 
g. If a patient lives in a remote area, testing can be performed locally and the results 
communicated to the PI site promptly.  
h. If patients develop elevations of AST or ALT >2 times baseline measure or total 
bilirubin >1.5 times BLM while on study, testing should be repeated within 48 to 72 
hours. Persistent elevations should be followed by repeat testing and physical 
examination 2-3 times per week with or without drug discontinuation. 
Concomitant Medication:  
 
 Standard of care for patients with liver transplantation (LT) will be allowed. This includes 
changes in immunosuppression as necessary. Additionally, standard of care management of 
metabolic co-morbidities including hypertension, diabetes, hyperlipidemia will also be 
allowed. Patient with stable doses of statins (simvastatin, pravastatin, atorvastatin, 
fluvastatin, lovastatin, rosuvastatin) or fibrates (clofibrate, fenofibrate) will be allowed; 
however, the dose should remain stable throughout the study period. 
 
Restricted Medications: 
 
Patients are not permitted to take zileuton, vitamin E (>400 IU/day) or other drugs with 
potential effect on NAFLD/NASH such as ursodeoxycholic acid, S-adenosylmethionine 
(SAM-e), betaine, pentoxifylline.  
 
Patients are not permitted to take thiazolidinediones (pioglitazone, rosiglitazone), 
chemotherapy or other investigational medications during the study duration. 
 
Concomitant use of strong CYP2C8 Inhibitors/Substrates will be prohibited (Please refer 
Appendix 1. 
 
Patients also should not take any non-allowed over-the-counter medications or 
complementary and/or alternative medications. 
Total Subjects: 
A total 15 subjects will be enrolled in this study. 
Approximately 5 patients will be included in the pharmacokinetic 
study. 
Test product: 
Dose: 
 
Mode of administration: 
Saroglitazar magnesium  
4 mg tablet once daily (OD) in the morning 60 minutes before 
breakfast without food  
Oral 
Reference/Placebo 
therapy: 
Dose: 
Mode of administration: 
Not applicable 
Duration of treatment:  
24 weeks  
Criteria for efficacy 
Primary Endpoints:  
The primary endpoint is to assess the safety of Saroglitazar magnesium 
4 mg tablets in liver transplant recipients with NAFLD over 24 weeks 
of treatment.  
Safety will be assessed during the study period through the reporting 
of AEs, and by clinical laboratory tests and vital sign assessment at 
various time points during the study.  
 

 
 
Zydus Discovery DMCC 
CLINICAL TRIAL PROTOCOL  
Saroglitazar Magnesium – Phase 2A 
SARO.17.010 
 
Confidential 
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Approved by: 
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Protocol No.: SARO.17.010 
Version No.: 7.0 
 
Secondary Endpoints: 
Efficacy will be assessed through a number of exploratory endpoints. 
These include: 
1 
Changes in hepatic fat as determined by MRI-PDFF and 
MRE from baseline to EOT. 
2 
Changes in metabolic flexibility from baseline to EOT. 
3 
Changes in markers of insulin resistance FSIVGTT, HbA1c 
and fructosamine from baseline to EOT.  
4 
Changes in serum liver enzymes from baseline to EOT.  
5 
Changes in serum lipids from baseline to EOT. 
6 
Changes in atherogenic lipoprotein which includes sdLDL, 
LDL size and concentration, subtypes of VLDL and HDL 
from baseline to EOT. 
7 
Change in QoL score from baseline to EOT. 
8 
Pharmacokinetics of Saroglitazar following first dose and last 
dose in liver transplant recipients with nonalcoholic fatty 
liver disease. 
9 
Body composition assessment via change in adipose tissue 
and skeletal muscle volume from baseline to EOT by whole 
body MRI. 
 
Criteria for Safety 
1. 
Vitals: BP, pulse rate, oral temperature, respiratory rate  
2. 
The physical examination will consist of an evaluation of the 
head, neck, eyes, ears, nose, throat, chest, heart, lungs, abdomen, 
skin, extremities, and the neurological and musculoskeletal 
systems 
3. 
Body weight 
4. 
Laboratory assessment 
o Hematology: Hematocrit, hemoglobin, MCHC, MCV, 
platelet count, MPV, RBC count, WBC count, differential 
WBC count 
o Lipid profile: TC, TG, HDL, LDL, VLDL and non-HDL. 
o Liver function tests : AST, ALT, ALP, GGT, total 
protein, albumin, total bilirubin (with Conjugated 
bilirubin).  
o Amylase and lipase 
o Renal function tests : Serum creatinine, eGFR and BUN.  
o Coagulation Panel: APTT, PT/INR, TT. 
o Immunosuppression level (tacrolimus, cyclosporine or 
sirolimus) 
o Gut hormones: Ghrelin, glucagon like peptide, leptin, 
resistin, and adiponectin 
o Glycemic control: HbA1c and fasting plasma glucose 
o Urinalysis: Urine examination: physical examination 
(appearance, color, specific gravity and pH); microscopy 
(epithelial cells, red blood cells, pus or white blood cells, 
casts and crystals) and chemical examination (protein, 
glucose, bilirubin, urobilinogen, ketone bodies,  nitrite 
and blood); urine drug test (at screening) 

 
 
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CLINICAL TRIAL PROTOCOL  
Saroglitazar Magnesium – Phase 2A 
SARO.17.010 
 
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Approved by: 
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Protocol No.: SARO.17.010 
Version No.: 7.0 
 
o Creatine phosphokinase, CK-MB, troponin 1 and NT-
proBNP 
o Serum electrolytes: sodium, potassium, calcium, 
bicarbonate and chloride 
o Serology: HIV type 1 and type 2, HAV IgM, HBsAg, 
HCV, CMV (IgG), and EBV VCAIgG 
o Pregnancy test: Serum pregnancy test and urine 
pregnancy test for women of childbearing potential  
5. 
Cardiac function: standard 12-lead ECG and 2D ECHO 
6. 
Adverse event(s): Frequency and severity of AE(s)/SAE(s), drop-
out due to AEs/SAEs for all subjects enrolled will be recorded. 
AE’s will be assessed, and reported as appropriate, in accordance 
with applicable sections of the U.S. Code of Federal Regulations, 
Title 21 Part 312 for:  
 
Causality (relatedness)  
 
Severity 
 
Seriousness 
 
Expectedness 
Statistical Methods:   
Safety Analysis: All safety data collected will be listed and be summarized, as appropriate, by 
treatment groups.  
 
Efficacy analysis: Since the efficacy endpoints will be evaluated for exploratory purpose, formal 
statistical comparisons will not be made for these endpoints.  
 
Exploratory analysis: Point estimates and 95% CI will be calculated for all continuous exploratory 
parameters (i.e. MRI-PDFF and laboratory values). For categorical variables, descriptive statistics 
will be calculated with count and percentage of subjects in each category by treatment group. 
Descriptive statistics will be provided for all pharmacokinetic parameters. 
Sample Size: Due to exploratory nature of this study, no formal power calculations were used to 
determine sample size. The number of subjects was chosen based on clinical experience with other 
similar proof of concept studies. 
 
 

 
 
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CLINICAL TRIAL PROTOCOL  
Saroglitazar Magnesium – Phase 2A 
SARO.17.010 
 
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Approved by: 
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Version No.: 7.0 
 
ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aP2 
adipocyte fatty-acid-binding protein  
API 
active pharmaceutical ingredient 
Apo  
Apo lipoprotein 
APTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase  
BLM 
baseline measure 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CAP 
Controlled Attenuation Parameter 
CHL 
Cadila Healthcare Limited 
CPK 
creatine phosphokinase 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
eCRF 
Electronic case report form 
CYP 
Cytochrome450 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
EOT 
End of treatment 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
FA 
fatty acids  
FFA 
Free fatty acid 
FSIVGTT 
frequently sampled intravenous glucose tolerance test 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyltransferase 
HbA1c 
glycosylated hemoglobin 
HCV 
hepatitis C virus 
HDL 
High-density lipoprotein 
HIV 
Human Immunodeficiency Virus 
HBsAg 
Hepatitis B surface antigen  
ICF 
Inform consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 

 
 
Zydus Discovery DMCC 
CLINICAL TRIAL PROTOCOL  
Saroglitazar Magnesium – Phase 2A 
SARO.17.010 
 
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Approved by: 
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Version No.: 7.0 
 
Abbreviation 
Definition 
IP 
Investigational product 
IRB 
Institutional Review Board 
LDL 
Low-density lipoprotein 
LFT 
liver function test 
LOCF 
last observation carried forward 
LPL 
lipoprotein lipase  
LT 
liver transplantation 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MITT 
modified Intent-to-treat 
MPV 
mean platelet volume 
MRI-PDFF 
magnetic resonance imaging-proton density fat fraction  
MRE 
magnetic resonance elastography 
NAFLD 
Nonalcoholic fatty liver disease 
NASH 
Nonalcoholic steatohepatitis 
NME 
New molecular entity 
OD 
once daily 
PP 
per protocol 
PPAR 
peroxisome proliferator-activated receptors 
PT 
prothrombin time 
QoL 
Quality of life 
RBC 
red blood cell 
RFT 
renal function test 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sdLDL 
small dense low-density lipoprotein 
SOP 
standard operating procedure 
T2DM 
Type 2 diabetes mellitus 
TC 
total cholesterol 
TE 
Transient Elastography 
TG 
Triglycerides 
TT 
thrombin time 
TZDs 
thiazolidinediones  
VLDL 
very low-density lipoprotein 
WBC 
white blood cell 
 
 
 

 
 
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TABLE OF CONTENTS 
Contents 
STUDY PROTOCOL SUMMARY ...................................................................................... 3 
ABBREVIATIONS ............................................................................................................... 12 
TABLE OF CONTENTS ..................................................................................................... 14 
1 
STUDY FLOW CHART ............................................................................................ 17 
2 
INTRODUCTION ....................................................................................................... 21 
2.1 
MEDICAL BACKGROUND ......................................................................... 21 
2.2 
RATIONALE FOR CONDUCTING THE STUDY .................................... 21 
2.3 
DRUG PROFILE ............................................................................................ 23 
2.4 
RISK AND BENEFIT ..................................................................................... 24 
3 
STUDY OBJECTIVES ............................................................................................... 26 
3.1 
PRIMARY OBJECTIVE ............................................................................... 26 
3.2 
SECONDARY OBJECTIVES ....................................................................... 26 
3.3 
SAFETY ASSESSMENT ............................................................................... 26 
4 
STUDY POPULATION ............................................................................................. 29 
4.1 
NUMBER OF SUBJECTS PLANNED ......................................................... 29 
4.2 
INCLUSION CRITERIA ............................................................................... 29 
4.3 
EXCLUSION CRITERIA .............................................................................. 29 
4.4 
WITHDRAWAL CRITERIA ........................................................................ 31 
4.4.1 
Screen Failure ................................................................................... 31 
4.5 
HANDLING OF SUBJECT WITHDRAWAL............................................. 32 
5 
STUDY TREATMENTS/IP MANAGEMENT ........................................................ 33 
5.1 
TREATMENTS TO BE COMPARED ......................................................... 33 
5.1.1 
Investigational Product Description ............................................... 33 
5.1.2 
Comparator Drug Description ........................................................ 33 
5.2 
DOSAGE AND TREATMENT SCHEDULE .............................................. 33 
5.3 
PACKAGING, LABELLING AND SUPPLY .............................................. 34 
5.4 
STORAGE CONDITIONS AND STABILITY ............................................ 34 
5.5 
BLINDING ...................................................................................................... 35 
5.6 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUP .... 35 
5.7 
SELECTION OF DOSES ............................................................................... 35 
5.8 
CONCOMITANT MEDICATION ............................................................... 35 
5.8.1 
Subjects on concomitant anti-diabetic medication ........................ 36 
5.9 
STOPPING RULE(S) ..................................................................................... 37 
5.9.1 
Discontinuation of Patients from the Study Drug ......................... 38 
5.9.2 
Termination of Clinical Study ......................................................... 39 

 
 
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5.10 
RESTRICTED MEDICATIONS ................................................................... 40 
5.11 
OVERDOSE AND DRUG INTERACTION ................................................ 40 
5.12 
TREATMENT COMPLIANCE .................................................................... 41 
6 
OBSERVATIONS ....................................................................................................... 42 
6.1 
SAFETY ........................................................................................................... 42 
6.1.1 
Primary Endpoint ............................................................................. 42 
6.1.2 
Medical History and Demographic Information ........................... 42 
6.1.3 
Clinical Laboratory Assessments .................................................... 43 
6.1.4 
Twelve-lead Electrocardiograms and 2D ECHO........................... 44 
6.1.5 
Adverse events ................................................................................... 44 
6.2 
EFFICACY ...................................................................................................... 45 
6.2.1 
Magnetic Resonance Imaging-Derived Proton Density-Fat 
Fraction (MRI-PDFF) ...................................................................... 45 
6.2.2 
Controlled Attenuation Parameter (CAP) ..................................... 46 
6.2.3 
Magnetic Resonance Elastography (MRE) .................................... 47 
6.2.4 
Whole Body MRI .............................................................................. 47 
6.2.5 
Frequently Sampled Intravenous Glucose Tolerance Test 
(FSIVGTT) ........................................................................................ 47 
6.2.6 
Metabolic Flexibility ......................................................................... 48 
6.2.7 
Quality of Life Assessment ............................................................... 49 
6.2.8 
Pharmacokinetics Assessment ......................................................... 49 
6.2.9 
Appropriateness of Measurement ................................................... 50 
6.2.10 
Abnormal Laboratory Findings ...................................................... 50 
7 
INVESTIGATIONAL PLAN ..................................................................................... 51 
7.1 
STUDY DESIGN AND PLAN ....................................................................... 51 
7.2 
STUDY PROCEDURES AT EACH VISIT .................................................. 51 
7.3 
ADHERENCE TO PROTOCOL .................................................................. 55 
7.4 
PROTOCOL DEVIATION ............................................................................ 56 
7.5 
DATA MONITORING COMMITTEE ........................................................ 57 
7.6 
ADJUDICATION ............................................................................................ 57 
8 
BIOSTATISTICS AND DATA MANAGEMENT ................................................... 58 
8.1 
STATISTICAL DESIGN ............................................................................... 58 
8.2 
PLANNED ANALYSIS .................................................................................. 58 
8.2.1 
Population .......................................................................................... 58 
8.2.2 
Primary Analysis .............................................................................. 58 
8.2.3 
Safety Analysis .................................................................................. 60 
8.2.4 
Baseline Characteristics ................................................................... 60 
8.2.5 
Interim Analysis ................................................................................ 60 
8.2.6 
Handling of Missing Data ................................................................ 60 
8.3 
RANDOMIZATION ....................................................................................... 60 
8.4 
DETERMINATION OF SAMPLE SIZE ..................................................... 61 
9 
ADMINISTRATIVE MATTERS .............................................................................. 62 

 
 
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9.1 
ETHICS ............................................................................................................ 62 
9.1.1 
Institutional Committee Review and Communications ................ 62 
9.1.2 
Informed Consent and Subject Information .................................. 62 
9.2 
DATA MANAGEMENT AND RECORDKEEPING .................................. 63 
9.2.1 
Drug Accountability ......................................................................... 63 
9.2.2 
Data Management ............................................................................. 63 
9.2.3 
Source Documents ............................................................................ 64 
9.2.4 
Direct Access to Source Data/Documents ....................................... 65 
9.2.5 
Trial Monitoring ............................................................................... 65 
9.3 
QUALITY ASSURANCE AUDIT ................................................................. 66 
9.4 
PROCEDURES ............................................................................................... 66 
9.4.1 
Adverse Events .................................................................................. 66 
9.4.2 
Serious Adverse Events .................................................................... 67 
9.4.3 
Follow-up of Adverse Events ........................................................... 69 
9.4.4 
Evaluating Adverse Events .............................................................. 69 
9.4.5 
Expected Adverse Events ................................................................. 70 
9.4.6 
Pregnancy .......................................................................................... 71 
9.5 
RULES FOR AMENDING PROTOCOL .................................................... 71 
9.6 
FINANCIAL DISCLOSURE ......................................................................... 71 
9.7 
STATEMENT OF CONFIDENTIALITY .................................................... 72 
9.8 
FINAL REPORT AND PUBLICATION POLICY ..................................... 72 
9.9 
ARCHIVING ................................................................................................... 72 
10 
REFERENCES ............................................................................................................ 73 
11 
APPENDICES ............................................................................................................. 77 
12 
SIGNATURE PAGE ................................................................................................... 78 
 
 
 
 
 
 
 
 
 

 
 
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1 
STUDY FLOW CHART  
 
 
 

 
 
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2 
INTRODUCTION 
2.1 
MEDICAL BACKGROUND 
Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease 
(Angulo, 2002; Wieckowska and Feldstein, 2005) with an estimated global prevalence of 25% 
(Younossi et al., 2015). The severity of NAFLD ranges from simple hepatic steatosis to 
nonalcoholic steatohepatitis (NASH) and around 7–30% have NASH, of which 10–20% 
progress to liver cirrhosis, for which the only treatment is liver transplantation (LT) (Younossi 
et al., 2015). 
Non-alcoholic steatohepatitis is now the fastest growing and second most etiology of liver 
disease among new waitlist registrants for LT. Simultaneously to this course, the development 
and or recurrence of NASH after LT is certain to impose significant challenges. The genetic 
predisposition, immunosuppressive regimen and metabolic syndrome risk factors all play a 
role in the development of NAFLD/NASH after LT. In fact, NAFLD tends to recur 90% of 
the time after LT (Bhati et al. 2017) and patients with post-LT are at much higher risk of 
metabolic conditions such as diabetes, hypertension, hyperlipidemia and obesity. These 
metabolic conditions pose considerable risk to LT patients with NAFLD as these conditions 
or linked to post-LT mortality.  
Generally, 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. Moreover, a multidisciplinary approach is 
required to manage transplanted patients with NASH, which include cardiovascular medicine, 
endocrinology, surgery, nutrition, and behavioral psychology, etc., to reduce identified risk 
factors.   
2.2 
RATIONALE FOR CONDUCTING THE STUDY 
Saroglitazar magnesium is a novel predominately PPAR agonist and moderate PPARγ 
agonist. Pre-clinical studies with Saroglitazar magnesium using various animal models 
wherein, EC50 of PPARα: PPARγ >300; favorably modulated the lipid and glucose profile. 
Extensive preclinical safety pharmacology, pharmacokinetics and toxicological studies of 

 
 
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Saroglitazar magnesium showed favorable results. It was found to have superior or equivalent 
safety and efficacy profile compared to marketed fibrates or thiazolidinediones (TZDs) in pre-
clinical studies.  
PPARα activation by Saroglitazar magnesium increases the hepatic oxidation of fatty acids 
(FA) and reduces the synthesis and secretion of 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 LDL cholesterol. PPARα activation by Saroglitazar magnesium 
also induces an increase in the synthesis of apolipoproteins, A-I, A-II and 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 post-absorptive 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. 
Peroxisome proliferator-activated receptors (PPARs), the largest family of nuclear receptors, 
are now a prime focus of NAFLD/NASH research. There are three subtypes, PPAR-α, γ and 
δ. Upon receptor activation, all bind the retinoid X receptor (RXR) to form transcriptionally 
active heterodimers. PPARα is primarily expressed in tissues that use fatty acids as a fuel, such 
as the liver, muscle, heart and kidneys. In contrast, PPARγ is found predominantly in adipose 
tissue where it mediates differentiation of pre-adipocytes (adipogenesis), lipid storage and 
insulin action. 

 
 
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 PPARα is central to hepatic lipid homeostasis. When hepatic fatty acid levels increase, 
PPARα is activated, leading to transcription of such genes as liver fatty acid binding protein 
(LFABP), acyl-CoA oxidase (ACO), cytochrome P450 (CYP) 4A, microsomal triglyceride 
transfer protein (MTTP) and apolipoprotein B100 (apoB100). The net effect is catabolism and 
clearance of fatty acids. It has recently been appreciated that the liver may respond to newly 
synthesized fatty acids differently from those 'recycled' from peripheral stores, and this 
discrimination is mediated by selective effects on PPARα. This may explain why PPARα 
activation does not appear to occur as an adaptive response in fatty liver disease, when it would 
be an effective pathway to enhance insulin sensitivity and suppress inflammatory recruitment. 
Thus, while pharmacologic PPARα activation effectively 'cured' fibrosing steatohepatitis in a 
murine, dietary model, the efficacy of such agents is less clear in humans. PPARγ is found 
predominantly in adipocytes. It has both opposite and complementary functions to PPARα. 
Thus, PPARγ activation leads to differentiation of adipocytes from pre-adipocytes in-vitro. 
This increases the lipid storage capacity of the adipose mass, and in animals, also increases 
the number of small, insulin-sensitive adipocytes so as to improve insulin sensitivity. 
Increasingly, the importance of PPARγ is being recognized in the liver, despite the relatively 
low levels of expression normally found there. Steatosis is often associated with increased 
hepatocyte expression of PPARγ. 
Therefore, peroxisome proliferator-activated receptor (PPAR) agonists are known to lower 
high blood triglyceride levels (PPARα agonists) and improve insulin resistance (PPARγ 
agonists), and may offer a potential treatment not only for patients with NAFLD or NASH but 
also for post liver transplant NAFLD/NASH. 
2.3 
DRUG PROFILE 
Several research groups have developed or are attempting to develop dual PPARα/γ agonist, 
some of which may eventually reach desirable clinical efficacy and safety end point. But if the 
agonist has higher PPARγ binding properties then several of the side effects such as edema, 
weight gain, bone effects and cardiovascular complications may occur. Therefore, there has 
been an increasing interest to develop new molecular entities which can treat insulin 
resistance, lower plasma glucose in diabetic patients and improve lipid profile without weight 
gain and cardiovascular risk. 

 
 
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information about a given subject’s response to this therapy could guide their clinician in 
making long-term therapeutic decisions. Thus, a potential benefit of the study is to determine 
the safety, tolerability and efficacy among subjects. As for risk, the protocol is designed to 
minimize the risks to participants while maximizing the potential value of the knowledge it is 
designed to generate. On balance, we believe there is a reasonable prospect for individual and 
generalized benefit when compared to the risk of participation.  
 

 
 
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3 
STUDY OBJECTIVES 
The objective of this study is to evaluate the safety, tolerability and efficacy of Saroglitazar 
magnesium in liver transplant recipients with NAFLD. 
3.1 
PRIMARY OBJECTIVE 
To assess the safety of Saroglitazar magnesium 4 mg in liver transplant recipients with 
NAFLD over 24 weeks of treatment. 
3.2 
SECONDARY OBJECTIVES 
1 Changes in hepatic fat as determined by MRI-PDFF and MRE from baseline to end of 
treatment (EOT). 
2 Changes in metabolic flexibility from baseline to EOT. 
3 Changes in markers of insulin resistance [frequently sampled intravenous glucose 
tolerance test (FSIVGTT), glycosylated hemoglobin (HbA1c) and fructosamine] from 
baseline to EOT.  
4 Changes in serum liver enzymes from baseline to EOT.  
5 Changes in serum lipids from baseline to EOT. 
6 Changes in atherogenic lipoprotein which including small dense low-density 
lipoprotein (sdLDL), LDL size and concentration, subtypes of very low-density 
lipoprotein (VLDL), high-density lipoprotein (HDL) from baseline to EOT. 
7 Change in Quality of life score from baseline to EOT. 
8 Pharmacokinetics of Saroglitazar following first dose and last dose. 
9 Body composition: changes in adipose tissue and skeletal muscle volume by whole 
body MRI. 
3.3 
SAFETY ASSESSMENT 
1 Vitals: blood pressure, pulse rate, oral temperature, respiratory rate.  
2 The physical examination will consist of an evaluation of the head, neck, eyes, ears, 
nose, throat, chest, heart, lungs, abdomen, skin, extremities, and the neurological and 
musculoskeletal systems. 
3 Body weight. 
4 Laboratory assessment 

 
 
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 Hematology: hematocrit, hemoglobin, mean corpuscular hemoglobin concentration 
(MCHC), mean corpuscular volume (MCV), platelet count, mean platelet volume 
(MPV), red blood cell (RBC) count, white blood cell (WBC) count, differential 
WBC count. 
 Lipid profile: total cholesterol (TC), triglycerides (TG), high-density lipoprotein 
(HDL), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL) and 
non-HDL. 
 Liver function tests (LFTs): aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (with 
Conjugated bilirubin), gamma-glutamyltransferase (GGT), total protein and 
albumin.  
 Amylase and lipase 
 Renal function tests (RFTs): blood urea nitrogen (BUN), serum creatinine, and 
estimated glomerular filtration rate (eGFR).  
 Coagulation panel: activated partial thromboplastin time (APTT), prothrombin 
time/international normalized ratio (PT/INR), thrombin time (TT). 
 Immunosuppression level (tacrolimus, cyclosporine or sirolimus). 
 Gut hormones: Ghrelin, glucagon like peptide, leptin, resistin, and adiponectin 
 Glycemic control: HbA1c and fasting plasma glucose. 
 Urinalysis: urine examination: physical examination (appearance, color, specific 
gravity and pH); microscopy (epithelial cells, red blood cells, pus or white blood 
cells, casts and crystals) and chemical examination (protein, glucose, bilirubin, 
urobilinogen, ketone bodies, nitrite and blood); urine drug test (at screening). 
 Creatine phosphokinase (CPK),  CK-MB, troponin 1 and NT-proBNP.  
 Serum electrolytes: sodium, potassium, calcium, bicarbonate and chloride. 
 Serology: human immunodeficiency virus (HIV) type 1 and type 2, HAV IgM, 
hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), CMV (IgG), and 
EBV VCAIgG. 
 Pregnancy test: Serum pregnancy test and urine pregnacy test for women of 
childbearing potential. 

 
 
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5 Cardiac function: standard 12-lead electrocardiogram (ECG) and 2D echocardiogram 
(2D ECHO).  
6 Adverse event(s): Frequency and severity of AEs /serious adverse events (SAEs), drop-
outs due to AEs/SAEs for all subjects enrolled will be recorded. AE’s will be assessed, 
and reported as appropriate, in accordance with applicable sections of the U.S. Code of 
Federal Regulations, Title 21 Part 312 for:  
 Causality (relatedness)  
 Severity 
 Seriousness 
 Expectedness 

 
 
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4 
STUDY POPULATION 
4.1 
NUMBER OF SUBJECTS PLANNED 
A total 15 subjects will be enrolled in this open-label, single-arm study to receive Saroglitazar 
magnesium 4 mg. Approximately 5 patients will be included in the pharmacokinetic 
assessment sub-study.  
4.2 
INCLUSION CRITERIA 
1. Able and willing to give written informed consent and comply with the requirements of 
the study protocol. 
2. Male or female, 18 to 75 years of age, both inclusive.  
3. Patients who are at least 6 months post liver-transplant with evidence of NAFLD in the 
liver graft. 
4. Presence of NAFLD determined by Transient Elastography (TE) with a controlled 
attenuation parameter (CAP) score cut-off at 263 dB/m prior to enrollment.  
5. Patients with ≤20% variation in the levels of ALT, AST, ALP and total bilirubin 
between Visit 1 and Visit 1.1, if either Visit 1 or Visit 1.1 laboratory results are 
elevated above the reference range. 
6. History of medical compliance with immunosuppression. 
7. Female subjects of non-child bearing potential or on highly effective contraception. For 
male subjects with female partners of childbearing potential, willing to follow highly 
effective contraception measures during the study, either by the male participant or his 
female partner or both. 
4.3 
EXCLUSION CRITERIA 
1. Pregnant or lactating females. 
2. Patient with abnormal transaminases due to secondary intercurrent illness (should be 
determined over a period within last 12 months prior to screening). 
3. Patients with clinically significant bile duct strictures as assessed with MRI and elevated 
liver enzymes during screening. 
4. Recurrence of non-NASH causes of chronic liver disease after liver transplantation 
including autoimmune, viral, medications associated with steatosis and steatohepatitis 
(e.g., amiodarone and doxycycline) and alcoholic liver disease that are clinically active. 

 
 
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5. Graft cirrhosis as defined by:  
I.Cirrhosis on historical liver biopsy. 
II.Evidence of cirrhosis on imaging including portal venous collaterals.  
III. Prior history of decompensated liver disease including ascites, hepatic 
encephalopathy or variceal bleeding. 
IV.Evidence of esophageal varices on prior endoscopy.  
6. Body mass index (BMI) <18 kg/m2. 
7. Subjects with change in body weight >5% in the 3 months prior to enrollment. 
8. Subjects requiring corticosteroid or anticoagulation therapy. 
9. History of myopathies or evidence of active muscle diseases. 
10. Unstable cardiovascular disease, including: 
i. 
Unstable angina (i.e., new or worsening symptoms of coronary heart disease 
within the past 3 months), acute coronary syndrome within the past 6 months, 
acute myocardial infarction in the past 3 months or heart failure of New York 
Heart Association class (III-IV) or worsening congestive heart failure, or 
coronary artery intervention, within the past 6 months. 
ii. 
History of (within prior 3 months) or current unstable cardiac dysrhythmias. 
iii. 
Uncontrolled hypertension (systolic blood pressure >160 mmHg and/or diastolic 
blood pressure >100 mmHg. 
iv. 
Stroke or transient ischemic attack within the prior 6 months. 
11. History of bladder disease and/or hematuria or has current hematuria unless due to a 
urinary tract infection. 
12. Active malignancy post-liver transplantation. 
13. History of malignancy in the past 5 years and/or active neoplasm with the exception of 
resolved superficial non-melanoma skin cancer. 
14. History of chronic rejection of liver transplant graft. 
15. Acute cellular rejection of liver transplant graft within the past 6 months.  
16. Evidence of Acute cellular rejection (ACR) or chronic rejection (CR) or alternative 
etiologies to NAFLD must be ruled out within 4-6 weeks prior to enrollment into the 
study by either a liver biopsy or at the discretion (clinical judgement and according to 
local standard of care) of the treating hepatologist.  
17. Any of the following laboratory values: 

 
 
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a. White blood cell count <2.5 x 103/uL 
b. Neutrophil count <1.5 x 103/uL 
c. Serum bilirubin >1.5 mg/dL 
d. Serum ALT >3X ULN 
e. INR >1.2 
f. Renal impairment as demonstrated by baseline estimated glomerular filtration 
rate (eGFR) <60 mL/min/1.73m2 
g. Abnormal screening total creatine kinase 
h. Abnormal screening lipase or amylase 
18. Poorly controlled diabetes as defined by an HbA1c >8.5% within the past 6 months. 
19. Subjects with history of excessive alcohol intake, defined by ≥21 units of alcohol per 
week in males and ≥14 units of alcohol per week in females for two years prior to 
enrollment, where a “unit” of alcohol is equivalent to a 12 ounce (oz.) beer, 4-oz. glass 
of wine, or 1-oz. shot of hard liquor. 
20. Subject tests positive for a urine drug screen. 
21. Subject has a history of chronic (uncontrolled) pain. 
4.4 
WITHDRAWAL CRITERIA 
The Investigator may withdraw a subject from the study for any of the following: 
1 Subject who reports an SAE and if considered in Investigator or Medical Expert’s 
opinion it is not in the subject’s best interest to continue. 
2 Any subject found to have entered the study in violation of the protocol. 
3 Termination of the study by the Sponsor or Principal Investigator (PI) or the regulatory 
authorities or Independent Ethics Committee/Institutional Review Board (IEC/IRB). 
4 The subject is lost to follow-up. 
5 Any subject who wishes to withdraw his/her consent for participation in the study.  
6 In case a subject becomes pregnant, then she will be withdrawn from the study. 
4.4.1 Screen Failure 
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 the 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 must 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 PI 
(or designee) will document on a screening log the reason for the screening failure. 
4.5 
HANDLING OF SUBJECT WITHDRAWAL 
In case of withdrawal of consent, and unless otherwise stated by the subject in the withdrawal 
of consent, PI(s) will be encouraged to obtain information from the subject in order to follow 
the medical status of the subjects (especially when the subject withdraws his/her consent after 
having experienced an AE/SAE or an efficacy endpoint). Principal Investigator or designee(s) 
must make reasonable attempts (at least 3 attempts, one of which will be via a 
certified/traceable mail) to contact subjects that are lost to follow-up, in order to obtain health 
status and reason for withdrawal. These attempts must be documented in the medical records. 
In addition, if patient withdraws from the study, any data collected during the period of time 
will maintained as part of the study data. 
 
 
 

 
 
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day of a scheduled clinic visit the subject has already taken the IP, all procedures except blood 
sample collections will be performed. The subject will be asked to return in fasting condition 
the next day to have the blood sample collected, and will be reminded not to take the IP until 
after the blood sample collections. If the subject again returns having taken the IP, blood 
samples will be collected and the subject will be asked to return for the next scheduled visit. 
5.3 
PACKAGING, LABELLING AND SUPPLY 
Tablets of Saroglitazar magnesium 4 mg will be packed, labeled and supplied by the Sponsor 
according to all local legal requirements. 
 
 
 
. The 
investigator designee will confirm the receipt of IP in writing via fax/email.  
The PI or designee will maintain an accurate record of the receipt of the study drug, including 
the dates received. Unused drug supplies will be returned to the Sponsor (or designee) for 
destruction/destroyed at the site after approval for the same by the Sponsor. No study drug 
will be destroyed or returned until complete drug accountability has been performed by the 
study monitor. All supplies must be accounted for at the end of the study period.  
Investigational product must be dispensed to each subject in such a way that the subject can 
take the doses in accordance with the Protocol. A Drug Accountability Log(s) for recording 
the receipt, dispensing and return of the IP must be maintained by the PI or any designated 
personnel. The Drug Accountability Log(s) must be kept up to date and must be made 
available to the study monitor during monitoring visits.  
5.4 
STORAGE CONDITIONS AND STABILITY 
Saroglitazar magnesium tablets will be stored at room temperature (20°C to 25°C or 68°F to 
77°F) in a dry place away from light at the study site or pharmacy. If the IP temperature 
extends outside the 20-25°C range, a temperature excursion must be documented in the study-
specific temperature log, and sent to the Sponsor. 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 goes beyond the range of 15-300 C it will be considered as a 

 
 
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protocol deviation. Protect the IP from light. All IP supplies in the study will be stored in a 
secure location with access limited to the Site Pharmacist or the PI designated site staff. 
5.5 
BLINDING 
This is an open-label study, therefore, PI and participants will be made aware what treatment 
they will be administered.  
5.6 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUP 
All subjects will receive Saroglitazar magnesium 4 mg. A screening number will be assigned 
at the site and will be used to identify the subject throughout the study and will be entered on 
all documentation. The Screening Number will be assigned in numerical order at the site. A 
subject number will not be assigned to more than 1 subject. If a subject is not eligible to receive 
treatment, or if a subject discontinues from the study, the Screening Number cannot be 
assigned to another subject. 
Subjects will be considered randomized as soon as the first allocation treatment number/drug 
kit is assigned. The first study drug intake should take place as soon as possible after 
randomization (on the same day), under medical supervision. In the event a subject is 
randomized but is not administered study drug, this will be considered an early termination, 
not a screen failure. The randomization number and subject drug kit will not be reassigned to 
another subject. 
5.7 
SELECTION OF DOSES 
Saroglitazar magnesium 2 and 4 mg have favorably modified the lipid profile and glycemia in 
the dyslipidemic patients with or without diabetes mellitus during its development in Phase 2 
and 3 studies. Considering the efficacy, safety and tolerability of Saroglitazar magnesium, it 
is approved in India at the doses of 2 mg and 4 mg QD for the treatment of “Diabetic 
Dyslipidemia” and “Hypertriglyceridemia with T2DM not controlled by statin therapy”. 
Saroglitazar magnesium 4 mg dose has shown favorable effects on lipid profiles and on liver 
enzyme levels, therefore, this dose has been selected for this study. 
5.8 
CONCOMITANT MEDICATION 
1. Standard of care for patients with LT will be allowed. These include management 
of immunosuppression per site’s transplant related protocol. Additionally, 

 
 
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management of metabolic co-morbidities such as diabetes, hypertension, 
hyperlipidemia and obesity will also be done as per local standard of care.  
2. Patient with stable doses of statins (simvastatin, pravastatin, atorvastatin, 
fluvastatin, lovastatin, and rosuvastatin) or fibrates (clofibrate, fenofibrate) will 
be allowed in the study; however, their doses should remain stable throughout the 
study period. 
5.8.1 Subjects on concomitant anti-diabetic medication 
Patients on anti-diabetic medication must be assessed at scheduled visits for 
hyperglycemia/hypoglycemia; rescue medication will also be permitted, if required. 
Patients on concomitant anti-diabetic medication will be provided with a glucometer and 
instructions for use. All point-of-care (POC) glucose measurements collected/documented by 
patients during the study period must be performed on the study-provided glucometer. The 
investigational site will download/record the data from glucometer/patient diary for 
assessment of glucose levels from the previous visit. 
The patients should monitor their glucose levels as follows: 
 
Fasting blood glucose should be measured on at least two different days in a week. 
These measurements should be done in the morning before having breakfast and when 
the patient has been fasting for a minimum of 10 hours. 
 
Spontaneous measurements of blood glucose should be done in the event the patient 
suffers from suspected hypoglycemia. The PI or designee should inform the patients 
on recognizing the symptoms of hypoglycemia (i.e. palpitations, tremor, diaphoresis, 
hunger and/or cognitive impairment) and instruct them on the actions to be taken in 
accordance with standard-of-care. 
The American Diabetes Association (ADA) recommends the following treatment for 
non-severe hypoglycemia during which a patient is willing and able to consume oral 
treatment: 
1. Consume 15-20 grams of glucose or simple carbohydrates 
2. Recheck your blood glucose after 15 minutes 
3. If hypoglycemia continues, repeat #1 & #2 
4. Once your blood glucose returns to a normal level, consume a small snack if 
your next planned snack or meal is greater than 1 hour in the future. 

 
 
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Examples provided by the ADA of items containing 15 grams of simple carbohydrates 
include: 
 
Glucose tablets (follow instructions on the package) 
 
Gel tube (follow instructions on the package) 
 
2 tablespoons of raisins 
 
4 ounces (1/2 cup) of juice or regular (non-diet) soda 
 
1 tablespoon of sugar, honey or corn syrup 
 
8 ounces of nonfat or 1% milk 
 
Hard candy, gumdrops or jellybeans (read package for amount to consume) 
In the event of severe hypoglycemia when a patient is unconscious and possibly 
seizing, and/or unable to safely ingest carbohydrates, do not attempt oral treatment. If 
glucagon is available, this should be administered as soon as possible. If glucagon is 
not available, it is not able to be administered or persons witnessing the event do not 
feel able to handle the situation, emergency medical personnel should be summoned 
via calling 911. 
Principal Investigator will advise patients to report all hypoglycemic episodes occurring 
during the course of the study as they will be recorded in the electronic Case Report Form 
(eCRF). 
Treatment for such conditions should be initiated as soon as the need for treatment is identified 
by the PI, in accordance with treatment guidelines and standard of care, and should be adjusted 
as necessary to treat the patient’s condition(s). All treatment with these drugs must be recorded 
in the eCRF. 
5.9 
STOPPING RULE(S) 
Safety and tolerability will be evaluated by the incidence, severity, and relationship to study 
intervention of any AEs and changes from baseline in laboratory test results, physical 
examination findings, and vital sign measurements, at any time after the subject has received 
study intervention. If continuous safety analysis reveals an adverse trend, the PI may halt the 
study independently, or in consultation with the IRB/Sponsor, as appropriate. Furthermore, if 
three or more subjects develop the same SAE related to the IP or a procedure, the study will 
be suspended until the safety review outcome, in consultation with the IRB/Sponsor.  

 
 
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5.9.1 Discontinuation of Patients from the Study Drug 
1 Discontinue patient with an AE of CTCAE grade 3 or higher that is possibly or probably 
related to IP and discontinue patient with an AE of CTCAE grade 4 regardless of 
attribution to IP. 
2 If any of the following criteria are met, the patient must be immediately discontinued from 
IP and followed until resolution of adverse events and laboratory values return to 
baseline/stable:- 
a. Total Bilirubin ≥3.0 mg/dL. 
b. Total CK >5 X ULN. 
c. Amylase or lipase >ULN. 
d. eGFR <60 mL/min/1.73 m2 and where the value is reconfirmed after 24 hours 
repeat. Additionally, any subject who requires renal replacement therapy should 
also be discontinued from IP. 
e. Hemoglobin <10 mg/dL or hematocrit <30%; platelets <100,000/µL; WBC <4 x 
103/uL. 
f. If troponin and CK-MB exceed the 99th percentile of the upper reference limit of 
the particular assay, serial labs should be obtained along with serial 12-lead ECGs, 
and cardiology should be consulted. If a patient has symptoms of dyspnea, edema, 
or a presumptive diagnosis of heart failure, NT-proBNP should be measured as 
close to the event as possible. 
3 The criteria for discontinuing or temporarily interrupting study drug with close monitoring 
are as follows:  
a. When the baseline measurements (BLM) are <2x ULN, discontinue if ALT or 
AST increases to >5x BLM. 
b. When the BLM ≥2X ULN but <5X ULN, discontinue if ALT or AST increases 
to >3X BLM. 
c. When BLM ≥5X ULN, discontinue if ALT or AST increases to >2X BLM. 
d. For ALT or AST increases to >2X BLM accompanied by a concomitant total 
bilirubin increase to >2X BLM OR an INR increase by >0.2. 

 
 
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e. For elevations of liver enzymes accompanied by symptoms consistent with 
hepatic injury [e.g., fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%)]. 
f. Temporarily interrupted treatment should be permanently discontinued for 
recurrence of laboratory abnormalities or symptoms following re-challenge. 
g. If a patient lives in a remote area, testing can be performed locally and the results 
communicated to the PI/site promptly.  
h. If patients develop elevations of AST or ALT >2 times baseline measure or total 
bilirubin >1.5 times BLM while on study, testing should be repeated within 48 to 
72 hours. Persistent elevations should be followed by repeat testing and physical 
examination 2-3 times per week with or without drug discontinuation. 
5.9.2 Termination of Clinical Study 
If the PI, the Sponsor or the Medical Monitor becomes aware of conditions or events that 
suggest a possible hazard to patients if the clinical study continues, the clinical study may be 
terminated after appropriate consultation among the involved parties, the Sponsor or Principal 
Investigator (PI) or the regulatory authorities or Independent Ethics Committee/Institutional 
Review Board (IEC/IRB). Also, the clinical study may be terminated at the Sponsor’s 
discretion in the absence of such a finding. 
Conditions that may warrant termination of the clinical study include, but are not limited to: 
 The discovery of a relevant unexpected or unacceptable risk to the patients enrolled in 
the clinical study; 
 Three patients develop the same AE of CTCAE Grade 3; 
 OR two patients develop any AE of CTCAE Grade 4; 
 OR one patient develops an AE of CTCAE Grade 5; 
 Failure to enroll patients at the required rate; 
 A decision of the Sponsor to suspend or discontinue development of the study drug.  
Should the study be terminated and/or the site closed for whatever reason, all documentation 
pertaining to the study and IP must be returned to the Sponsor. Any actions of the Contract 

 
 
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Research Organization required for assessing or maintaining patient safety will continue as 
required, despite termination of the study by the Sponsor. 
5.10 RESTRICTED MEDICATIONS 
 Patients are not permitted to take zileuton, vitamin E (>400 IU/day) or other drugs with 
potential effect on NAFLD/NASH such as ursodeoxycholic acid, S-
adenosylmethionine (SAM-e), betaine, pentoxifylline.  
 Patients are not permitted to take thiazolidinediones (pioglitazone, rosiglitazone), 
chemotherapy or other investigational medications during the study duration. 
 Concomitant use of strong CYP2C8 Inhibitors/Substrates will be prohibited. 
 Patients also should not take any non-allowed over-the-counter medications or 
complementary and/or alternative medications. 
5.11 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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. 
5.12 TREATMENT COMPLIANCE 
The patients will be asked to bring their bottles of the IP to the next visit; compliance for 
dosing will be assessed by examination of the bottles and tablet count by study personnel. 
Compliance will be documented on Individual drug accountability log(s). Study medication 
compliance <80% or >120% will be considered protocol deviations and require patients to be 
counselled on proper IP compliance. 

 
 
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6 
OBSERVATIONS 
6.1 
SAFETY  
6.1.1 Primary Endpoint 
The primary endpoint is to assess the safety of Saroglitazar magnesium 4 mg tablets in liver 
transplant recipients with NAFLD over 24 weeks of treatment.  
Safety will be assessed during the study period through the reporting of AEs, and by clinical 
laboratory tests and vital sign assessment at various time points during the study.  
6.1.2 Medical History and Demographic Information 
The medical history comprises: 
 Complete medical history 
 Medication history 
 Reproductive history 
The following demographic information will be recorded: 
 Gender  
 Age  
 Ethnic origin  
 Race  
 Height, without shoes  
 Body weight, without shoes  
 BMI  
6.1.2.1 Vital Signs 
The following vital signs will be assessed at time points described in the Schedule of 
Assessments (Table 1): 
 Sitting BP (systolic and diastolic; mmHg)  
 Pulse (beats per minute) 
 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. 

 
 
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6.1.2.2 Physical Examinations 
Physical examination will be performed in accordance with the Schedule of Assessments 
(Table 1). The physical examination will consist of an evaluation of the head, neck, eyes, ears, 
nose, throat, chest, heart, lungs, abdomen, skin, extremities, and the neurological and 
musculoskeletal systems. 
Patients’ body weight will be recorded during all physical examinations. Height will be 
recorded at Screening Visit only. 
6.1.3 Clinical Laboratory Assessments  
All biological samples, with the exception of pharmacokinetic samples will be assayed at 
Institution laboratory by using analytical methods in compliance with standard and validated 
methodologies, with adherence to written standard operating procedures (SOPs) of the 
Institution throughout the study duration.   
If multiple bioanalytical assay methods/local laboratories will be used, then cross-comparison 
among methods shall be performed to allow comparison of efficacy and safety 
parameters/values obtained by different assay methods. All laboratory tests done at the local 
laboratory will be per the site’s policies and SOPs. 
Details regarding the sample processing, handling, storage, and shipment of PK samples will 
be offered separately in the study-specific laboratory manual prior to the initiation of the trial. 
6.1.3.1 Sample Collection 
The total amount of blood drawn for each patient over the study will not exceed 500 mL. 
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. Blood 
samples will be collected for clinical laboratory testing at the time points indicated in the 
Schedule of Assessments (Table 1). Safety laboratory variables are listed in below mentioned 
Table 3. 
Table 3: Safety Laboratory Assessments 
Hematology  
Hematocrit, hemoglobin, MCHC, MCV, platelet count, MPV, RBC count, 
WBC count, differential WBC count 
Coagulation Panel: APTT, PT/INR ratio, TT.  

 
 
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Clinical chemistry  
 
Lipid profile: TC, TG, HDL, LDL, VLDL and non-HDL. 
Liver function tests: AST, ALT, ALP, total bilirubin (with Conjugated 
bilirubin), GGT, total protein and albumin 
Amylase and lipase 
Renal function tests: BUN, serum creatinine, eGFR  
eGFR will be calculated by using Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation. 
Creatine phosphokinase, CK-MB, troponin 1 and NT-proBNP 
Serum electrolytes: sodium, potassium, calcium, bicarbonate and chloride 
Gut hormones: Ghrelin, glucagon like peptide, leptin, resistin, and 
adiponectin 
HbA1c and fasting plasma glucose 
Serology  
 
HIV type 1 and type 2 HAV IgM, 
HBsAg 
HCV 
Immunosuppression level (tacrolimus, cyclosporine or sirolimus) 
CMV (IgG), and EBV VCAIgG 
Urinalysis  
Physical examination (appearance, color, specific gravity and pH); 
microscopy (epithelial cells, red blood cells, pus or white blood cells, casts 
and crystals) and chemical examination (protein, glucose, bilirubin, 
urobilinogen, ketone bodies, nitrite and blood) 
Urine drug testing 
Pregnancy test  
 
Serum pregnancy test for women of childbearing potential at the Screening 
Visit 1, and Visit 8. 
Urine pregnancy test will be performed on Visit 2 to7 and Visit 9. 
 
6.1.4 Twelve-lead Electrocardiograms and 2D ECHO 
A standard 12-lead electrocardiogram will be performed locally at the study site in accordance 
with the Schedule of Assessments (Table 1). Twelve-lead electrocardiogram recordings will 
be taken in triplicate at the Screening Visit and as a single recording at all other applicable 
visits. A 5-minute rest period in between vital signs and ECG measurements is recommended. 
A 2D ECHO will be performed at baseline and end of the treatment visit. 
6.1.5 Adverse events  
Adverse event reporting will begin after the informed consent has been signed and will 
continue until end of follow-up period. The Common Terminology Criteria for Adverse 
Event (CTCAE) (Version 4.03 or higher) system will be used for reporting and grading AEs. 
Please refer Section 9.4 for details description. 
All AEs will be captured in the AE eCRF. At a minimum, SAEs will be reported in the eCRFs 
as per the timelines defined in the Protocol in adverse event section.  
Serious adverse events reporting must comply with the concerned regulatory requirements and 
IEC/IRB reporting requirements. 

 
 
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Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the PI that may make it infeasible to perform the test. 
In these cases, the PI will take all steps necessary to ensure the safety and well-being of the 
patient. When a protocol required test cannot be performed the PI will document the reason 
and the corrective and preventive actions which he/she has taken to ensure that normal 
processes are adhered to as soon as possible. The study team will be informed of these 
incidents in a timely fashion. 
6.2 
EFFICACY  
Efficacy will be assessed through a number of exploratory endpoints. 
1 Changes in hepatic fat as determined by MRI-PDFF and MRE from baseline to EOT. 
2 Changes in metabolic flexibility from baseline to EOT. 
3 Changes in markers of insulin resistance FSIVGTT, HbA1c and fructosamine from 
baseline to EOT.  
4 Changes in serum liver enzymes from baseline to EOT.  
5 Changes in serum lipids from baseline to EOT. 
6 Changes in atherogenic lipoprotein which includes sdLDL, LDL size and 
concentration, subtypes of VLDL and HDL from baseline to EOT. 
7 Change in QoL score from baseline to EOT. 
8 Pharmacokinetics of Saroglitazar following first dose and last dose in liver transplant 
recipients with nonalcoholic fatty liver disease. 
9 Body composition assessment via change in adipose tissue and skeletal muscle volume 
from baseline to EOT by whole body MRI. 
6.2.1 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 

 
 
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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 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). The procedure will be conducted per the site’s policies and 
SOPs for the procedure which will be followed for the study. 
6.2.2 Controlled Attenuation Parameter (CAP) 
CAP based on FibroScan is a promising tool for noninvasive semiquantitative assessment of 
liver fat content (De Ledinghen V, 2012). CAP measures the ultrasound attenuation at the 
center frequency of the FibroScan M probe (3.5 MHz), with values range from 100 to 400 
dB/m. Besides CAP being able to provide an instantaneous assessment of liver steatosis, some 
advantages, such as quantificational accuracy and ease of performance (which provide for 
instantaneous results), as well as inexpensive cost and reproducibility are highlighted when 
compared with other imaging methods (De Ledinghen V et al, 2014). In a prospective study 
of 153 patients, the areas under the receiver operating characteristics curves of CAP for ≥5%, 
>33% and >66% steatosis were 0.79, 0.76 and 0.70, respectively (Myers RP et al, 2012).  
See below table for vibration-controlled transient elastography cutoff values for CAP 
(Siddiqui et. al. CGH 2019). This table indicates 263 dB/m cutoff value to optimize sensitivity. 
Steatosis 
grade: 
Non-event 
vs event 
Prevalence 
of event 
Cross-
validated 
AUROC  
(95% CI) 
Cut-off 
criteria 
Cut-off 
(dB/m) 
 
Sens 
Spec 
PPV 
NPV 
0 vs 1-3 
95% 
0.76  
(0.64, 0.89) 
Sens = 
90% 
263 
0.90 
0.35 
0.96 
0.15 
 
 
 
Spec = 
90% 
353 
0.29 
0.90 
0.98 
0.06 
 
 
 
Youden’s 
index 
285 
0.80 
0.77 
0.99 
0.16 
 
 
 
 
 
 
 
 
 

 
 
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0-1 vs 2-3 
58% 
0.70  
(0.64, 0.75) 
Sens = 
90% 
280 
0.90 
0.35 
0.64 
0.72 
 
 
 
Spec = 
90% 
367 
0.20 
0.90 
0.70 
0.46 
 
 
 
Youden’s 
index 
311 
0.77 
0.57 
0.70 
0.66 
 
 
 
 
 
 
 
 
 
0-2 vs 3 
27% 
0.58  
(0.51, 0.64) 
Sens = 
90% 
274 
0.90 
0.20 
0.29 
0.84 
 
 
 
Spec = 
90% 
380 
0.03 
0.90 
0.10 
0.72 
 
 
 
Youden’s 
index 
306 
0.80 
0.40 
0.32 
0.85 
6.2.3 Magnetic Resonance Elastography (MRE) 
Magnetic resonance elastography (MRE) is a dynamic elasticity imaging technique that uses 
mechanical waves to quantitatively assess the shear modulus or stiffness of tissues 
(Muthupillai et al., 1995).  
The three basic steps of this MRE are i) shear waves with frequencies ranging from 50 – 500 
Hz are induced in the tissue using an external driver, ii) the waves are imaged inside the body 
using a special MRI technique and iii) the resulting data are processed to generate quantitative 
images displaying the stiffness of tissue. The procedure will be conducted per the site’s 
policies and SOPs for the procedure which will be followed for the study. 
6.2.4 Whole Body MRI 
Body composition is linked to cardiometabolic health and will be evaluated in patients. 
Subjects will be scanned in a research-dedicated Phillips Ingenia 3.0T Omega HP Multi-
Transmit MRI scanner using 6-minute dual-echo Dixen Vibe protocol, providing a water and 
fat separated volumetric data set covering neck to knees. Acquired images will be analyzed 
for visceral adipose tissue, subcutaneous adipose tissue, thigh muscle volume, and muscle fat 
infiltration in the anterior thighs. Liver fat content will be quantified via proton density fat 
fraction as published previously (Linge et. al, 2018).   
6.2.5 Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) 
The Frequently Sampled Intravenous Glucose Tolerance Test assesses insulin sensitivity by a 
computed mathematical analysis of glucose and insulin dynamics. FSIVGTT consists of an 
intravenously administered bolus of glucose and an infusion of insulin 20 minutes after 

 
 
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glucose injection. Blood samples are collected periodically for total test duration of 120 
minutes. The procedure will be performed as per Institution standard operating guideline. 
6.2.6 Metabolic Flexibility 
Energy expenditure: The recording of the components of energy balance, i.e. energy intake 
and expenditure is extremely important to understand the individual’s response to 
pharmacologic or lifestyle modifications interventions. Yet, estimation of energy expenditure 
by equations, and food dietary recording are imprecise and subject to recall bias, respectively. 
The indirect calorimetry technique, by measuring the oxygen consumption allows a precise 
measurement of energy expenditure; additionally, the measurement of carbon dioxide 
production provides the opportunity of measuring the respiratory quotient (RQ) and in turn 
calculating the substrate utilization (carbohydrate vs. fat). Virginia Commonwealth University 
has a newly established indirect calorimeters suite with two whole room indirect calorimeters, 
a small 4’x8’ “flex room” for short term studies and a larger 10’x10’ room, fitted with hospital 
bed, sink, and toilet which allows long-term studies. Additionally, recent improvements in the 
data acquisition algorithm allow the recording of acute changes in energy expenditure. By 
coupling minute by minute measurements of energy expenditure with wearable sensors able 
to capture spatial movements, researchers have the unique opportunity to precisely measure 
the energy expenditure in its components. Finally, by providing study meals with known 
calorie content and macronutrient composition researchers are also able to control the energy 
intake arm of the energy balance equation (Galgani and Ravussin, 2008). 
Metabolic Flexibility: The switch from carbohydrate oxidation to lipid oxidation defined as 
a drop in RQ during an overnight fasting is one of the gold-standard measures to assess 
metabolic flexibility. Insulin-resistant and T2DM patients are characterized by a metabolic 
inflexibility, which is associated with even worse insulin resistance, and they typically present 
with an impaired drop in RQ overnight (higher RQ), defining metabolic inflexibility, and 
specifically metabolic inflexibility to lipids. A significant change in mean 14-hour RQ, as well 
as changes of the RQ area under the curve between baseline and the end of the intervention 
would suggest improvements in metabolic flexibility, which is associated with improved 
metabolic outcomes (Goodpaster and Sparks, 2017; Galgani et al., 2008).  

 
 
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6.2.7 Quality of Life Assessment 
6.2.7.1 SF-36 Health Survey 
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. 
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. 
6.2.8 Pharmacokinetics Assessment 
Pharmacokinetics of Saroglitazar will be assessed following first dose and last dose in liver 
transplant recipients with NAFLD. 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 3, 4, 5, 6 and 7. The sampling will be performed only in approximately 
5 patients participating in the PK evaluation. A separate PK manual will be created describing 
the detailed procedures for PK sample handling, storage, shipment, bioanalysis, quality 
oversight and reporting of data.  
The following pharmacokinetic parameters will be evaluated for first and last dose: 
a. Peak plasma concentration (Cmax) 
b. Time to reach peak plasma concentration (Tmax) 
c. Area under plasma concentration vs. time curve till the last time point (AUC0-t) 
d. Area under plasma concentration vs. time curve extrapolated to the infinity (AUC0-∞) 
after first dose 
e. Area under plasma concentration vs. time curve in a 24 h dosing interval (AUCtau) 
f. Elimination rate constant (λz) 
g. Elimination half-life (t1/2) 
h. Apparent volume of distribution (Vd/F) 
i. Apparent clearance (CL/F) 
j. Minimal or trough plasma concentration (Cmin) -for last dose only  
k. Accumulation index calculated as a ratio of AUCtau (last dose)/AUCtau (first dose) 

 
 
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l. Fluctuation index 
6.2.9 Appropriateness of Measurement 
The endpoints chosen for the given study [safety and efficacy] are appropriate for the 
assessment of outcome of the study. 
6.2.10 Abnormal Laboratory Findings 
In addition, a clinically significant value outside the normal or reference range in a routine 
safety assessment, such as clinical laboratory, vital signs or standard 12-lead ECG, and 2D 
ECHO may signify an adverse finding. Additional examinations or repetition of test will be 
performed as medically indicated. 
If the PI considers the abnormality as of major medical relevance, he/she should also record 
this as an AE. If the findings contribute to a clinical diagnosis (e.g. hepatitis in case of 
increased liver enzymes), this diagnosis should be recorded as an AE. 
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 
1. The test result is associated with accompanying symptoms, and/or 
2. The test result requires additional diagnostic testing or medical/surgical 
intervention, and/or 
3. The test result leads to change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment or other therapy, and/or 
4. The test result leads to any of the outcomes included in the definition of an SAE, 
and/or 
5. The test result is considered to be an AE by the PI or designee. 
For any abnormal test result that meets one of the above conditions except for the last 
condition, the PI or designee will provide a justification in the source documentation for not 
reporting the abnormal test finding as an AE. 
Each AE shall be evaluated for severity, seriousness, duration, resolution, action taken and its 
association with the study treatment. The participant may be withdrawn or terminated from 
the study depending on the seriousness of the AE(s). 
 
 

 
 
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7 
INVESTIGATIONAL PLAN 
7.1 
STUDY DESIGN AND PLAN 
This study is designed to evaluate the safety, tolerability and efficacy of Saroglitazar 
magnesium in liver transplant recipients with NAFLD.  
1. This study will be initiated only after obtaining the approval of IEC/IRB and clinical trial 
permission from the applicable regulatory agencies. 
2. It is the responsibility of the PI to ensure that the study is conducted in accordance with 
the protocol, with International Council for Harmonization Good Clinical Practice (ICH-
GCP), and with all other applicable regulatory requirements. Informed consent must be 
obtained from each study subjects before the start of any study-related procedures. 
3. All laboratory reports should be reviewed by the PI and/or his/her designee and any 
abnormal findings should be addressed. 
4. All protocol deviations/violations occurring in the study shall be documented and 
informed to the Sponsor and to the IEC/IRB in accordance with their standard 
procedures. 
5. This study consists of 3 Periods and a total 9 visits;  
a) 5-week Screening Period (Visit 1 and Visit 1.1) 
b) 24-week Treatment Period (Visit 2 to Visit 8) 
c) 4-week Follow-up Period (Visit 9) 
7.2 
STUDY PROCEDURES AT EACH VISIT 
Study Schedules: 
 
Visit 1, Screening Visit [Week -5; Day -35] 
 All patient will be required to sign and date the IRB/IEC approved ICF after all study-
related procedures have been explained by the PI/Designee and understanding the 
contents.  
  Patients will be screened to participate in the study based on eligibility criteria. 
 CAP 
 MRI (Whole Body + PDFF) and MRE will be performed at any point during screening 
but only after the assessment of Visit 1 laboratory results. The same will be considered 
for the baseline assessment. 

 
 
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 Patients demographics, complete medical history and prior medication history will be 
recorded. 
 Physical examination, height, body weight measurements, vital signs, laboratory 
assessments and standard 12-lead ECG recording will be performed to establish 
eligibility of the patient to participate in the study as per inclusion/exclusion criteria. 
 All laboratory investigations will be carried out after at least 10-hour fasting.  
 Laboratory parameters will be assessed as per Table 1 (Schedule of Events). 
 Serum pregnancy test will be performed for females of child-bearing potential. 
 AE assessment 
Visit 1.1, Screening Visit [Week -1; Day -7] 
 Liver enzymes (AST, ALT, ALP and total bilirubin) will be re-measured at least 4- 
week from Day -35 to determine eligibility. The variation in the levels of the repeat 
measures of serum ALT, AST, ALP and total bilirubin at Day -7 (Visit 1.1) must be 
≤20%, compared to the Day -35 (Visit 1) levels to be eligible for study entry.  
 AE assessment 
Visit 2, [Week 1; Day 1(±3 Days)] 
 Patients satisfying inclusion and exclusion criteria will be enrolled in the study.  
 Concomitant medication will be recorded. 
 Dietary assessment will be performed using Diet History Questionnaire (Appendix 2). 
 Physical examination, vital signs, body weight measurements, 12-lead ECG and 2D 
ECHO will be performed. 
 Metabolic flexibility and FSIVGTT will be performed.  
 Baseline safety and efficacy evaluation will be performed as per Table 1 (Schedule of 
Events), including AE assessment. A window of ±3 days will be given to perform 
baseline assessments. 
 Urine pregnancy test will be performed for females of child-bearing potential.  
 Quality of life assessments (SF-36 Health Survey) will be performed. 
 Pharmacokinetic samples will be drawn from applicable patients. 
 Dispensing of IP for the next four weeks. 
  Glucometer assessment for diabetic patient. 
 

 
 
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Visit 3, [Week 4; Day 29 (±3 Days)] 
 Concomitant medication will be recorded. 
 Physical examination, vital signs and body weight measurements will be performed. 
 IP bottles will be collected by the PI or designee for checking the compliance. 
 Dispensing of IP for the next four weeks. 
 Safety evaluation will be performed as per Table 1 (Schedule of Events), including AE 
assessment. 
 Pharmacokinetic sample will be drawn from applicable patients. 
 Urine pregnancy test will be performed for females of child-bearing potential. 
 Glucometer assessment for diabetic patient. 
Visit 4, [Week 8; Day 57 (±3 Days)] 
 Concomitant medication will be recorded. 
 Physical examination, vital signs and body weight measurements will be performed. 
 IP bottles will be collected by the PI or designee for checking the compliance. 
 Dispensing of IP for the next four weeks.  
 Safety evaluation will be performed as per Table 1 (Schedule of Events), including AE 
assessment. 
 Pharmacokinetic sample will be drawn from applicable patients. 
 Urine pregnancy test will be performed for females of child-bearing potential. 
 Glucometer assessment for diabetic patient. 
Visit 5, [Week 12; Day 85 (±3 Days)] 
 Concomitant medication will be recorded. 
 Physical examination, vital signs, body weight measurements and 12-lead ECG will be 
performed. 
 Dietary assessment will be performed using Diet History Questionnaire (Appendix 2). 
 IP bottles will be collected by the PI or designee for checking the compliance. 
 Dispensing of IP for next four weeks. 
 Safety and efficacy parameters will be assessed as per Table 1 (Schedule of Events), 
including AE assessment. 
 Pharmacokinetic sample will be drawn from applicable patients. 

 
 
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 Urine pregnancy test will be performed for females of child-bearing potential. 
 Quality of life assessments (SF-36 Health Survey) will be performed. 
 Glucometer assessment for diabetic patient. 
Visit 6, [Week 16; Day 113 (±3 Days)] 
 Concomitant medication will be recorded. 
 Physical examination, vital signs, and body weight measurements will be performed. 
 IP bottles will be collected by the PI or designee for checking the compliance. 
 Pharmacokinetic sample will be drawn from applicable patients. 
 Dispensing of IP for next four weeks. 
 Safety parameters will be assessed as per Table 1 (Schedule of Events), including AE 
assessment. 
 Urine pregnancy test will be performed for females of child-bearing potential. 
 Glucometer assessment for diabetic patient. 
Visit 7, [Week 20; Day 141 (±3 Days)] 
 Concomitant medication will be recorded. 
 Physical examination, vital signs, and body weight measurements will be performed. 
 IP bottles will be collected by the PI or designee for checking the compliance. 
 Dispensing of IP for next four weeks. 
 Safety and efficacy parameters will be assessed as per Table 1 (Schedule of Events), 
including AE assessment. 
 Pharmacokinetic sample will be drawn from applicable patients. 
 Urine pregnancy test will be performed for females of child-bearing potential. 
 Glucometer assessment for diabetic patient. 
Visit 8, [Week 24; Day 169 (±3 Days)] 
 Concomitant medication will be recorded. 
 Dietary assessment will be performed using Diet History Questionnaire (Appendix 2). 
 Physical examination, vital signs, body weight measurements, 12-lead ECG, 2D 
ECHO, MRI (Whole Body + PDFF) and MRE will be performed. 
 Metabolic flexibility and FSIVGTT will be performed.  
 IP bottles will be collected by the PI or designee for checking the compliance. 

 
 
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 Safety and efficacy evaluation will be performed as per Table 1 (Schedule of Events), 
including AE assessment. 
 Pharmacokinetic samples will be drawn from applicable patients. 
 Serum pregnancy will be performed for female of child-bearing potential. 
 Quality of life assessments (SF-36 Health Survey) will be performed. 
 Glucometer assessment for diabetic patient. 
Visit 9, [Week 28; Day 197 (±3 Days)] 
 Concomitant medication will be recorded 
 Physical examination, vital signs and body weight measurements will be performed. 
 Safety parameters will be assessed as per Table 1 (Schedule of Events), including AE 
assessment. 
  Urine pregnancy test will be performed for females of child-bearing potential. 
 Glucometer assessment for diabetic patient. 
Unscheduled visits  
Unscheduled visits are permitted at any time during the study at the discretion of the PI or 
designee for assessment and management of AEs and any concurrent clinical conditions, Data 
will be captured in the eCRF. 
If further investigations are required in case of any AE, PI will assess the AE and take 
necessary action, as required.  
Immunosuppression levels will be monitored on Day -1, Day 1, Day 3, Day 7 and Weekly 
(Days 14, 21 and 28) for first month. If the Immunosuppression levels remain stable as per the 
opinion of the transplant hepatologist, they will then be monitored on a monthly basis (Days 
57, 85, 113, 141 and 169) until the end of the study or as per the opinion of the transplant 
hepatologist/study investigator for clinical care. 
If due to any reason after randomization, the patient discontinues the study before the End of 
Study Visit, all procedures of End of Study Visit (Visit 9) should be carried out. 
7.3 
ADHERENCE TO PROTOCOL 
The PI and the site staff shall strictly adhere to the protocol and GCP guidelines. All patients 
will be strictly required to follow the instructions given to them as per this protocol. For any 

 
 
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deviation or violation from the protocol, considered serious, the patient may be withdrawn 
from the study at the discretion of the Sponsor or the PI. 
7.4 
PROTOCOL DEVIATION 
For the purpose of this study, no distinction will be made between Protocol Violations and 
Deviations. Deviations will be categorized as Clinical Study Report (CSR) non-reportable 
protocol deviations and as CSR reportable protocol deviations. A CSR non-reportable protocol 
deviation includes any deviations that do not necessarily influence the results/outcome of 
primary endpoints or patient safety. A CSR non-reportable protocol deviation does not require 
immediate notification to the IEC/IRB, unless otherwise specified by IEC/IRB requirements. 
All CSR non-reportable protocol deviations will be noted in monitoring reports and provided 
to the PI by monitor. 
A CSR reportable protocol deviation includes any violation that may influence the 
results/outcome of primary endpoints or patient safety. CSR reportable protocol deviations 
must be reported immediately to the IEC/IRB, as specified by the IEC/IRB requirements. All 
CSR reportable protocol deviations will also be reported to the Sponsor immediately. These 
deviations will also be noted in the monitoring reports and provided to the PI by monitor. 
Note: Persistent non-compliance of CSR non-reportable protocol deviations may rise to the 
level of being considered CSR reportable protocol deviations (i.e., persistent non-compliance 
with dosing). 
The Sponsor reserves the right to terminate the study at a given site in the event of monitoring 
and/or auditing findings of serious or persistent non-compliance with the protocol, SOPs, 
GCP, and/or applicable regulatory requirement(s) by the PI/institution. In all cases of site 
closure due to protocol deviations, the IEC/IRB and regulatory authorities will be informed. 
The CSR will provide the list of protocol deviation/violations in a separate section. The result 
will be analysed for all participants with CSR reportable protocol deviations.  
Protocol deviations/violations will include but are not limited to the following: 
 Patients that did not meet entry criteria but are enrolled into the study; 
 Patients that received the wrong treatment or incorrect dose; 
 Patients that received an excluded medication; 
 Patients that met the discontinuation criteria but continued in the study; 
 Failure to report within specified time lines of the planned visits; 

 
 
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 Failure to perform a study procedure/assessment; 
 IP non-compliance (<80% or >120%). 
7.5 
DATA MONITORING COMMITTEE 
As per DMC charter, an independent external Data Monitoring Committee (DMC) will 
monitor the study for safety events. The DMC will have a formal structure and will operate 
according to a previously agreed upon remit. Safety data will be reviewed regularly by a DMC. 
The DMC will meet on an ad hoc basis if there are at least 3 treatment-related AEs of CTCAE 
Grade ≥3 severity observed in the study. In the event of 2 similar treatment-related AEs of 
CTCAE Grade 4- or one treatment related AE of CTCAE Grade 5, the DMC will review the 
data and advise the Sponsor regarding stopping or continuing the study. 
7.6 
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 PI. A detailed CAC Charter and adjudication process will be described in a separate 
document. 

 
 
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8 
BIOSTATISTICS AND DATA MANAGEMENT 
8.1 
STATISTICAL DESIGN 
Statistical Analysis Plan (SAP) will be prepared and finalized prior to database lock. The SAP 
will include detailed statistical aspects of the efficacy and safety analysis. Statistical analysis 
will be performed using SAS® (version 9.4 or higher) (SAS Institute Inc., USA). 
8.2 
PLANNED ANALYSIS 
8.2.1 Population 
8.2.1.1 Safety population 
The safety population includes all enrolled patients who received at least single dose of IP. 
8.2.1.2 Modified intent-to-treat population (mITT) 
The modified intent-to-treat (mITT) population includes: 
1. All enrolled patients who received at least single dose of the IP. 
2. Appear for at least one post baseline visit. 
All secondary efficacy objectives will be analyzed using mITT population with post-baseline 
last observation carried forward (LOCF) as an imputation method for missing values.  
8.2.1.3 Per-protocol population (PP) 
The per-protocol population (PP) includes: 
1. All enrolled patients who meet all the inclusion/exclusion criteria 
2. Completed the study in compliance with the protocol 
3. Do not have any major protocol violations 
8.2.2 Primary Analysis 
The primary endpoint is to assess the safety of Saroglitazar magnesium 4 mg tablets in liver 
transplant recipients with NAFLD. 
Primary analysis will be carried out on safety population. 
All AEs observed during the study period will be listed and assessed for causality, severity 
and seriousness. All AEs will be summarized using the Medical Dictionary for Regulatory 
Activities (MedDRA) (version 19 or higher) by body system, frequency, severity, seriousness, 

 
 
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relationship to study drug and expectedness. Adverse events will be summarized by counts 
and percentages.  
8.2.2.1 Secondary Analysis 
Efficacy will be assessed through a number of exploratory endpoints which will be 
summarized at each time point, as appropriate. 
Following secondary endpoints will be analyzed: 
 Changes in hepatic fat as determined by MRI-PDFF and MRE from baseline to 
EOT. 
 Changes in metabolic flexibility from baseline to EOT. 
 Changes in markers of insulin resistance FSIVGTT, HbA1c and fructosamine 
from baseline to EOT.  
 Changes in serum liver enzymes from baseline to EOT.  
 Changes in serum lipids from baseline to EOT. 
 Changes in atherogenic lipoprotein which includes sdLDL, LDL size and 
concentration, subtypes of VLDL and HDL from baseline to EOT 
 Change in QoL score from baseline to EOT 
 Pharmacokinetics of Saroglitazar following first dose and last dose in liver 
transplant recipients with nonalcoholic fatty liver disease (Descriptive statistics 
will be provided as detailed in Section 6.2.6). 
 Body composition assessment via changes in adipose tissue and skeletal muscle 
volume from baseline to EOT by whole body MRI. 
 
The change from baseline will be determined as: 
Change = Post-baseline value – Baseline value. 
Change from baseline for efficacy variables will be summarized appropriately.  
All efficacy analyses will be based primarily on the mITT population and analyses based on 
the Per Protocol (PP) analysis set will be supporting.  
All continuous efficacy exploratory parameters will be analysed and summarized 
appropriately. These analyses will also be supported by descriptive summaries (n, mean, 
standard deviation, median, minimum and maximum). 

 
 
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8.2.3 Safety Analysis 
All safety analysis will be carried out on the safety population. The frequency tabulations of 
abnormal clinical laboratory values for the parameter will be presented by visit. All safety 
parameters (clinical laboratory testing, ECG, physical examination and vital signs) will be 
summarized using the following descriptive statistics: N, mean, median, standard deviation, 
minimum and maximum for continuous variables, and patient counts and percentages for 
categorical variables. 
8.2.4 Baseline Characteristics 
Demographic and baseline characteristics will be summarized as appropriate. Subject 
disposition and reason for withdrawal will be presented and summarized.  
Unless otherwise stated, all the continuous variables will be represented by n, mean, standard 
deviation, minimum, median and maximum. All the categorical variables will be presented as 
counts and percentages. 
8.2.5 Interim Analysis 
No interim analysis is planned for the study. 
8.2.6 Handling of Missing Data 
Clarifications, wherever possible, will be obtained from the PI or designee for any missing 
data or for any illegible entry, unused or unauthenticated data and this will be recorded in the 
data handling report before the final database lock.  
Patients who are discontinued from the study should be excluded from the PP analysis set. 
Any enrolled patient who is discontinued from the study for any reason and have at least a 
post-baseline efficacy data will be included in the mITT analysis set using post-baseline LOCF 
imputation method for missing values. No imputation method will be employed for drug 
concentration or PK parameters.  
8.3 
RANDOMIZATION 
As this is a single-arm study, a randomization schedule is not required. 

 
 
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8.4 
DETERMINATION OF SAMPLE SIZE 
Due to the exploratory nature of this study, no formal power calculations were used to 
determine sample size. The number of patients was chosen based on clinical experience with 
other similar proof of concept studies. Approximately 5 patients will be included in the 
pharmacokinetic assessment sub-study. 

 
 
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9 
ADMINISTRATIVE MATTERS 
The study will be carried out in compliance with the protocol, in accordance with the ICH 
Harmonised Tripartite Guideline for GCP and in accordance with applicable regulatory 
requirements. 
9.1 
ETHICS 
9.1.1 Institutional Committee Review and Communications 
The study will not be initiated before the protocol and the informed consent and patient 
information form have been reviewed and have received approval/favorable opinion from a 
registered IEC/IRB. Should a protocol amendment be made that requires central/IEC/IRB 
approval, the changes in the protocol will not be instituted until the amendment and revised 
informed consent (if appropriate) have been reviewed and received approval/favorable opinion 
from the IEC/IRB. A protocol amendment intended to eliminate an apparent immediate hazard 
to patients may be implemented immediately provided that the appropriate regulatory 
authorities and IEC/IRB are notified as soon as possible (no longer than 5 days) and an 
approval is requested. Modification only for logistical or administrative changes may be 
implemented immediately; however, both the IRB/IEC and the Regulatory Authorities will be 
notified as soon as possible. 
The constitution of the IEC/IRB must comply with the concerned regulatory requirements. A 
list of the IEC/IRB members, with names and qualifications, will be requested. If such a list is 
unavailable, the PI or designee must provide the name and address of the IEC/IRB along with 
a statement from the IEC/IRB that it is organised according to GCP and applicable laws and 
regulations. The IEC/IRB must also perform all duties outlined by the requirements of the 
regulatory agencies. 
9.1.2 Informed Consent and Subject Information 
Prior to patient participation in the study, written informed consent will be obtained from each 
patient (or the patient’s legally accepted representative) according to the regulatory and legal 
requirements of the participating country and site. Each signature must be dated by each 
signatory and the informed consent and any additional patient information form retained by 
the PI or designee as part of the study records. A signed copy of the informed consent and any 

 
 
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additional patient information must be given to each patient or the patient’s legally authorised 
representative. 
The patient must be informed that his/her medical records may be examined by authorised 
monitors or Clinical Quality Assurance auditors appointed by the Sponsor, by appropriate 
IEC/IRB members and by inspectors from regulatory authorities. 
Should a protocol amendment be made, the patient informed consent form and subject 
information form may need to be revised to reflect the changes to the protocol. It is the 
responsibility of the PI to ensure that an amended consent form is reviewed and has received 
approval/favorable opinion from the IEC/IRB, and that it is signed by all patients subsequently 
entered in the study and those currently in the study, if affected by the amendment. 
9.2 
DATA MANAGEMENT AND RECORDKEEPING 
9.2.1 Drug Accountability 
Drug supplies, which will be provided by the Sponsor, must be kept in a secure, controlled 
access storage area under storage conditions defined by the Sponsor. A temperature log must 
be maintained to make certain that the drug supplies are stored at the correct temperature. 
The PI and/or pharmacist must maintain records of the product’s delivery to the study site, the 
inventory at the site, the dispensation to each patient, and the return to the Sponsor or 
alternative disposition of unused product(s). These records will include dates, quantities, 
batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned 
to the IP(s) and study participants. The PI or designee will maintain records that document 
adequately that the patients were provided the doses specified by the protocol and reconcile 
all IP(s) received from the Sponsor. At the time of return to the Sponsor, the PI or designee 
must verify that all unused or partially used drug supplies have been returned by the clinical 
trial subject and that no remaining supplies are in the PI or site’s possession. 
9.2.2 Data Management 
9.2.2.1 Data Handling 
Data will be recorded by the PI or designee into eCRFs and reviewed by the study monitor 
during monitoring visits. The study monitor will verify data recorded in the EDC system 
against source documents. All corrections or changes made to any study data must be 
appropriately tracked in an audit trail in the EDC system. An eCRF will be considered 

 
 
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complete when all missing, incorrect, and/or inconsistent data has been accounted for, and the 
eCRF is signed by the PI. 
9.2.2.2 Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
9.2.2.3 Data Entry 
Data must be recorded in to the EDC system in a timely manner as the study is in progress. 
All site personnel must log into the system using their secure user name and password in order 
to enter, review, or correct study data. These procedures must comply with the appropriate 
international regulations. All passwords will be strictly confidential. 
9.2.2.4 Medical Information Coding 
For medical information, the following thesauri will be used: 
 Latest version of MedDRA for AEs and medical history, and 
 WHO Drug Dictionary for prior and concomitant medications. 
9.2.2.5 Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, 
will be referred to the investigative site for reconciliation/resolution through data queries. 
The eCRFs must be reviewed and approved/signed by the PI. 
9.2.3 Source Documents 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the PI’s site. Data reported on the 
eCRFs must be consistent with the source documents or the discrepancies must be explained. 
The PI or designee may need to request previous medical records or transfer records from 
another institution, depending on the study; also, current medical records – not just shadow 
charts – must be available. 

 
 
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The following data to be reported on the eCRF should be included and derived from source 
documents: 
 Subject identification (subject number, gender, date of birth/age) 
 Subject participation in the study (subject number, date informed consent given) 
 Dates of subject’s visits 
 Medical history 
 Medication history 
 AEs (onset and end) 
 SAEs (onset and end) 
 Originals or copies of laboratory results: All laboratory reports must be reviewed by 
the PI and/or his/her designee; any abnormal findings should be addressed. 
 Conclusion of subject’s participation in the trial. 
9.2.4 Direct Access to Source Data/Documents 
The PI/institution will permit study-related monitoring, audits, IEC/IRB reviews and 
regulatory inspections by providing direct access to all related source data/documents. Case 
report forms and all source documents, including progress notes and copies of laboratory and 
medical test results, must be available at all times for review by the Sponsor’s clinical trial 
monitor(s), auditor(s) and inspection by applicable regulatory authorities. The on-site monitor 
will review all eCRFs and ICFs. The accuracy of the data will be verified by reviewing the 
documents described in Section 9.2.3. 
All ECG’s will be conducted locally. A photocopy should be made of the ECG, and assessment 
of clinical significance should be conducted by site staff personnel delegated to do so. 
9.2.5 Trial Monitoring 
It is the responsibility of the Principal Investigator to ensure that the study is conducted in 
accordance with the protocol, with ICH GCP, and with all other applicable regulatory 
requirements and that valid data are entered into the eCRFs. 
To achieve this objective, the study monitor’s duties are to aid the PI, and at the same time, 
the Sponsor in the maintenance of complete, legible, well-organized and easily retrievable 
data. Before the enrolment of any subject in this study, the Sponsor or their designee will 
review with the PI and site personnel the following documents: protocol, Investigator’s 

 
 
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Brochure, eCRFs and procedures for their completion, informed consent process, and the 
procedure for reporting SAEs. 
The PI will permit the Sponsor or their designee to monitor the study as frequently as deemed 
necessary to determine that data recording and protocol adherence are satisfactory. During the 
monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is 
entered by the site, the monitor will review the data for safety information, completeness, 
accuracy, and logical consistency. Computer programs that identify data inconsistencies may 
be used to help monitor the clinical study. If necessary, requests for clarification or correction 
will be sent to PIs. The PI and his/her staff will be expected to cooperate with the monitor and 
provide any missing information. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring 
log. 
9.3 
QUALITY ASSURANCE AUDIT 
A quality assurance audit of this study may be conducted by the Sponsor or Sponsor’s 
designees. The quality assurance auditor must have access to all medical records, the study-
related files and correspondence, and the informed consent documentation that is relevant to 
this clinical trial. 
9.4 
PROCEDURES 
9.4.1 Adverse Events 
All AEs occurring during the course of the clinical trial from the signing of the informed 
consent onwards will be collected, documented, and reported to the Sponsor by the PI or 
designee according to the specific definitions and instructions detailed in this section. 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. 
Any medical condition already present at screening should not be reported as an AE unless 
the medical condition or signs or symptoms present at baseline changes in severity or 
seriousness at any time during the study. In this case, it should be reported as an AE. 

 
 
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Clinically significant abnormal laboratory or other examination (e.g. electrocardiogram) 
findings that are detected during the study or are present at screening and significantly worsen 
during the study should be reported as AEs. The PI will exercise his or her medical and 
scientific judgment in deciding whether an abnormal laboratory finding or other abnormal 
assessment is clinically significant. Clinically significant abnormal laboratory values 
occurring during the clinical study will be followed until repeat tests return to normal, 
stabilize, or are no longer clinically significant. Any abnormal test that is determined to be an 
error does not require reporting as an AE. 
9.4.2 Serious Adverse Events 
A serious adverse event is any AE occurring at any dose or during any use of Sponsor's product 
that: 
 Results in death; 
 Is life threatening; 
 Results in persistent or significant disability/incapacity; 
 Results in inpatient hospitalization or prolongs an existing inpatient 
hospitalization; 
 Is a congenital anomaly/birth defect; 
 Is another important medical event that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
Serious Adverse Event Reporting-Procedures for Investigator:  
Initial Reports: 
Any SAE, or follow-up to a SAE, including death due to any cause that occurs to any subject 
from the time the consent is signed through 4-week following cessation of treatment, whether 
or not related to the Sponsor's product, must be reported to the Sponsor within 24 hours of the 
knowledge of the occurrence to investigational site. 
Additionally, any SAE, considered by the PI or designee, who is a qualified physician, to be 
related to the Sponsor’s product, that is brought to the attention of the PI or designee at any 

 
 
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9.4.3 Follow-up of Adverse Events 
All AEs experienced by a patient, irrespective of the suspected causality, will be monitored 
until the AE has been resolved, any abnormal laboratory values have returned to baseline or 
stabilized at a level acceptable to the PI and Medical Expert(s), until there is a satisfactory 
explanation for the changes observed, until the patient is lost to follow-up, or until the 
patient has died. 
9.4.4 Evaluating Adverse Events 
Each AE will be assessed by the PI or a medically-qualified investigator with regard to the 
following categories: 
Severity  
The PI or designee 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 eCRF. The Common 
Terminology Criteria for Adverse Event (CTCAE) (Version 4.03 or higher) system will be 
used for reporting and grading AEs severity of events not classified in CTCAE 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 or designee 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 eCRF. 
Causal relationship will be classified according to the following criteria: 
 Unrelated 

 
 
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 Possibly related: Suggests that the association of the AE with the study drug is 
unknown. However, the AE is not reasonably supported/explained 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/results in death  
 Unknown 
9.4.5 Expected Adverse Events 
Adverse events reported by 2% or more patients treated with Saroglitazar magnesium during 
the double-blind, active-controlled study with pioglitazone as the comparator regardless of 
causality included gastritis and asthenia. In the double-blind placebo controlled study, AEs 
reported by 2% or more patients treated with Saroglitazar magnesium included gastritis, 
dyspepsia, pyrexia and pain. The details of AE(s) experienced during the Saroglitazar 
magnesium studies are mentioned in the IB. Principal Investigator(s) are advised to provide 
protocol education for patients and caregivers for potential symptoms of adverse effects that 
should be reported to the site/PI, such as skeletal muscle pain, weight gain, peripheral edema, 
shortness of breath, hypoglycaemia, etc.   

 
 
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9.4.6 Pregnancy 
At the Screening Visit and the End of treatment Visit every female subject of childbearing 
potential will be tested for serum pregnancy test and urine pregnancy test will be performed 
at other visits. Women are advised not to become pregnant during the study and for at least 4- 
week after the end of the treatment period. Adequate contraceptive measures shall be used to 
prevent pregnancy. Even when contraceptive methods are used, there is a small risk that 
pregnancy might occur. In case a patient becomes pregnant, then she will be withdrawn from 
the study and adequate monitoring of the patients will be conducted. 
Although pregnancy and lactation are not considered AEs, it is the responsibility of the PI or 
their designees to report any pregnancy or lactation in a patient (spontaneously reported to 
them) that occurs during the study. All patients 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 events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
The PI or designee should report the pregnancy to the Sponsor within 24 hours of being 
notified. The Sponsor will then forward the completed Exposure-in-Utero form to the PI.  
9.5 
RULES FOR AMENDING PROTOCOL 
All amendments must be documented, dated and signed by all signatories (or their successors) 
of the original protocol and then will be submitted to Regulatory Authorities/IEC/IRB. 
Modification only for logistical or administrative changes may be implemented immediately; 
however, both the IEC/IRB and the Regulatory Authorities will be notified immediately.  
9.6 
FINANCIAL DISCLOSURE 
The PI and sub-investigators are required to provide financial disclosure information to the 
Sponsor to permit the Sponsor to fulfil their obligations. In addition, the PI/sub-investigator 
must commit to promptly update this information if any relevant changes occur during the 
study and for a period of 1 year after the completion of the study. 

 
 
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9.7 
STATEMENT OF CONFIDENTIALITY 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions of participating 
physicians and site personnel, the Sponsor’s representatives, to the IEC/IRB and the regulatory 
authorities as required under the law. Subject confidentiality will be further ensured by 
utilising subject identification code numbers to correspond to treatment data in the computer 
files. 
Such medical information may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. 
Data generated as a result of this study are to be made available for inspection on request by 
participating physicians, the Sponsor’s representatives, by the IEC/IRB and the regulatory 
authorities. 
9.8 
FINAL REPORT AND PUBLICATION POLICY 
A report will be prepared by the Sponsor. It will include the tabulated raw data and the 
biostatistical report on the data. 
Zydus Discovery DMCC is, as much as possible, dedicated to support the process of free 
exchange of relevant scientific information. Any publication of the results of this study must 
be consistent with the ZYDUS publication policy. The rights of the PI and of the Sponsor with 
regard to publication of the results of this study are described in the Investigator agreement. 
9.9 
ARCHIVING 
Subject’s files, identification codes and other source data (including original reports of test 
results, dispensing logs and records of informed consent), IEC/IRB approval letter, 
correspondence and other documents pertaining to the conduct of the study will be kept as 
per the SOPs of the institution. No document pertinent to the study shall be destroyed without 
prior written agreement between the Sponsor and the PI. All documents should be preserved 
safely after the completion/termination of the study for at least a period of 5 years if it is not 
possible to maintain the same permanently. 
 
 

 
 
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25. Noureddin M, Lam J, Peterson MR, et al. Utility of magnetic resonance imaging versus 
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28. Yokoo T, Shiehmorteza M, Hamilton G, et al. Estimation of hepatic proton-density fat 
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29. Younossi ZM, Otgonsuren M, Henry L, et al. Association of nonalcoholic fatty liver 
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31. Wieckowska A, Feldstein AE. Nonalcoholic fatty liver disease in the pediatric 
population: a review. Curr Opin Petiatr. 2005;17(5):636-41. 
32. Linge J, Borga M, West J, et al. Body Composition Profiling in the UK Biobank 
Imaging Study. Obesity (Silver Spring). 2018 Nov; 26 (11):1785-1795. 
33. Siddiqui MS, Vuppalanchi R, Van Natta ML, et al. Vibration-controlled transient 
elastography to assess fibrosis and steatosis in patients with nonalcoholic fatty liver 
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11 APPENDICES 
Appendix 1: 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 
 
Appendix 2: NATIONAL INSTITUTES OF HEALTH- Diet History Questionnaire 
(https://epi.grants.cancer.gov/dhq2/forms/)