Conditions: Nonalcoholic Fatty Liver Disease
Keywords: Saroglitazar Magnesium Nonalcoholic Fatty Liver Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 4
Healthy volunteers: no

Brief summary:
Saroglitazar Magnesium 4 mg for NAFLD in People Living with HIV in the US

Detailed description:
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of Saroglitazar Magnesium for the Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in People Living with Human Immunodeficiency Virus (HIV) in the US

The four participants enrolled on version 3.0 protocol were terminated as the primary endpoint was revised from biopsy to an imaging-based approach in the subsequent protocol version 4.0. These changes were done due to recruiting challenges pertaining to biopsy. However, no participants were enrolled in the revised protocol (version 4.0) as, by then the decision to terminate the study was taken by the Sponsor considering the modifications in the internal R\&D focus and a revised commercialization strategy.

The version 3.0 protocol is dated 02/Jun/2022 and not 02/Jun/2023 as mentioned in the delayed result section erroneously, which cannot be corrected now as it is locked for editing.

Arms:
arm 1: Saroglitazar Magnesium 4 mg tablet orally administered once daily in the morning before breakfast without food, for the duration of treatment (24 weeks) arm 2: Placebo tablet orally administered once daily in the morning before breakfast without food, for the duration of treatment (24 weeks).

Interventions: intervention 1: Saroglitazar Magnesium 4 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects randomized to Saroglitazar Magnesium 4 mg arm will receive Saroglitazar Magnesium 4 mg treatment until the duration of treatment (24 weeks). intervention 2: Subjects randomized to Placebo arm will receive Placebo treatment until the duration of treatment (24 weeks).

Protocol document:
Prot_000.pdf: 
CLINICAL TRIAL PROTOCOL 
Saroglitazar Magnesium SARO.20.001 
CONFIDENTIAL 
Page 1 of 109 
Approved by: Dr. Deven Parmar 
Protocol No.: SARO.20.001 
Version No.: 4.0 
Clinical Trial Protocol 
Protocol No.: 
SARO.20.001 
Protocol Version 
Number and 
Date 
Version 4.0, 17/NOV/2023 
Reference IND 
No. 
154765 
Supersedes 
Protocol Version 
Number and 
Date 
Version 3.0, 02/JUN/2022 
Investigational: 
product(s) 
Saroglitazar Magnesium 
Scientific Title: 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial 
of Saroglitazar Magnesium for the Treatment of Nonalcoholic Fatty 
Liver 
Disease 
(NAFLD) 
in 
People 
Living 
with 
Human 
Immunodeficiency Virus (HIV) in the US 
Public Title: 
Saroglitazar Magnesium 4 mg for NAFLD in People Living with HIV 
in the US (SARONAPLUS) 
Clinical Phase: 
2a 
Sponsor 
Zydus Therapeutics Inc. 
73C Route 31N, Pennington 
New Jersey 08534, USA 
Sponsor’s 
Signatory 
Deven V Parmar MD, FCP 
NCT05211284


 
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Protocol Chair 
and Lead-
Principal 
Investigator 
 
 
 
 
 
 
 
 
  
 
 
Protocol Co-
Chair 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
Medical 
Monitors 
Taufik Momin, MD 
 
 
 
Clinical 
Laboratory 
Each site will use its local laboratory 
Data 
Management 
and Statistical 
Analysis: 
 
 
 
  


 
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Confidential 
This protocol is the property of Zydus Therapeutics Inc. and may not - 
in full or in part - be retrieved, passed on, reproduced, published or 
otherwise used without the express permission of Zydus Therapeutics 


 
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1. 
CLINICAL TRIAL PROTOCOL SUMMARY 
Name of Sponsor: 
Zydus Therapeutics Inc.  
73C Route 31N, Pennington 
New Jersey 08534, USA 
Name of Investigational product: 
Saroglitazar Magnesium 4 mg 
Name of active ingredient of investigational 
product 
Saroglitazar Magnesium 
Name of the comparator drug 
Placebo  
Name of active ingredient of comparator product 
Placebo 
Potential Indication 
NAFLD with HIV 
Study Participants 
NAFLD with HIV 
Number of Participants to be Randomized 
Approximately 120 
Number of site(s) 
Approximately 8 
Study Number: 
SARO.20.001 
Planned treatment Period 
24 Weeks  
Study Duration 
36 Weeks 
Title of study: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of 
Saroglitazar Magnesium, for the Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in 
People Living with Human Immunodeficiency Virus (HIV) in the US 
Clinical phase: 2a 
Background: 
Nonalcoholic fatty liver disease (NAFLD) is one of the most common types of chronic liver 
disease and the second leading cause for liver transplantation in the United States (US)[1, 2, 3].  
The severity of NAFLD ranges from nonalcoholic fatty liver (simple steatosis) to nonalcoholic 
steatohepatitis (NASH)[4,5]. NASH is the most severe form of NAFLD and is characterized by 
hepatocellular injury, inflammation and risk of progression to NASH-related cirrhosis and 
NASH-related hepatocellular carcinoma. NAFLD is also considered to be the hepatic 
component of the metabolic syndrome, which includes dyslipidemia, peripheral insulin 
resistance, obesity, type 2 diabetes mellitus (T2DM), and hypertension[4,5]. 
NAFLD in people living with human immunodeficiency virus (PLWH) is not well studied. 
Numerous studies have been conducted to further understand the diagnosis, mechanisms, 
progression, and therapies of NASH[6-10]. However, all of these studies have systematically 
excluded PLWH, as NAFLD in these patients was thought to be different from that in the general 
population due to HIV itself, antiretroviral therapy (ART), concomitant medications, and 
co-infections. This resulted in major knowledge gap regarding NAFLD in the setting of HIV. 
Prevalence of NAFLD in PLWH in the US is not well defined. NAFLD is projected to become 
the leading cause of liver disease in the aging HIV population[11] The reported prevalence of 
NAFLD in mono-infected PLWH ranges from 15% to 54% when assessed by imaging 
modalities and the vibration-controlled transient elastography (VCTE), and up to 73% in studies 






 
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Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in 
this study: 
1. History of significant alcohol consumption (defined as >2 drinks/day on average for 
men, >1 drinks/day on average for women) for at least 3 consecutive months (12 
consecutive weeks) within 5 year before screening (Note 1: 1 drink =12 ounces of 
beer, 8-9 ounces of malt liquor, 4 ounces of wine or 1 ounce of spirits/hard liquor. 
Note 2: Use sex assigned at birth for alcohol consumption limits). 
2. History of other acute or chronic liver disease, including, but not limited to 
autoimmune, primary biliary cholangitis, Wilson9s disease, alpha-1-antitrypsin 
deficiency, hemochromatosis, hepatitis B virus (HBV), and ongoing or recent (within 
the past 3 years) hepatitis C RNA positivity. (Exceptions: a. Participants with 
previously treated hepatitis C infection are eligible for consideration if their sustained 
virologic response was achieved more than 3 years prior to screening. The proportion 
of such participants in this trial will not exceed 25% of the study cohort. b. 
Participants with prior acute HBV infection that is resolved but currently do not have 
hepatitis B surface antigen (HBsAg) or detectable HBV Deoxyribonucleic acid 
(HBV DNA) are eligible). 
3. History of liver transplant. 
4. Liver biopsy or radiologic imaging consistent with the clinical presence of cirrhosis 
or portal hypertension at screening. 
5. Participants whose Visit 2 ALT, AST, or alkaline phosphatase (ALP) values exceed 
their Visit 1 values by more than 50%.  
Note: These participants will be required to have a third value measured at-least one 
week after V2, to assess for a trend. If the third value shows a continued increase 
g10% compared to the Visit 2 values, the participant is considered ineligible for 
randomization. 
6. Ongoing use of steatogenic medications or supra-physiologic hormonal therapies 
(exception: transgender women on stable dose [for g3 months] of feminizing 
hormonal therapy), within 3 months prior to screening until time of randomization 
or anticipated use of medications that cause significant changes in weight during the 
study period; (Refer Appendix 7 for 8List of Steatogenic Medications Or Supra-
Physiologic Hormonal Therapies Or Medications That Cause Significant Weight 
Change9). 
7. Uncontrolled type 2 diabetes mellitus, defined as HbA1c >9.5% at screening. 
8. Any of the following laboratory values at screening: 
a. ALT or AST >250 U/L. 


 
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b. Total bilirubin >1.5 mg/dL and direct bilirubin > 0.5 mg/dL (unless due to 
Gilbert9s disease or atazanavir use per the opinion of the site investigator). 
c. Platelet count <150,000/mm3. 
d. Estimated glomerular filtration rate (e-GFR) <60 mL/min/1.73m2 using the 
chronic kidney disease-epidemiology collaboration (CKD-EPI) equation 
(Refer Appendix 6 for 8CKD-EPI Calculator9). 
e. International normalized ratio (INR) >1.3. 
f. Albumin < 3.6 g/dL 
9. History of malignancy in the past 5 years and/or active neoplasm with the exception 
of superficial, non-melanoma, skin cancer. 
10. Unstable cardiovascular disease, including: 
a. Unstable angina, (i.e., new or worsening symptoms of coronary heart disease) 
and/or acute myocardial infarction within the 3 months preceding screening 
b. Acute coronary syndrome or coronary artery intervention, within the 3 months 
preceding screening  
c. Heart failure of New York Heart Association (NYHA) class (III-IV) or 
worsening congestive heart failure within the 6 months preceding screening.  
d. History of (within 3 months preceding screening) or current unstable cardiac 
dysrhythmias.  
e. Uncontrolled hypertension (systolic blood pressure [SBP] >155 mm Hg 
and/or diastolic blood pressure [DBP] >95 mm Hg) at screening. 
f. Stroke or transient ischemic attack within the 6 months preceding screening. 
11. Unstable pulmonary disease (based upon site investigator9s evaluation) at 
screening. 
12. Use of drugs that are known CYP2C8 inhibitors/substrates (Refer Appendix 2 for 
the 8List of Known CYP2C8 inhibitors/substrates9) in the last 28 days preceding 
screening. 
13. History of severe illness or any other conditions (such as poorly controlled 
psychiatric disease, active gastrointestinal conditions that might interfere with drug 
absorption, etc.) that require systemic treatment/or hospitalization, until participant 
either completes therapy or is clinically stable on therapy as per the opinion of the 
site investigator, for at least 7 days prior to screening. 
14. Use of thiazolidinediones or Telmisartan within 3 months prior to screening until 
time of randomization. 
15. Use of unstable doses of sodium-glucose cotransporter-2 (SGLT2) inhibitors (e.g. 
canagliflozin, empagliflozin, dapagliflozin, etc.), glucose0dependent insulinotropic 
polypeptide (GIP) and/or glucagon-like peptide (GLP)-1 agonists (e.g. semaglutide, 
exenatide, liraglutide, lixisenatide, tirzepatide etc.) within 6 months prior to 
screening until time of randomization. 


 
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16. Use of pentoxifylline, ursodeoxycholic acid, antioxidants such as vitamin E 
(>200 IU/day), glutathione, orlistat, betaine, or non-prescribed complementary 
alternative medications within 6 months prior to screening until time of 
randomization. 
17. Known allergy, sensitivity or intolerance to the study medication or formulation 
ingredients. 
18. History of any known bleeding disorder or coagulopathy. 
19. Any condition that in the opinion of the site investigator, would compromise the 
participant9s ability to participate in the study. 
20. Unstable doses of anti-diabetic agents, including sulfonylureas, biguanides or 
dipeptidyl peptidase-4 (DPP-4) inhibitors in the 3 months prior to screening until 
time of randomization. 
21. Unstable doses of lipid-lowering agents such as statins (e.g. simvastatin, pravastatin, 
atorvastatin, fluvastatin, lovastatin, rosuvastatin, etc.) or fibrates (clofibrate, 
Fenofibrate) in the 3 months prior to screening until time of randomization. 
22. Participant with weight change >5% within 6 months prior to screening until time 
of randomization. 
23. History of bariatric surgery or currently undergoing evaluation for bariatric surgery. 
24. Participation in another interventional clinical study and/or receipt of any other 
investigational medication within 3 months prior to screening  
25. History of COVID-19 infection in the last 30 days prior to screening. 
26. Pregnancy-related exclusions, include: 
 
a. Pregnant/lactating female (including positive pregnancy test at screening) 
b. Pregnancy should be avoided by male and female participants either by complete 
abstinence or the use of acceptable effective contraceptive measures for the duration 
of the study and for at least 1 month after the end of the study treatment. Refer 
Appendix 3 Contraceptive Guidance  
 
27. Participants having an absolute contraindication to MRI (eg., any implants, magnetic 
metals, cardiac pacemakers, neurostimulator) as per investigators9 discretion 
Trial Design: This phase 2a study is a randomized, placebo-controlled, double-blind, 
multicenter parallel-arm trial to evaluate the safety and efficacy of Saroglitazar Magnesium 
4 mg compared with placebo in NAFLD in PLWH. Eligible participants will be randomized in 
a 1:1 ratio to receive Saroglitazar Magnesium 4 mg or placebo. This study plans to enroll 
approximately 120 PLWH with NAFLD from within the catchment area of approximately 8 
participating clinical centers or community HIV practices in the US. The study will be conducted 
over a period of 36 weeks, including upto 8-week screening period, 24-week treatment period, 
and 4-weeks safety follow-up period (Figure 1 and Section 2 Schedule of Assessments). 
Participants will be evaluated at the study sites for 10 scheduled visits. 
• Screening: Week -8 (Visit 1) and Week -6 (Visit 2); Screening period will last up to 8 weeks. 
Visit 2 must occur at least 14 days after Visit 1. 


 
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• Randomization: Day 1 (Visit 3) can occur at any time point after visit 2 but within 8 weeks 
of screening period and participant can be randomized upon confirmation of eligibility 
criteria.  
• Treatment Period: Week 0 (Visit 3), Week 2 (Visit 4), Week 4 (Visit 5), Week 8 (Visit 6), 
Week 12 (Visit 7), Week 16 (Visit 8), Week 24/EOT (Visit 9).  
• Safety Follow-up: Week 28 (Visit 10) 
Participants will be monitored during the study at every visit for the development of any AEs, 
including treatment-emergent AEs and AEs of special interest (weight gain and DILI). 
The study scheme is provided in Figure 1. 
 
 


 
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Total Enrollment: 
Approximately 120 participants (60 in each of the Saroglitazar 
Magnesium 4 mg and Placebo arms) 
Test product: 
 
 Mode of 
administration: 
Saroglitazar Magnesium 4 mg tablets 
Oral (once daily in the morning before breakfast without food) 
Reference therapy: 
 
 Mode of 
administration: 
Placebo tablets 
Oral (once daily in the morning before breakfast without food) 
Duration of 
treatment:  
24 weeks 
Statistical Methods: 
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 software (version 9.4 or higher) (SAS Institute Inc., USA). 
Demographic characteristics and baseline characteristics will be summarized by treatment, 
subject disposition, reasons for withdrawal, or by any other variables, as appropriate. 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. 
The primary efficacy endpoint is the change from baseline in hepatic fat content at Week 
24/EOT as measured by MRI-PDFF.  
Comparison of change from baseline in hepatic fat content between Saroglitazar 4 mg and 
placebo will be evaluated using mixed models for repeated measures (MMRM) including visit 
and treatment as factors, baseline value as a covariate and an interaction term treatment x visit. 
The p-value for the treatment differences (Saroglitazar Magnesium versus Placebo), estimate 
of LSMEANS treatment difference (Saroglitazar Magnesium 3 Placebo), and the two-sided 
90% confidence interval of the LSMEANS difference will be generated from the MMRM 
model. Observed values and changes from baseline will be summarized descriptively at each 
visit for all continuous parameters.  
All continuous secondary and exploratory efficacy endpoints will be analyzed similar to the 
primary efficacy endpoints and the categorical variables will be analyzed using the chi-square 
test. All statistical analysis will be conducted at one-sided alpha of 0.05. 
All safety parameters will be summarized descriptively. 


 
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Sample Size Justification: 
The primary efficacy endpoint is the mean change from baseline in hepatic fat content assessed 
by MRI-PDFF at Week 24/EOT in PLWH with NAFLD. In a previously conducted Phase 2 
study in NAFLD participants, the mean change from baseline in hepatic fat content at Week 16 
in Saroglitazar 4 mg group was -4.2 (SD=6.2) and in Placebo was -0.3 (SD=5.7)[30]. 
Assuming a similar treatment effect on hepatic fat content in Saroglitazar 4 mg group at Week 
24/EOT in this study, a sample size of 102 participants (51 participants in each treatment arm) 
will provide 80% power to detect a treatment difference of at least 3 in change from baseline in 
hepatic fat content at Week 24 between Saroglitazar 4 mg and Placebo using a one-sided 5% 
level of significance based on two-sided t-test, assuming a common standard deviation of 6. 
Assuming a dropout rate of 15% at week 24, approximately 120 participants (60 participants in 
each treatment arm) will be randomized in a 1:1 ratio to receive either Saroglitazar 4 mg or 
placebo. 
Data and Safety Monitoring Board: 
For the trial, an external oversight will be provided by an unblinded Data and Safety Monitoring 
Board (DSMB). Further information on the DSMB review process will be provided in a separate 
charter of DSMB. 
Hepatic Safety Adjudication Committee: 
A separate blinded Hepatic Safety Adjudication Committee (HSAC) will be established. The 
committee will review, monitor and adjudicate possible cases of Drug Induced Liver Injury 
(DILI) in the study. 
 




 
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3. 
ABBREVIATIONS 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
API 
Active pharmaceutical ingredient 
APRI 
Aspartate aminotransferase to Platelet Ratio Index 
Apo 
Apolipoprotein 
ART 
Antiretroviral therapy 
AST 
Aspartate aminotransferase 
AUDIT 
The Alcohol Use Disorders Identification Test 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CAP 
Controlled attenuation parameter 
CBC 
Complete blood count 
CFRs 
Code of federal regulations 
CKD-EPI 
Chronic kidney disease-epidemiology collaboration 
CMH 
Cochran-Mantel-Haenszel 
CMP 
Comprehensive metabolic panel 
cGMP 
Current-Good Manufacturing Practices 
CI 
Confidence interval 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CRP 
C-reactive protein 
CSR 
Clinical study report 
CYP 
Cytochrome P-450 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic acid 
DPP-4 
Dipeptidyl peptidase-4 
DSMB 
Data and Safety Monitoring Board 
EC50 
Half maximal effective concentration 
EDC 
Electronic data capture 
e-GFR 
Estimated glomerular filtration rate 
ELF 
Enhanced liver fibrosis 
EOT 
End of Treatment 
EOS 
End of Study 
ET 
Early Termination 
FAST 
Fibroscan-AST  
FDA 
Food and Drug Administration 
FIB-4 
Fibrosis-4 index 


 
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GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GIP 
glucose0dependent insulinotropic polypeptide 
GLP 1 RA 
Glucagon-like peptide receptor agonist 
HAV IgM 
Hepatitis A virus immunoglobulin M 
HbA1c 
Glycosylated hemoglobin 
HBV 
Hepatitis B virus 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
HSAC  
Hepatic Safety Adjudication Committee  
HR 
Heart rate 
HR-QOL 
Health-related quality of life 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
The International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) 
ITT 
Intent-to-treat 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional review board 
IWRS 
Interactive Web Response System 
LDL 
Low-density lipoprotein 
LFT 
Liver Function test 
LoE 
Lack of Efficacy 
LPL 
Lipoprotein lipase 
LSM 
Liver stiffness measurement 
LSMEANS 
Least Squares Means 
MTD 
Maximum tolerated dose 
MAR 
Missing at random 
MI 
Multiple Imputation 
MNAR 
Missing not at random 
NAFLD 
Nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
Nonalcoholic steatohepatitis 
NFS 
NAFLD Fibrosis Score 
NYHA 
New York Heart Association 
ox-LDL 
Oxidized LDL 
PRO-C3 
Procollagen 3 
PPARs 
Peroxisome proliferator-activated receptors 
PLWH 
People living with human immunodeficiency virus 


 
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RIR 
Relative improvement ratio 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SF-36 
Short Form-36 
SGLT2 
Sodium-glucose cotransporter-2 inhibitors 
sIRB 
Single IRB 
SOPs 
Standard operating procedures 
SUSARs 
Suspected unexpected serious adverse reaction 
TBL 
Total bilirubin 
T2DM 
Type 2 diabetes mellitus 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse events 
TG 
Triglyceride 
ULN 
Upper limit of normal 
US 
United States 
VCTE 
Vibration-controlled transient elastography 
VLDL 
Very low-density lipoprotein 
WBC 
White blood cell 


 
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4. 
TABLE OF CONTENTS 
Contents 
1. 
CLINICAL TRIAL PROTOCOL SUMMARY .......................................................... 4 
2. 
SCHEDULE OF ASSESSMENT ................................................................................ 13 
3. 
ABBREVIATIONS ...................................................................................................... 16 
4. 
TABLE OF CONTENTS ............................................................................................. 19 
5. 
INTRODUCTION ........................................................................................................ 24 
5.1 
BACKGROUND ............................................................................................... 24 
5.2 
RATIONALE FOR CONDUCTING THE STUDY ..................................... 24 
5.3 
DRUG PROFILE ............................................................................................. 25 
5.4 
BENEFIT/RISK ASSESSMENT .................................................................... 28 
6. 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 30 
7. 
STUDY POPULATION ............................................................................................... 32 
7.1 
NUMBER OF PARTICIPANTS PLANNED ................................................ 32 
7.2 
INCLUSION CRITERIA ................................................................................ 32 
7.3 
EXCLUSION CRITERIA ............................................................................... 32 
7.4 
PARTICIPANT WITHDRAWAL .................................................................. 35 
7.5 
SCREEN FAILURE ......................................................................................... 35 
7.6 
DISCONTINUATION OF PARTICIPANTS FROM THE STUDY AND 
STUDY DRUG .................................................................................................. 35 
7.6.1 
Discontinuation of Study Drug ......................................................... 35 
7.6.1.1. Discontinuation Due to AE/SAE ........................................................ 35 
7.6.1.2 Drug Induced Liver Injury & Liver Function Monitoring .............. 36 
7.6.1.3 Temporarily interrupting the study drug for important biological 
considerations:.................................................................................... 38 
7.6.2 Discontinuation of Participant From the Study ................................... 38 
7.6.3 Lost to Follow-up ..................................................................................... 39 
7.6.4 Discontinuation of Trial .......................................................................... 39 
8. 
STUDY TREATMENTS/INVESTIGATIONAL PRODUCT (IP) MANAGEMENT
 ........................................................................................................................................ 40 
8.1 
TREATMENTS TO BE COMPARED .......................................................... 40 
8.1.1 
Investigational Product Description ................................................. 40 
8.1.2 
Comparator Drug Description.......................................................... 41 
8.2 
DOSAGE AND TREATMENT SCHEDULE ................................................ 41 
8.3 
PACKAGING, LABELLING AND SUPPLY ............................................... 41 
8.4 
STORAGE CONDITIONS .............................................................................. 42 


 
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8.5 
BLINDING/UNBLINDING ............................................................................. 42 
8.6 
METHOD OF ASSIGNING PARTICIPANT TO TREATMENT GROUP43 
8.7 
SELECTION OF DOSES ................................................................................ 43 
8.8 
CONCOMITANT MEDICATIONS AND OTHER RESTRICTIONS ...... 43 
8.8.1 
Previous and Concomitant Medications .......................................... 43 
8.8.2 
Permitted Concomitant Medication:................................................ 44 
8.8.3 
Prohibited Concomitant Medications .............................................. 45 
8.8.4 
Other Restrictions .............................................................................. 46 
8.9 
OVERDOSE AND DRUG INTERACTION ................................................. 46 
8.10 
TREATMENT COMPLIANCE ..................................................................... 47 
9. 
OBSERVATIONS ........................................................................................................ 49 
9.1 
CRITERIA FOR SAFETY .............................................................................. 49 
9.1.1 
Safety and Tolerability Variables ..................................................... 49 
9.1.2 
Medical History and Demographic Information ............................ 49 
9.1.3 
Clinical Laboratory Assessments ..................................................... 49 
9.2 
EFFICACY ....................................................................................................... 50 
9.2.1 
Primary Endpoint .............................................................................. 50 
9.2.2 
Secondary endpoints .......................................................................... 51 
9.2.3 
Exploratory Endpoints ...................................................................... 51 
9.2.4 
Health-related Quality of Life (HR-QoL) ........................................ 51 
9.2.5 
VCTE/FibroScan®.............................................................................. 51 
9.2.6 
Blood Samples .................................................................................... 52 
9.2.7 
Total Amount of Blood ...................................................................... 52 
9.2.8 
Biospecimen Banking......................................................................... 52 
9.2.9 
ELF score ............................................................................................ 52 
9.2.10 
PRO-C3 ............................................................................................... 52 
9.2.11 
NFS ...................................................................................................... 53 
9.2.12 
FIB-4 index ......................................................................................... 53 
9.2.13 
APRI .................................................................................................... 53 
9.3 
APPROPRIATENESS OF MEASUREMENT ............................................. 53 
9.4 
ABNORMAL LABORATORY FINDINGS .................................................. 54 
10. 
INVESTIGATIONAL PLAN ...................................................................................... 55 
10.1 
TRIAL DESIGN AND PLAN ......................................................................... 55 
10.2 
STUDY PROCEDURES AT EACH VISIT ................................................... 55 
10.2.1 
Screening Period ................................................................................ 55 
10.2.2 
Visit 3: Randomization Visit: [0 Weeks. Day 1, +3 days) ............... 56 
10.2.3 
Treatment and Follow-up Period: Week 2 to Week 28 .................. 57 
10.2.4 
Safety Follow-up Period: Visit 10: Week 28 visit (Day 197 ± 3 days)59 
10.2.5 
Early Termination (ET) visit ............................................................ 59 
10.3 
STANDARDIZED QUESTIONNAIRES ....................................................... 60 


 
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10.4 
ADHERENCE TO PROTOCOL .................................................................... 60 
10.5 
DATA AND SAFETY MONITORING BOARD .......................................... 60 
10.6 
PROTOCOL DEVIATIONS ........................................................................... 61 
11. 
STATISTICAL CONSIDERATIONS ........................................................................ 62 
11.1 
GENERAL CONSIDERATIONS ................................................................... 62 
11.2 
PARTICIPANT EVALUABILITY ................................................................ 62 
11.3 
ANALYSIS POPULATIONS .......................................................................... 62 
11.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ...................... 63 
11.5 
PRIMARY EFFICACY ANALYSIS .............................................................. 63 
11.5.1 
Intercurrent Events ........................................................................... 63 
11.5.2 
Estimands for the Primary Efficacy Endpoint ................................ 63 
11.5.3 
Statistical Hypotheses ........................................................................ 65 
11.5.4 
Statistical Methods ............................................................................. 65 
11.5.5 
Subgroups ........................................................................................... 65 
11.5.6 
Handling of Missing Data .................................................................. 65 
11.5.7 
Sensitivity and Supportive Analyses ................................................ 66 
11.6 
SECONDARY EFFICACY ENDPOINT AND ANALYSIS ........................ 66 
11.6.1 
Definitions Applying to All Estimands ............................................. 66 
11.6.2 
Details of Each Estimand for the Secondary Efficacy Endpoints 
Involved in Construction of the Primary Efficacy Endpoint ......... 66 
11.6.3 
Details of Each Estimand for the Secondary Efficacy Endpoints Not 
Involved in Construction of the Primary Efficacy Endpoint ......... 67 
11.6.4 
Statistical Methods for the Analysis of Secondary Efficacy Endpoints.
.............................................................................................................. 68 
11.7 
MULTIPLICITY .............................................................................................. 69 
11.8 
EXPLORATORY ANALYSES ...................................................................... 69 
11.9 
SAFETY ANALYSIS ....................................................................................... 69 
11.9.1 
Treatment Exposure .......................................................................... 69 
11.9.2 
Medical History .................................................................................. 69 
11.9.3 
Concomitant Therapies ..................................................................... 70 
11.9.4 
Safety Parameters .............................................................................. 70 
11.10 INTERIM ANALYSIS ..................................................................................... 70 
11.11 SAMPLE SIZE DETERMINATION ............................................................. 70 
11.12 COVID-19 CONSIDERATIONS .................................................................... 71 
12. 
ADMINISTRATIVE MATTERS ............................................................................... 72 
12.1 
ETHICS ............................................................................................................. 72 
12.1.1 
Institutional Committee Review and Communications ................. 72 
12.1.2 
Informed Consent and Participant Information ............................. 72 
12.1.3 
Compensation and Insurance ........................................................... 73 


 
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12.2 
RECORD KEEPING ....................................................................................... 73 
12.2.1 
Drug Accountability........................................................................... 73 
12.2.2 
Emergency Code Break (Unblinding) .............................................. 74 
12.2.3 
Electronic Case Report Forms .......................................................... 74 
12.2.4 
Data Management .............................................................................. 75 
12.2.5 
Source Documents .............................................................................. 75 
12.2.6 
Direct access to Source Data/Documents ......................................... 76 
12.2.7 
Trial Monitoring ................................................................................ 77 
12.3 
QUALITY AUDITS ......................................................................................... 77 
12.4 
PROCEDURES ................................................................................................ 77 
12.4.1 
Adverse Events ................................................................................... 77 
12.4.2 
Serious Adverse Event ....................................................................... 80 
12.4.3 
Hepatic Safety Adjudication Committee ......................................... 82 
12.4.4 
Expected Adverse Events .................................................................. 82 
12.4.5 
Pregnancy ........................................................................................... 82 
12.5 
UNANTICIPATED PROBLEMS ................................................................... 84 
12.6 
RULES FOR AMENDING PROTOCOL ...................................................... 84 
12.7 
FINANCIAL DISCLOSURE .......................................................................... 84 
12.8 
DISCONTINUATION OF THE TRIAL BY THE SPONSOR .................... 84 
12.9 
STATEMENT OF CONFIDENTIALITY ..................................................... 85 
12.10 FINAL REPORT AND PUBLICATION POLICY ...................................... 85 
12.11 ARCHIVING .................................................................................................... 85 
13. 
REFERENCES ............................................................................................................. 86 
14. 
SIGNATURE PAGE(S) ............................................................................................... 89 
15. 
APPENDICES .............................................................................................................. 93 
15.1 
APPENDIX 1: PARTICIPATING STUDY CENTERS ............................... 93 
15.2 
APPENDIX 2: LIST OF KNOWN CYP2C8 INHIBITORS/SUBSTRATES94 
15.3 
APPENDIX 3: CONTRACEPTIVE GUIDANCE ........................................ 95 
15.4 
APPENDIX 4: HEALTH-RELATED QUALITY OF LIFE ASSESSMENT 
QUESTIONNAIRE .......................................................................................... 98 
15.5 
APPENDIX 5: AUDIT QUESTIONNAIRE .................................................. 99 
15.6 
APPENDIX 6: CKD-EPI CALCULATOR .................................................. 101 
15.7 
APPENDIX 7: LIST OF STEATOGENIC MEDICATIONS OR SUPRA-
PHYSIOLOGIC HORMONAL THERAPIES OR MEDICATIONS THAT 
CAUSE SIGNIFICANT WEIGHT CHANGE ............................................ 102 
15.8 
APPENDIX 8: DIET AND EXERCISE GUIDANCE ................................ 103 
15.9 
APPENDIX 9: INSTRUCTIONS FOR STANDARDIZED HIP 
CIRCUMFERENCE AND MINIMUM WAIST CIRCUMFERENCE 
MEASUREMENT .......................................................................................... 107 


 
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15.10 APPENDIX 10: PROTOCOL AMENDMENT TEMPLATE ................... 108 
 


 
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5. 
INTRODUCTION 
5.1 
BACKGROUND 
Nonalcoholic fatty liver disease (NAFLD) is one of the most common types of chronic liver 
disease and the second leading cause for liver transplantation in the United State (US)[1, 2, 3]. The 
severity of NAFLD ranges from nonalcoholic fatty liver (simple steatosis) to nonalcoholic 
steatohepatitis (NASH)[4,5]. NASH is the most severe form of NAFLD and is characterized by 
hepatocellular injury, inflammation and risk of progression to NASH-related cirrhosis and NASH 
related hepatocellular carcinoma. NAFLD is also considered to be the hepatic component of the 
metabolic syndrome, which includes dyslipidemia, peripheral insulin resistance, obesity, type 2 
diabetes mellitus (T2DM), and hypertension[4,5]. 
NAFLD in people living with human immunodeficiency virus (PLWH) is not well studied. 
Numerous studies have been conducted to further understand the diagnosis, mechanisms, 
progression and therapies of NASH[6-10]. However, all studies have systematically excluded 
PLWH, as NAFLD in these patients was thought to be different from that in the general population 
due to HIV itself, antiretroviral therapy (ART), concomitant medications, and co-infections. This 
resulted in major knowledge gap regarding NAFLD in the setting of HIV. Prevalence of NAFLD 
in PLWH in the US is not well defined. NAFLD is projected to become the leading cause of liver 
disease in the aging HIV population[11]. The reported prevalence of NAFLD in mono-infected 
PLWH ranges from 15% to 54% when assessed by imaging modalities and the vibration-controlled 
transient elastography (VCTE), and up to 73% in studies including liver biopsy, exceeding the 
reported prevalence of NAFLD in the general population [3, 12-18]. Obesity, insulin resistance, and 
other components of the metabolic syndrome have been reported in some studies to increase the 
risk for NAFLD in PLWH[14, 16, 19-22]. 
Currently, there are no available therapies for NASH in PLWH. There is tremendous interest in 
developing pharmacologic therapies for NASH in the general population, but these studies 
systematically exclude PLWH. There have been studies of tesamorelin[23] and aramchol[24] in 
PLWH with NAFLD with imaging endpoints, similarly this study of Saroglitazar Magnesium has 
been designed for NAFLD in PLWH with imaging endpoints. 
5.2 
RATIONALE FOR CONDUCTING THE STUDY 
There is a strong scientific rationale for targeting the peroxisome proliferator-activated receptors 
(PPAR) axis to improve metabolic dysfunction and hepatic steatosis in PLWH. Saroglitazar 
Magnesium is a novel PPARα/γ agonist having predominant PPARα and moderate PPARγ 
actions[5]. Saroglitazar Magnesium is currently approved for treating <diabetic dyslipidemia and 
hypertriglyceridemia in T2DM not controlled by statin= (February 2013), <add-on therapy to 
metformin for treatment of type 2 diabetes mellitus= (January 2020), <non-cirrhotic nonalcoholic 
steatohepatitis= (March 2020), 8NAFLD with comorbidities (Either Obesity, T2DM, Dyslipidemia 
or Metabolic Syndrome)9 (since December 2020) in India, and has a well-estabilshed safety 
profile. 


 
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Saroglitazar Magnesium has shown improving steatohepatitis in a number of established animal 
models, improving hepatic steatosis, inflammation, and ballooning, and preventing the 
development of fibrosis more prominently than pioglitazone and fenofibrate. In a diet-induced-
obesity NASH model, Saroglitazar Magnesium was associated with 18% weight loss; reduced 
serum levels of alanine aminotransferase (ALT), total cholesterol, and triglycerides (TG); and 
significantly reduced steatosis and necroinflammation[26]. 
In a pooled analysis from several phase 2 trials of dyslipidemia in both diabetic and non-diabetic 
adults (who have high prevalence of NAFLD), Saroglitazar Magnesium administered for 12 weeks 
was associated with improvement in serum ALT, lipids, and glucose control in a dose-dependent 
manner. Commonly reported adverse events (AEs) include nausea, pyrexia, headache, gastritis, 
and constipation. Serious AEs (SAEs) observed with other PPARγ agonists, such as weight gain, 
heart failure, cardiac events, bone loss, or DILI, have not been reported[27]. 
In a 12-week, open label study to treat lipodystrophy-related hypertriglyceridemia in PLWH on 
stable ART, Saroglitazar Magnesium 4 mg daily showed significant improvement in TG, very 
low-density lipoprotein (VLDL), high-density lipoprotein (HDL), ALT, gamma-glutamyl 
transferase (GGT), and alkaline phosphatase (ALP). The frequency of AEs was 8%, and all but 
one event (severe abdominal pain that resolved) were mild to moderate in nature[28]. In vitro, 
Saroglitazar Magnesium does not significantly inhibit or induce human cytochrome P-450 (CYP) 
isoenzymes, including CYP3A4. 
For this trial, the 4 mg daily oral dose was chosen based on pharmacokinetics, dose ranging studies, 
the previous HIV lipodystrophy study, as well as two studies in primary NAFLD. 
Therefore, this randomized, double-blind, placebo-controlled study is designed to evaluate the 
efficacy and safety of Saroglitazar Magnesium 4 mg for treatment of NAFLD in PLWH. 
5.3 
DRUG PROFILE 
 
 
 
 
 
 
 
 
 
Saroglitazar Magnesium, through PPARα agonist action, increases the hepatic oxidation of fatty 
acids and lowers the synthesis and secretion of TG, which leads to increased diversion of fatty 
acids from tissues in the periphery to the liver. Saroglitazar Magnesium also increases lipolysis, 
removes TG-rich particles from plasma by activating lipoprotein lipase (LPL), and reduces 
production of apolipoprotein (Apo) C-III, which is an inhibitor of LPL activities. Saroglitazar 
Magnesium also reduces LDL and increases HDL, Apo A-I, and Apo A-II. Saroglitazar 


 
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Magnesium, through PPARγ agonist action, regulates the transcription of insulin-responsive genes 
and thereby increases insulin sensitivity, increases glucose uptake, and reduces blood glucose 
level [29]. 
The drug was developed with an expectation to achieve optimum anti-dyslipidemic and anti-
hyperglycemic effects, while avoiding AEs such as peripheral edema, weight gain, cardiovascular 
events, renal and/or liver toxicity etc., which are commonly seen with other dual PPAR or PPARγ 
agonists. The pharmacological effects of Saroglitazar Magnesium were extensively evaluated in 
various pre-clinical models and clinical trials [29, 30, 32, 33]. 
Preclinical Experience 
Extensive pre-clinical trials were done with Saroglitazar Magnesium using various animal models 
wherein, half maximal effective concentration (EC50) of PPARα: PPARγ > 300; In vitro 
Saroglitazar Magnesium resulted in a 4615-fold higher activation of human PPARα (EC50 = 
0.650 pM) than activation of human PPARγ (EC50 = 3 nM) in a transactivation assay. Saroglitazar 
Magnesium favorably modulated the lipid and glucose profile[32, 33]. Non-clinical pharmacological 
studies showed no significant safety concern at any of the doses tested. 
In experimental NASH model (animal model of mice with choline-deficient, high-fat diet-induced 
NASH), Saroglitazar Magnesium reduced hepatic steatosis, ballooning, and inflammation; 
prevented development of fibrosis; and also reduced ALT, aspartate aminotransferase (AST), and 
expression of inflammatory and fibrosis biomarkers[26]. In this experimental NASH model, 
Saroglitazar Magnesium (3 mg/kg) significantly reduced the overall NAFLD activity score (NAS) 
compared to pioglitazone (25 mg/kg) and fenofibrate (100 mg/kg)[26]. In carbon 
tetrachloride-induced fibrosis model, Saroglitazar Magnesium (4 mg/kg) exhibited anti-fibrotic 
effect [26]. 
Clinical Experience 
Maximum tolerated dose (MTD) in Phase 1 study was 16 mg/day for 10 days. In a Phase 1 study 
of a total of 136 healthy human volunteers, Saroglitazar Magnesium was found to be well tolerated 
in single as well as multiple doses without any safety concern. Several Phase 2 studies were 
conducted to evaluate the safety and efficacy of Saroglitazar Magnesium in dyslipidemic 
participants with and without diabetes, participants with impaired glucose tolerance test, and 
participants with NASH[29]. 
NAFLD/NASH Clinical Development: 
The clinical evidence of the efficacy of Saroglitazar Magnesium in NASH has been evaluated in 
two Phase 2 studies in the US, one Phase 2 study in India, and one Phase 3 study in India, and one 
phase 3 study in Mexico. ALT level, which is a clinically accepted endpoint for the NASH trials 


 
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was used as the endpoint in two Phase 2 studies. The NAS, which is evaluated through liver biopsy 
was the endpoint in one Phase 2 study and two Phase 3 studies. 
A Phase 2 study of 12 weeks duration was conducted to evaluate the safety and efficacy of 
Saroglitazar Magnesium 4 mg in 32 patients with biopsy-proven NASH along with 
ALT >1.5 times the upper limit of normal (ULN) (CTRI identifier: CTRI/2010/091/000108). 
There was a statistically significant reduction in the ALT levels (U/L) from baseline 
(95.86 ± 37.65) to Week 6 (52.79 ± 28.42) and Week 12 (44.37 ± 35.43). There was also a 
statistically significant decrease in HOMA-IR from baseline to Week 12. In patients with baseline 
TG g150 mg/dL, there was also a statistically significant reduction in TG (mg/dL) from baseline 
(247.15 ± 63.24) to Week 12 (185.31 ± 72.01). 
In the US, a Phase 2 study of 16 weeks duration was conducted to evaluate the efficacy and safety 
of Saroglitazar Magnesium 1 mg, 2 mg, and 4 mg compared to placebo in 106 adult subjects with 
NAFLD/NASH along with ALT g50 U/L[30]. Percentage change in ALT levels from baseline to 
Week 16 was the primary efficacy endpoint. The change in mean ALT from baseline to Week 16 
was -26.2±33.4% with Saroglitazar Magnesium 1 mg, -27.0±26.5% with Saroglitazar Magnesium 
2 mg, and -44.9±26.2% with Saroglitazar Magnesium 4 mg compared to 2.6±32.1% with placebo 
(p<0.001 for all). Saroglitazar Magnesium 4 mg, compared to placebo, significantly reduced mean 
liver fat content (LFC) measured by magnetic resonance-proton density fat fraction [-4.21±6.23% 
versus -0.28±5.41%, p=0.002] at week 16. Saroglitazar Magnesium 4 mg was associated with 
improvements in enhanced liver fibrosis score, glycemic parameters, and atherogenic dyslipidemia 
at week 16. Lipoprotein analysis of serum samples obtained at baseline and week 16 from subjects 
was done using the Liposcale® test, a previously reported two-dimensional proton nuclear 
magnetic resonance spectroscopy (2D-1H-NMR) (OWL Metabolomics, Derio, Spain). 
Saroglitazar Magnesium improved CVD risk in subjects with abnormal baseline lipoprotein levels. 
Saroglitazar Magnesium reduced LDL-TG, VLDL-TG the ratio HDL-TG/HDL-C and remnant 
cholesterol, which are associated with increased CVD risk. A decrease of >20% in these variables 
from baseline to Week 16 was observed in higher proportions of the Saroglitazar Magnesium 
groups (1 mg, 2 mg, and 4 mg) and in a dose-dependent manner compared to placebo, with 
Saroglitazar Magnesium 4 mg having the greatest beneficial effect. 
In the US, a Phase 2 study of 24 weeks duration was conducted to evaluate the safety and efficacy 
of Saroglitazar Magnesium 2 mg and 4 mg compared to placebo in 16 adult subjects with biopsy 
proven NASH without cirrhosis[31]. For the study primary efficacy endpoint, the changes in NAS 
at week 24 were -1.9±1.57, -1.5±0.84, and -1.3±0.58 in Saroglitazar Magnesium 4 mg, Saroglitazar 
Magnesium 2 mg, and placebo groups, respectively. For the study secondary endpoints, 
Saroglitazar Magnesium 4 mg and 2 mg improved liver histology, liver parameters, lipid 
parameters, glycemic control, and insulin resistance parameters over a period of 24 weeks. 
In India, a Phase 3 study of 52 weeks duration was conducted to evaluate the efficacy and safety 
of Saroglitazar Magnesium 4 mg compared to placebo in 102 adult subjects with biopsy proven 
NASH without cirrhosis (CTRI identifier: CTRI/2015/10/006236). For the study primary efficacy 


 
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endpoint, there was a statistically significant higher proportion of subjects with decrease in 
NAS g2 points spread across at least 2 of the NAS components without worsening of fibrosis at 
week 52 in Saroglitazar Magnesium 4 mg group (52.3%) compared to placebo group (23.5%) 
(p-value: 0.0427). For the study secondary efficacy endpoints, Saroglitazar Magnesium 4 mg 
significantly reduced mean score of hepatocyte ballooning, steatosis, and NAS from baseline to 
Week 52 (p-value <0.05). Saroglitazar Magnesium 4 mg also improved liver parameters and lipid 
parameters from baseline to Week 52. 
Other Indications: 
Several clinical trials were conducted to evaluate the safety and efficacy of Saroglitazar 
Magnesium in dyslipidemic participants with and without diabetes, participants with impaired 
glucose tolerance test in India are summarized below. 
A Phase 3 study of 24-week duration was conducted in 122 subjects to evaluate the efficacy and 
safety of Saroglitazar Magnesium in diabetic dyslipidemic patients compared to pioglitazone. 
There was a statistically significant reduction in the TG levels at all visits compared to baseline in 
Saroglitazar Magnesium 2 mg and 4 mg groups. There was a statistically significant reduction in 
the TG levels from baseline to Week 24 in Saroglitazar Magnesium 4 mg (45%) compared to 
pioglitazone 45 mg (15.5%)[32]. 
A Phase 3 study of 12-week duration was conducted in 302 subjects to evaluate the efficacy and 
safety of Saroglitazar Magnesium in diabetic dyslipidemic patients not controlled with atorvastatin 
10 mg. There was a statistically significant reduction in TG levels from baseline to Week 12 in 
Saroglitazar Magnesium 2 mg and 4 mg groups (> 45%) compared to Placebo. There was also a 
statistically significant reduction from baseline to Week 12 in LDL-C (>27.5%), total cholesterol 
(>22%), and Apo B (>27%) levels in Saroglitazar Magnesium 2 mg and 4 mg[33]. 
A Phase 3 study of 56-week duration was conducted to evaluate the efficacy and safety of 
Saroglitazar Magnesium 2 mg and 4 mg as compared to pioglitazone 30 mg in 1155 adults with 
type 2 diabetes mellitus. The results showed that Saroglitazar Magnesium (2 mg and 4 mg) and 
pioglitazone 30 mg significantly reduce glycosylated hemoglobin (HbA1c), as compared to 
baseline after 24 weeks of treatment. In addition, Saroglitazar Magnesium (2 mg and 4 mg) and 
pioglitazone 30 mg significantly reduce HbA1c, as compared to baseline after 12 and 56 weeks of 
treatment. In this study, no significant safety findings were reported which were related to 
Saroglitazar Magnesium[35]. 
5.4 
BENEFIT/RISK ASSESSMENT 
NAFLD is considered to be the hepatic component of the metabolic syndrome, which includes 
dyslipidemia, peripheral insulin resistance, obesity, T2DM, and hypertension. Due to rising 
prevalence of obesity, T2DM, and hypertension, NAFLD has emerged as a major public health 
threat worldwide. Participants with NAFLD are more likely to die from CVD compared to 


 
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liver-related death. Therefore, the ideal drug to treat NAFLD/NASH should reduce the risk of 
CVD along with improving liver parameters and liver histology. 
The safety and tolerability of Saroglitazar Magnesium is well defined based on pre-clinical and 
clinical trials (Phase 1 to Phase 3)[26, 30, 34]. 
 
 
. Overall, Saroglitazar Magnesium has a 
favorable safety profile. Considering the efficacy results of pre-clinical and clinical trials, 
Saroglitazar Magnesium can improve lipid parameters and glycemic parameters including insulin 
resistance in patients with dyslipidemia. Moreover, Saroglitazar Magnesium has shown promising 
results in pre-clinical and clinical trials of Saroglitazar Magnesium in patients with 
NAFLD/NASH[26, 34, 30]. In pre-clinical trials, Saroglitazar Magnesium reduced hepatic steatosis, 
prevented development of fibrosis and reduced ALT and AST. 
In a Phase 2 clinical study, Saroglitazar Magnesium significantly reduced ALT from baseline to 
Week-12[29]. In a Phase 3 study, Saroglitazar Magnesium 4 mg showed statistically significant 
reduction in proportion of subjects with decrease in NAS g2 spread across at least 2 of the NAS 
components without worsening of fibrosis, reduced mean score of steatosis, lobular inflammation, 
and hepatocyte ballooning, also reduced AST, ALT, ALP, and GGT without significant safety 
findings (preliminary unpublished results). Saroglitazar could reduce the risk of cardiovascular 
diseases along with improving liver parameters and liver histology in participants with NASH. 
Recently (March 2020), Saroglitazar has also received approval for marketing for treatment of 
non-cirrhotic nonalcoholic steatohepatitis in India. Therefore, the available information on 
Saroglitazar Magnesium suggests a favorable risk-benefit ratio. 
The benefit-risk analysis evaluation has not revealed any significant risks that have an impact on 
the existing efficacy and safety profile of Saroglitazar Magnesium. Based on the assessment of all 
the safety issues and the benefits; the benefit-risk assessment was considered to remain favorable 
and unchanged. 
More detailed information about the known and expected benefits and risks of Saroglitazar 
Magnesium may be found in the Investigator9s Brochure.[29] 
 




 
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1d) Change from baseline in NMR lipoprofile at Week 
24/EOT 
1e) Change from baseline in enhanced liver fibrosis 
(ELF) score at Week 24/EOT 


 
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7. 
STUDY POPULATION 
7.1 
NUMBER OF PARTICIPANTS PLANNED 
It is planned to enroll approximately 120 participants with NAFLD in People Living with HIV in 
this study. Participants with NAFLD who meet the eligibility criteria will be randomized in a 1:1 
ratio to receive Saroglitazar Magnesium 4 mg or Placebo once daily orally for 24 weeks. 
7.2 
INCLUSION CRITERIA 
To be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Adults (g18 years of age) with documented HIV. 
2. Documented diagnosis of NAFLD established by imaging (ultrasound, CT scan or 
MRI) or liver biopsy within 6 months before screening, based on American 
Association for the Study of Liver Disease [AASLD] criteria 
3. Hepatic fat fraction g8% by MRI-PDFF 
4. ALT level g31 U/L in men and g19 U/L in women at Visit 1 and 2 
5. HIV-1 RNA <200 copies/mL for g6 months on ART (must have screening HIV-1 
RNA value and one clinical care value within 6 months prior to screening and up to 
the randomization that meets the criteria). 
6. Stable ART regimen for g3 months prior to screening and stable up to the 
randomization and no active plans to change ART while on study. 
7. Willingness to participate in the study. 
7.3 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in 
this study: 
1) History of significant alcohol consumption (defined as >2 drinks/day on average for men, >1 
drinks/day on average for women) for at least 3 consecutive months (12 consecutive weeks) 
within 5 year before screening (Note 1: 1 drink =12 ounces of beer, 8-9 ounces of malt liquor, 
4 ounces of wine or 1 ounce of spirits/hard liquor. Note 2: Use sex assigned at birth for alcohol 
consumption limits). 
2) History of other acute or chronic liver disease, including, but not limited to autoimmune, 
primary 
biliary 
cholangitis, 
Wilson9s 
disease, 
alpha-1-antitrypsin 
deficiency, 
hemochromatosis, hepatitis B virus (HBV), and ongoing or recent (within the past 3 years) 
hepatitis C RNA positivity. (Exceptions: a. Participants with previously treated hepatitis C 
infection are eligible for consideration if their sustained virologic response was achieved more 
than 3 years prior to screening. The proportion of such participants in this trial will not exceed 
25% of the study cohort. b. Participants with prior acute HBV infection that is resolved but 
currently do not have hepatitis B surface antigen (HBsAg) or detectable HBV DNA are 
eligible).  


 
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3) History of liver transplant. 
4) Liver biopsy or radiologic imaging consistent with the clinical presence of cirrhosis or portal 
hypertension at screening. 
5) Participants whose Visit 2 ALT, AST, or alkaline phosphatase (ALP) values exceed their 
Visit 1 values by more than 50%.  
Note: These participants will be required to have a third value measured at-least one week 
after V2, to assess for a trend. If the third value shows a continued increase g10% compared 
to the Visit 2 values, the participant is considered ineligible for randomization. 
6) Ongoing use of steatogenic medications or supra-physiologic hormonal therapies (Exception: 
transgender women on stable (g3 month) feminizing hormonal therapy not excluded), within 
3 months prior to screening until time of randomization or anticipated use of medications that 
cause significant changes in weight during the study period (Refer Appendix 7 for 8List of 
Steatogenic Medications Or Supra-Physiologic Hormonal Therapies Or Medications That 
Cause Significant Weight Change9). 
7) Uncontrolled T2DM, defined as HbA1c >9.5% at screening. 
8) Any of the following laboratory values at screening: 
a. ALT or AST >250 U/L 
b. Total bilirubin >1.5 mg/dL and direct bilirubin > 0.5 mg/dL (unless due to 
Gilbert9s disease or atazanavir use per the opinion of the site investigator) 
c. Platelet count <150,000/mm3 
d. Estimated glomerular filtration rate (e-GFR) <60 mL/min/1.73m2 using the 
chronic kidney disease-epidemiology collaboration (CKD-EPI) equation 
(Refer Appendix 6 for 8CKD-EPI Calculator9) 
e. International normalized ratio (INR) >1.3. 
f. Albumin < 3.6 g/dL 
9) History of malignancy in the past 5 years and/or active neoplasm with the exception of 
superficial, non-melanoma, skin cancer. 
10) Unstable cardiovascular disease, including: 
a) Unstable angina, (i.e., new or worsening symptoms of coronary heart disease) 
and/or acute myocardial infarction within the 3 months preceding screening 
b) Acute coronary syndrome or coronary artery intervention within the 3 months 
preceding screening,  
c) Heart failure of New York Heart Association (NYHA) class (III-IV) or 
worsening congestive heart failure within the 6 months preceding screening. 
d) History of (within 3 months preceding screening) or current unstable cardiac 
dysrhythmias. 
e) Uncontrolled hypertension (systolic blood pressure [SBP] >155 mmHg and/or 
diastolic blood pressure [DBP] >95 mmHg) at screening. 
f) Stroke or transient ischemic attack within the 6 months preceding screening. 


 
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11) Unstable pulmonary disease (based upon site investigator9s evaluation) at screening. 
12) Use of drugs that are known CYP2C8 inhibitors/substrates (Refer Appendix 2 for the 8List of 
Known CYP2C8 Inhibitors/Substrates9) in the last 28 days prior to screening. 
13) History of severe illness or any other conditions that require systematic treatment/or 
hospitalization, until participant either completes therapy or is clinically stable on therapy as 
per the opinion of the investigator, for at least 7 days prior to screening (such as poorly 
controlled psychiatric disease, active gastrointestinal conditions that might interfere with drug 
absorption, etc.). 
14) Use of thiazolidinediones or Telmisartan within 3 months prior to screening or until time of 
randomization. 
15) Use of unstable doses of SGLT2 inhibitors (e.g. canagliflozin, empagliflozin, dapagliflozin, 
etc.), glucose0dependent insulinotropic polypeptide (GIP) and/or GLP-1 agonists (e.g. 
semaglutide, exenatide, liraglutide, lixisenatide, tirzepatide etc.) within 6 months prior to 
screening until time of randomization. 
16) Use of pentoxifylline, ursodeoxycholic acid, antioxidants such as vitamin E (>200 IU/day), 
glutathione, orlistat, betaine, or non-prescribed complementary alternative medications 
within 6 months prior to screening until time of randomization. 
17) Known allergy, sensitivity or intolerance to the study medication or formulation ingredients. 
18) History of any known bleeding disorder or coagulopathy. 
19) Any condition that in the opinion of the site investigator, would compromise the participant9s 
ability to participate in the study. 
20) Unstable doses of anti-diabetic agents including sulfonylureas, biguanides or DPP-4 
inhibitors in the last 3 months prior to screening until time of randomization. 
21) Unstable doses of lipid lowering agents such as statins (e.g. simvastatin, pravastatin, 
atorvastatin, fluvastatin, lovastatin, rosuvastatin, etc.) or fibrates (clofibrate, Fenofibrate) in 
the last 3 months prior to screening until time of randomization. 
22) Participant with weight change >5% within 6 months prior to screening until time of 
randomization. 
23) History of bariatric surgery or currently undergoing evaluation for bariatric surgery. 
24) Participation in another interventional clinical study and/or receipt of any other 
investigational medication within 3 months prior to screening. 
25) History of COVID-19 infection in the last 30 days prior to screening.  
26) Pregnancy-related exclusions, include: 
a. Pregnant/lactating female (including positive pregnancy test at screening) 
b. Pregnancy should be avoided by male and female participants either by complete 
abstinence or the use of acceptable effective contraceptive measures for the duration of 
the study and for at least 1 month after the end of the study treatment. Refer Appendix 3 
Contraceptive Guidance  
27. Participants having an absolute contraindication to MRI (eg., any implants, magnetic 
metals, cardiac pacemakers, neurostimulator) as per investigators9 discretion 


 
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7.4 
PARTICIPANT WITHDRAWAL 
A participant may withdraw from the study at any time without penalty and for any reason without 
prejudice to her/his future medical care. Although a participant is not obliged to give his/her reason 
for withdrawing prematurely, the investigator will make a reasonable effort to obtain the reason 
while fully respecting the participant9s rights. If there is a medical reason for withdrawal, the 
participant will remain under the supervision of the investigator for follow-up of AE(s) as detailed 
in Section 12.4.1.6.  
Every effort will be made to continue clinical and/or laboratory follow-up, as appropriate, in 
participants who wish to withdraw from the study medication, and reasonable efforts will be made 
to contact a participant who fails to attend any follow-up appointments, in order to ensure that 
he/she is in satisfactory health. A participant9s withdrawal of consent and agreement to undergo a 
final examination will be documented on the case report form (CRF) and on the investigator9s 
copy of the informed consent form (ICF), which will be countersigned and dated by the participant. 
Safety follow-up within 4 weeks from the date of withdrawal will be conducted for all participants 
who receive the study medication but do not complete the study according to the study protocol. 
7.5 
Screen Failure 
A screen failure occurs when a participant who has signed the ICF does not meet all the entry 
criteria outlined in this protocol and has not been randomized. 
Participants who fail to meet all the screening criteria will not be rescreened unless approved by 
the sponsor or its designee in writing. Screening laboratory tests may be repeated once following 
the approval of the sponsor or its designee, if the laboratory test results seem implausible or 
inaccurate. No study procedures (including safety follow-up) will be performed for these 
participants. 
For participants who fail to meet the inclusion criteria or who meet at least one of the exclusion 
criteria, the investigator (or designee) will document on a screening form the reason for the 
screening failure. 
7.6 
DISCONTINUATION OF PARTICIPANTS FROM THE STUDY AND STUDY 
DRUG 
7.6.1 
Discontinuation of Study Drug 
7.6.1.1. Discontinuation Due to AE/SAE 
The following clinical events warrant discontinuation of the study drug; however, the participant 
will continue to be followed for safety, and the relevant laboratory tests will be performed until 


 
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the event has resolved, i.e., clinical laboratory value(s) has/have returned to baseline or is/are no 
longer of clinical significance.  
• Any AE (CTCAE, Version 5.0 or higher) of Grade g3 that is possibly or likely study drug-
related  
• Any AE of CTCAE Grade g 4 regardless of attribution to the study drug. 
• SAE that may be related to the study drug may warrant discontinuation, as per the discretion 
of the site investigator. 
• In the opinion of the site investigator, continuation of the study drug poses a health risk to 
the participant 
7.6.1.2 Drug Induced Liver Injury & Liver Function Monitoring 
Monitoring of DILI will be done during this study as per Tables 1 and 2: 
A separate blinded HSAC will be established. The committee will review, monitor and adjudicate 
possible cases of DILI in the study (refer to Section 12.4.3). 
(Note: Prior to using these tables, R ratio would be calculated as alanine aminotransferase 
(ALT)/ALT upper limit of normal (ULN) divided by alkaline phosphatase (ALP)/ALP ULN 
(ALT/ULN÷ALP/ULN).


 
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Table 1. Algorithm for Monitoring and Management of Elevated ALT in Participants with Normal or Elevated 
Baseline ALTa 
Treatment 
emergent 
ALT 
elevations 
Treatment emergent 
total bilirubin 
elevations 
Liver‐related 
Symptoms (as a 
variable) 
Actionb 
Normal/near normal baselinea: 
ALT g5x ULN 
Elevated baseline a: 
ALT g3x baseline or g300 U/L 
(whichever occurs first) 
Normal 
Participants with 
Gilbert's 
syndrome: 
No change in baseline 
TBL 
None 
Repeat ALT, AST, ALP, 
TBL, in 205 days.  
Follow0up 
for 
symptoms. 
Initiate evaluation for other 
etiologies of abnormal liver 
tests. 
Normal/near normal baselinea: 
ALT g3x ULN 
Elevated baselinea: 
ALT g2x baseline or g300 U/L 
(whichever occurs first) 
Normal Participants 
with Gilbert's 
syndrome: 
No change in baseline 
TBL 
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain 
Repeat ALT, AST, ALP, 
TBL, in 205 days.  
Follow0up 
for 
symptoms. 
Initiate evaluation for other 
etiologies of abnormal liver 
tests. 
Normal/near normal baselinea 
ALT g8 x ULN 
Elevated baselinea: 
ALT g5x baseline or g500 U/L 
(whichever occurs first) 
Normal Participants 
with Gilbert's 
syndrome: 
No change in baseline 
TBL 
None 
Interrupt study drug. 
Initiate close monitoring and 
workup 
for 
competing 
etiologies. 
Study drug can be restarted 
only if another etiology is 
identified and liver enzymes 
return to baseline. 
Normal/near normal baselinea: 
ALT g3x ULN 
Elevated baselinea: 
ALT g2x baseline or g300 U/L 
(whichever occurs first) 
TBL g2x ULN 
Participants with 
Gilbert's syndrome: 
Doubling of direct 
bilirubin or 
increased INR to >1.5 
None 
Interrupt study drug. 
Initiate close monitoring and 
workup 
for 
competing 
etiologies. 
Study drug can be restarted 
only if another etiology is 
identified and liver enzymes 
return to baseline. 
Normal/near normal baseline a: 
ALT g5x ULN 
Elevated baseline a: 
ALT g3x baseline or g300 U/L 
(whichever occurs first) 
Normal or elevated 
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain 
Interrupt study drug. 
Initiate close monitoring and 
workup for competing 
etiologies. 
Study drug can be restarted 
only if another etiology is 
identified and liver enzymes 
return to baseline. 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin, ULN= upper limit of normal. 
Modified from Chalasani N, Regev A. Drug0induced liver injury in participants with pre-existing chronic liver 
disease in drug development: how to identify and manage? Gastroenterology. 2016;151:104601051. 
aElevated baseline is defined as ALT g1.5x ULN. Normal/near normal baseline is defined as ALT < 1.5x ULN. In 
participants with a sizable stable decrease in ALT (>50% of the baseline value) during treatment, a new baseline, 
corresponding to the ALT nadir, should be established on an individual basis for subsequent determination of a 
DILI signal. 
bThe actions of close observation, monitoring, and drug interruption often overlap. Occasionally, workup is initiated 
after drug interruption. 


 
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Table 2. Detection and monitoring of elevated serum alkaline phosphatase 
Treatment Emergent 
Serum Alkaline 
Phosphatase (ALP) 
elevations 
Serum Total Bilirubin 
Action/Follow-up 
>2 times upper limit of 
normal (ULN) or > 250 
IU/L whichever comes 
first, (unless ALP not of 
hepatic origin) 
Within normal range 
• 
Work up for cholestasis  
• 
Repeat liver profile within one week 
• 
If there is progressive increase in ALP (e.g. increase 
by 50% from previous value) or there is associated 
doubling of direct bilirubin + exceeds ULN, interrupt 
the investigational product 
• 
Restart the investigational product only if a competing 
etiology is identified and ALP is returning close to 
baseline 
>2 times ULN 
g 2 times ULN 
or 
In case of pre-existing 
Gilbert9s, doubling of 
direct bilirubin + 
exceeding ULN 
• 
Work up for cholestasis  
• 
Interrupt the investigational product 
• 
Repeat liver profile within 2-3 days 
• 
Restart the investigational product only if a competing 
etiology is identified and ALP is returning close to 
baseline 
1-2 times ULN  
  
>3 mg/dl 
or 
In case of pre-existing 
Gilbert9s, doubling of 
direct bilirubin + 
exceeding ULN  
• 
Work up for cholestasis  
• 
Interrupt the investigational product 
• 
Repeat liver profile within 2-3 days 
• 
Restart the investigational product only if a competing 
etiology is identified and ALP is returning close to 
baseline 
7.6.1.3 Temporarily interrupting the study drug for important biological considerations: 
• Total CPK >5x ULN (if normal at baseline), or >5x baseline (if elevated at baseline)  
• 
Total CPK >3 x ULN (if normal at baseline) or >3x baseline (if elevated at baseline) 
associated with: 
a. Elevation for more than 2 weeks OR 
b. Symptoms concerning for rhabdomyolysis/myositis. 
• Estimated glomerular filtration rate (e-GFR; calculated from CKD-EPI Equation) f40 
mL/min/1.73 m2 and where the value is reconfirmed between 24 to 72 hours from the time 
the site is made aware of the initial results Additionally, any participant who requires renal 
replacement therapy for any reason should also be discontinued from the study medication. 
• 
Complete blood counts (CBCs): hemoglobin <10 g/dL; platelets <100,000/µL; and 
absolute neutrophil count <1,000 /µL. 
7.6.2 Discontinuation of Participant From the Study 
A study completion CRF, which includes the reason for discontinuation, must be completed for 
all participant who are discontinued from the study. If the participant is discontinued 


 
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prematurely, the study completion CRF should clearly indicate the reason for discontinuation. If 
the participant discontinues due to an AE, an AE CRF must be completed. 
1. Participant9s decision to withdraw consent for trial participation: In case of withdrawal 
of consent and unless otherwise stated by the participant in the withdrawal of consent, 
investigator will be encouraged to obtain information from the participant in order to 
follow the medical status of the participants (especially when the participant withdraws 
his/her consent after having experienced an AE/SAE or an efficacy endpoint). Principal 
Investigator or designee(s) must make reasonable attempts to contact participants that 
are lost to follow-up, in order to obtain health status and reason for withdrawal. These 
attempts must be documented in the study forms. 
2. Noncompliance to the protocol requirements, including any major deviation which may 
influence the results/outcome of primary endpoint or participant safety.  
3. Either the investigator or the sponsor decides that discontinuing the participant from 
the study is in the participant9s best interest. 
4. A participant may also be discontinued from the study by the regulatory authorities or 
institutional review board (IRB). 
5. If the participant becomes pregnant, as specified in Section 12.4.5. 
7.6.3 Lost to Follow-up 
Principal Investigator or designee(s) must make reasonable attempts to contact participants that 
are lost to follow-up, in order to obtain health status and reason for withdrawal. These attempts 
must be documented in the study forms. 
7.6.4 Discontinuation of Trial 
If the Investigator, the Sponsor or the Medical Monitor becomes aware of conditions or events that 
suggest a possible hazard to subjects if the clinical study continues, then the clinical study may be 
terminated after appropriate consultation among the involved parties. Also, the clinical study may 
be terminated at the Sponsor9s discretion in the absence of such a finding. Should the study be 
terminated and/or the site closed for whatever reason, a copy of all documentation pertaining to 
the study and the study medication must be returned to the Sponsor. All site-specific documents 
will be archived at study site. 




 
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* 
*Round-up quantity 
8.1.2 Comparator Drug Description 
Placebo will be used as comparator, which will be formulated as identical appearing tablets, and 
will contain all the excipients mentioned in Table 4, except Saroglitazar Magnesium. The IP will 
be manufactured following pharmaceutical grade cGMP guidelines. 
8.2 
DOSAGE AND TREATMENT SCHEDULE 
Participants will ingest either Saroglitazar Magnesium 4 mg or Placebo orally once each morning 
before breakfast without food for a period of 24 weeks. 
However, on every scheduled clinical visit, participants will be instructed not to take the IP until 
after fasting blood sample collection. 
8.3 
PACKAGING, LABELLING AND SUPPLY 
The study medication will be packaged by the sponsor according to all the local legal requirements. 
 
 
 


 
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An adequate quantity of the study medication will be shipped to each site. The site9s investigational 
drug pharmacy will maintain an accurate record of the receipt of the study medication, including 
the date received. Until dispensed to the participants, the study medication will be stored at room 
temperature (20°C to 25°C or 68°F to 77°F) in a dry place at the study site or pharmacy in a secure 
locked area and that is accessible to authorized personnel only. 
8.4 
STORAGE CONDITIONS 
Investigational products will be stored at room temperature (20°C to 25°C or 68°F to 77°F) in a 
dry place excursions permitted to 15-30°C (59-86°F) at the study site or pharmacy. If the IP 
temperature extends outside the 20°C to 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°C to 
30°C (59ºF to 86ºF), quarantine is not required, and the IP is acceptable for use. If the excursion 
is outside of the 15°C to 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°C to 300 C, it will be 
considered as a protocol deviation. All IP supplies in the study will be stored at the study site or 
pharmacy in a secure locked area that is accessible to authorized personnel only. Participants 
should store the study medication at 25°C (77°F) with excursions permitted to 15 to 30°C (59 to 
86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. 
8.5 
BLINDING/UNBLINDING 
The study will be performed in a double-blind manner. All study medication will be supplied in 
identical packages and study medication bottles. The study medication tablets will be similar in 
color, smell, taste, and appearance, thereby maintaining double-blind conditions. 
The intent of blinding is to limit the occurrence of conscious and unconscious bias in the conduct 
and interpretation of the clinical study. The essential aim of blinding, therefore, is to prevent 
identification of the treatments by the investigator, participant, and others associated with the 
conduct of the study until all such opportunities for bias have passed. 
All members of the clinical study team, investigators, and site staff will be blinded to treatment 
assignments while the study is in progress. In addition, biostatisticians who are directly involved 
in the analysis of the study results will remain blinded to treatment assignment while the study is 
in progress. For the purposes of Data and Safety Monitoring Board (DSMB) review, a separate 
unblinded statistician will be utilized; further details will be included in the DSMB Charter. 
In case a participant experiences an AE, which meets the criteria of a Suspected Unexpected 
Serious Adverse Reaction (SUSAR) in order to fulfill expedited regulatory reporting requirements 


 
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or in the event of a medical emergency during the study where the knowledge of participant 
treatment is required, the investigator will unblind the treatment assignment for a specific 
participant via IWRS. In this event, neither the Sponsor representatives nor any other study 
personnel will have access to the treatment code. This level of blinding will be maintained 
throughout the conduct of the study. The Investigator should notify the Sponsor prior to unblinding 
a participant if there is sufficient time. Further, the Sponsor must be informed whenever the 
randomization code is broken and the reasons for unblinding. 
8.6 
METHOD OF ASSIGNING PARTICIPANT TO TREATMENT GROUP 
Participants will be randomized in a 1:1 ratio to receive Saroglitazar Magnesium 4 mg once daily 
orally or Placebo. The randomization scheme will be stratified by clinical center. This scheme will 
ensure that the two groups will be balanced by calendar time of enrollment (to minimize secular 
effects) and by clinic (to minimize clinic-specific effects of differences in patient populations and 
management). 
The randomization scheme will be prepared by an unblinded statistician or designee. Requests for 
randomizations will be made by the clinics using IWRS (Interactive Web Response System). An 
assignment will be issued only if the database shows that the patient is eligible, has signed the 
consent statement, and has had all required baseline data keyed into the database. 
Treatment assignments are double masked throughout the study until all data collection for the 
trial has been completed (i.e., after completion of the post-trial follow-up for all participants). The 
block randomization schedule will be generated using SAS® software (Version: 9.4 or higher; SAS 
Institute Inc., USA). 
8.7 
SELECTION OF DOSES 
Saroglitazar Magnesium 4 mg has been selected for this study based on previous 
pharmacokinetics, dose ranging studies, HIV lipodystrophy study, and two published studies in 
primary NAFLD[30, 31]. 
8.8 
CONCOMITANT MEDICATIONS AND OTHER RESTRICTIONS 
8.8.1 Previous and Concomitant Medications 
Any medication the participant takes, other than the study drug, including herbal and other 
non-traditional remedies, is considered a concomitant medication. All concomitant medications 
and any changes in the dosage or regimen of a concomitant medication for the 6 months preceding 
Visit 1 (screening visit) until the end of the study (i.e., the safety follow-up visit-12) must be 
recorded in the CRF. 


 
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8.8.2 Permitted Concomitant Medication: 
• With the exception of prohibited concomitant medications, the following medications that 
the participants have been taking at stable dosages for at least 3 months before screening 
(Visit 1) until the end of study will be permitted as concomitant medications: 
o Lipid-lowering drugs- statins and fibrates, 
o Anti-hypertensives 
o Stable ART regimen. 
• The SGLT2 inhibitors (e.g. canagliflozin, empagliflozin, dapagliflozin, etc.), glucose0
dependent insulinotropic polypeptide (GIP) and/or GLP-1 agonists (e.g. semaglutide, 
exenatide, liraglutide, lixisenatide, tirzepatide etc.) that the participants have been taking 
stable doses for at least 6 months before screening (Visit 1) until the end of study 
• Antidiabetic medications i.e., metformin, sulfonylureas, insulin, dipeptidyl peptidase 4 
inhibitors (gliptins) will be permitted if the dose has been stable for 3 months prior to 
screening (visit 1) until the end of study  
• In case of further adjustment of anti-diabetic treatment is needed during the study, the 
following guidance should be exercised in line with local standard practice as considered 
appropriate by treating physician:  
o Maximizing doses of metformin, dipeptidyl peptidase 4 inhibitors (DPP-4 
inhibitors or gliptins), sulfonylurea (excluding those more prone to induce 
hypoglycemia).  
o For participants receiving SGLT2 inhibitors, GIP and/or GLP1-RAs at screening, 
it is recommended to avoid increase in dose of SGLT2 inhibitors, GIP and/or GLP1 
RAs throughout study. 
o For participants not receiving SGLT2 inhibitors, GIP and/or GLP1-RAs at 
screening, treatment with SGLT2 inhibitors, GIP and/or GLP1-RAs should not be 
started throughout study. 
• 
The Investigator at his/her discretion will also be allowed to offer a rescue medication for 
clinically significant conditions correlated with the laboratory findings, if required, 
however, such interventions shall be recorded in the eCRF with description of type of 
intervention, dose and duration. Throughout the study, investigators may prescribe any 
concomitant medications or treatments deemed necessary to provide adequate supportive 
care except for prohibited medications listed in Section 8.8.3. If medication given is in 
violation to the protocol, then such subjects will be withdrawn from the trial. Allowed over-
the-counter medications (OTC) such as acetaminophen (maximum 1 gram/day), ibuprofen 
(maximum 800 mg/day), naproxen (maximum 440 mg/day), antacids such as H2 receptor 
blockers, and proton-pump inhibitors for shorter duration (up to 14 days) as per the 
investigator9s discretion. Participants will also be instructed about the importance of not 


 
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taking any other medication throughout the study (including OTC medications) without 
consulting the Investigator. 
• The stable doses of allowed concomitant medications should not be changed either 
at/between the screening visits or at randomization visit. Upon randomization of 
participants, they will be discouraged from making any changes in allowed concomitant 
medications and encouraged to make alternative options. However, the site investigator at 
his/her discretion can modify the dose of the current regimen or change any permitted 
medication to another permitted medication if clinically indicated. 
• The site investigator should be alerted if, during the course of the study, a participant 
requires a new medicine or therapy or a change to an established dosing regimen. All 
medications that target NAFLD or NASH, or have been suggested to target the underlying 
causes of NAFLD or NASH, should be reviewed and agreed upon by the Investigator and 
Sponsor9s representatives including Medical Expert/Medical monitor before being taken 
by the participant. 
8.8.3 Prohibited Concomitant Medications 
Participants are not permitted to take the following medications during the study period/until the 
end of the study. 
• Parenteral nutrition and Vitamin E (>200 IU/day). Increase in dose of Vitamin E is 
not allowed throughout the study 
• Other drugs with potential effects on NAFLD, such as ursodeoxycholic acid, 
pentoxifylline, glutathione, orlistat, betaine, or non-prescribed complementary 
alternative medications 6 months prior to screening until the end of the study. 
• Thiazolidinediones, telmisartan 3 months prior to screening until the end of the 
study. 
• Chemotherapy.  
• Other investigational medications 3 months prior to screening until the end of the 
study. 
• Any medication that causes hepatic steatosis (e.g., amiodarone, tamoxifen, 
methotrexate, systemic glucocorticoids, anabolic steroids, tetracycline, estrogens in 
doses higher than used in oral contraceptives or post-menopausal hormone 
replacement therapy [except for transgender women on stable dosing], vitamin A, 
L-asparaginase, valproate, chloroquine, stavudine) 3 months prior to screening until 
the end of the study. 
• Known CYP2C8 inhibitors/substrates (Refer Appendix 2 for the 8List of Known 
CYP2C8 Inhibitors/Substrates9) 4 weeks prior to screening until the end of the study. 


 
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8.8.4 Other Restrictions 
8.8.4.1 
Alcohol 
Participants are encouraged to stop alcohol consumption entirely during the study. Details of 
alcohol consumption will be evaluated through the AUDIT questionnaire throughout the study 
period (Refer Appendix 5) (Note: 1 unit = 12 ounces of beer, 4 ounces of wine or 1 ounce of 
spirits/hard liquor. 
8.8.4.2 
Diet and Exercise 
Participants are encouraged to maintain lifestyle modifications, including diet and exercise, 
previously undertaken (Refer Appendix 8). Participants should make no major changes in the type 
or amount of exercise in which they take during the study. 
8.9 
OVERDOSE AND DRUG INTERACTION 
No incidence of overdose with Saroglitazar Magnesium has been reported. In case of overdose 
with Saroglitazar Magnesium, general supportive care of the participant is indicated, including 
monitoring of vital signs and observation of clinical status. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


 
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8.10 
TREATMENT COMPLIANCE 
Participants will be instructed by study personnel/coordinator on the importance of being 
compliant with the use of the study drug throughout the clinical trial. At each study visit, previously 
dispensed unused study drug will be retrieved by the study personnel/coordinator from respective 


 
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participant and compliance will be assessed. Compliance will be also documented by recording 
the number of tablets dispensed, number of tablets consumed by participant, the number of tablets 
missed, if any, and number of tablets returned back to study personnel/coordinator since the last 
study visit. If treatment is interrupted, whatever the cause, duration, and reason of the interruption 
should be documented appropriately in source records. Although 100% compliance to study 
medication is desired and should be encouraged throughout the treatment phase, a compliance of 
g80% and f120% over a total duration of treatment will be considered acceptable. 


 
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9. 
OBSERVATIONS 
9.1 
CRITERIA FOR SAFETY 
Safety will be assessed at each scheduled visit and assessment will include AEs/SAE, clinical 
laboratory tests, vital signs, physical examination, and body weight assessment. 
9.1.1 Safety and Tolerability Variables 
The following safety assessments will be evaluated through the study period: 
1. Frequency and severity of treatment-emergent AEs (TEAEs, including treatment-
emergent serious AEs [TESAEs], TEAE leading to discontinuation, TEAE related to 
IP, AE of special interest [DILI, and weight gain], and SUSARs). 
2. Changes in physical examination 
3. Changes in vital signs. 
4. Changes in laboratory parameters  
9.1.2 Medical History and Demographic Information 
The medical history comprises: 
• General medical history. 
• Medication history. 
• Alcohol history. 
The following demographic information will be recorded: 
• Gender. 
• Age. 
• Ethnicity. 
• Race.  
9.1.3 Clinical Laboratory Assessments 
9.1.3.1 
Sample Collection 
Blood samples will be collected for clinical laboratory testing at the time points indicated in the 
Section 2 Schedule of Assessments. . All laboratory investigations will be performed with at least 
8-hours fasting blood samples. Safety laboratory variables are listed below: 
1. CBC includes hemoglobin, white blood cell count with differential, absolute neutrophil 
count (ANC), red blood cell count, platelet count, mean corpuscular volume, and 
hematocrit. 
2. INR. 
3. CMP includes potassium, sodium, chloride, serum bicarbonate, calcium, phosphate, 
blood urea nitrogen (BUN), creatinine, uric acid, glucose, total protein, and LFT (ALT, 
AST, ALP, bilirubin [total, direct, and indirect bilirubin], and serum albumin). 


 
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4. e-GFR (will be calculated by CKD-EPI equation using creatinine value from CMP, 
refer Appendix 6). 
5. CPK. 
6. Urine Analysis: 
• Urine Chemical Examinations: pH, specific gravity, protein, glucose, bilirubin, 
ketone bodies, and nitrite 
• Urine Microscopy: epithelial cells, RBCs, pus cells, cast, and crystals. 
• Lipid profile includes TG, HDL, LDL, VLDL, TC, and non-HDL-C 
9.1.3.2 
Urine and Serum Pregnancy Tests 
Urine and serum pregnancy test (participants of child-bearing potential) will be processed by a 
local laboratory during all scheduled visits (Section 2 Schedule of Assessments). 
9.1.3.3 
Vital Signs 
The following vital signs will be assessed at time points described in the Schedule of Assessments 
(Section 2): 
• Sitting SBP and DBP (mmHg). 
• Heart rate (pulse) (beats per minute). 
• Body temperature (°F). 
• Respiratory rate (breaths per minute). 
Vital signs will be measured before any blood draw that occurs at the same visit and after the 
participant has been resting for at least 5 minutes. 
9.1.3.4 
Physical Examinations 
Physical examinations will be performed in accordance with the Schedule of Assessments 
(Section 2). Participants9 body weight (standing scale) will be recorded during all physical 
examinations. The extremities will be examined for any signs of edema in complete and targeted 
physical examination. Height will be recorded at Screening Visit only. Standardized hip 
circumference and minimum waist circumference (Refer Appendix 9) will be measured, as per 
time points mentioned in the Schedule of Assessments. 
9.2 
EFFICACY 
9.2.1 Primary Endpoint 
Change from baseline in hepatic fat content at Week 24/EOT  


 
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9.2.2 Secondary endpoints 
The following secondary efficacy endpoints will be evaluated from baseline to end-of-treatment 
(Week 24): 
1. Proportion of participants with reduction of at least 30% in hepatic fat content from 
baseline to 24 week/EOT  
2. Change from baseline in LSM, CAP, and FAST score at Week 24/EOT. 
3. Change from baseline in enhanced liver fibrosis score at Week 24/EOT. 
4. Change from baseline in PRO-C3 levels at Week 24/EOT. 
5. Change from baseline in FIB-4, APRI and NFS at Week 24/EOT. 
6. Change from baseline in liver enzyme parameters (ALT and AST levels) at Week 
24/EOT. 
7. Change from baseline in TG, HDL, LDL, VLDL, total cholesterol, and non-HDL 
cholesterol at Week 24/EOT. 
8. Change from baseline in fasting plasma glucose at Week 24/EOT. 
9. Change from baseline in body weight, BMI, hip circumference, and minimum waist 
circumference at Week 24/EOT. 
10. Change from baseline in SF-36 Questionnaire mental and physical component scores 
at Week 24/EOT 
9.2.3 Exploratory Endpoints 
1. Change from baseline in C-peptide at Week 24/EOT 
2. Change from baseline in Insulin, HbA1c, and TG/HDL ratio at Week 24/EOT 
3. Change from baseline in Free fatty acids at Week 24/EOT 
4. Change from baseline in NMR lipoprofile at Week 24/EOT 
5. Change from baseline in ELF levels at Week 24/EOT 
9.2.4 Health-related Quality of Life (HR-QoL) 
Subjective HR-QoL assessments will be measured using the SF-36 Version 2.0 (See Appendix 4), 
which is a 36-item patient response questionnaire that measures HR-QoL across 8 domains, which 
has both physical and emotional based components. The 8 domains are physical functioning, role 
physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental 
health. 
9.2.5 VCTE/FibroScan® 
Liver stiffness measurements will be performed by VCTE using the FibroScan as per time points 
mentioned in the Schedule of Assessments (Section 2). The appropriate FibroScan measurement 
probe should be used based on the manufacturer9s recommendation for probe choice according to 
chest circumference and age.  


 
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VCTE/FibroScan® procedure will be performed based on institutional practice. The 
VCTE/FibroScan® exam will only be considered acceptable if it results in 12 (or based on 
institutional practice) measurements with a 70% success rate, and the interquartile range for liver 
stiffness measurement (LSM) is less than 30% of the value of the median. CAP will be 
simultaneously measured with LSM using the same probe. 
9.2.6 Blood Samples 
Multiple venipunctures should be avoided when collecting blood samples. It is recommended to 
collect blood sample for safety and efficacy measurement as per time points mentioned in the 
Schedule of Assessments (Section 2). 
9.2.7 Total Amount of Blood 
The total amount of blood drawn from each participant will not exceed 292 mL during the course 
of study. 
9.2.8 Biospecimen Banking 
Biospecimens for banking include plasma and serum. Approximately 86 mL of whole blood will 
be collected as per time points mentioned in the Schedule of Assessments (Section 2).  
Biospecimens for banking also include optional collection of stool. This will be collected as per 
time points mentioned in the Schedule of Assessments (Section 2). The biospecimens will be 
shipped to the Indiana University Biorepository. 
9.2.9 ELF score 
Enhanced liver fibrosis score is an extracellular matrix marker set consisting of tissue inhibitor of 
metalloproteinases 1 (TIMP-1), amino-terminal pro-peptide of type III procollagen (PIIINP), and 
hyaluronic acid (HA) showing good correlations with fibrosis stages in chronic liver disease. These 
biomarkers will be measured on the stored sample. 
9.2.10 PRO-C3 
PRO-C3 is the pro-peptide of type III collagen and it is an accurate biomarker for the formation of 
fibrotic tissue in the liver. Type III collagen is one of the most abundant proteins in fibrotic tissue 
and is a reliable biomarker for liver fibrosis. These biomarkers will be measured on the stored 
sample. 


 
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9.2.11 NFS 
The NFS is based on six readily available variables (age, BMI, hyperglycemia, platelet count, 
albumin, and AST/ALT ratio) and is calculated using the published formula. A score 0.676 had 
67% sensitivity and 97% specificity to identify the presence of advanced fibrosis. 
Formula: -1.675 + 0.037 × Age (years) + 0.094 × BMI (kg/m2) + 1.13 × IFG/diabetes (yes = 1, 
no = 0) + 0.99 × AST/ALT ratio 3 0.013 × Platelet (× 109 /L) 3 0.66 × Albumin (g/dL). 
It will be calculated at Weeks 4, 12, and 24/EOT. 
9.2.12 FIB-4 index 
FIB-4 index is an algorithm based on platelet count, age, AST, and ALT that offers dual cut-off 
values (participants with score 3.25 are likely to have advanced fibrosis). 
Formula: Age (years) × AST [U/L]/(Platelet [109/L] × ALT [U/L]1/2). 
It will be calculated at Weeks 4, 12, and 24/EOT. 
9.2.13 APRI 
Aspartate aminotransferase [AST] to platelet ratio index (APRI) is a non-invasive marker of 
advanced fibrosis in participants with NAFLD. 
Formula: (AST [IU/L])/(AST upper limit of normal [IU/L])/(Platelet [109 /L]) × 100. 
It will be calculated at Weeks 4, 12, and 24/EOT. 
Microbiome Assessment 
Stool specimens for microbiome assessment will be collected and stored in freezer at -80°C as per 
time points mentioned in the Schedule of Assessments (Section 2). Further metagenomics, 
transcriptomic, and metabolomics studies will be conducted as an ancillary study to the parent 
trial. Stool banking is optional and requires additional consent. 
9.3 
APPROPRIATENESS OF MEASUREMENT 
The endpoints chosen for the given study (safety and efficacy) are appropriate for the assessment 
of the outcome of the study. 


 
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9.4 
ABNORMAL LABORATORY FINDINGS 
A clinically significant value outside the normal or reference range in a routine safety 
assessment, such as clinical laboratory, vital signs, may signify an AE finding. Additional 
examinations or repetition of test will be performed as medically indicated. 
If the investigator considers the abnormality as of 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 investigator or designee. 
For any abnormal test result that meets one of the above conditions except for the last condition, 
the investigator 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 the severity, seriousness, duration, resolution, action taken, and 
its association with the study medication. The study participant may be withdrawn or terminated 
from the study depending on the seriousness of the AE(s). 


 
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10. 
INVESTIGATIONAL PLAN 
10.1 
TRIAL DESIGN AND PLAN 
This phase 2a study is a randomized, placebo-controlled, double-blind, multicenter, parallel-
arm trial to evaluate the safety and efficacy of Saroglitazar Magnesium 4 mg compared with 
placebo in NAFLD in PLWH. Eligible participants will be randomized in a 1:1 ratio to 
receive Saroglitazar Magnesium 4 mg or placebo. This study plans to enroll approximately 
120 PLWH with NAFLD from within the catchment area of approximately 8 participating 
clinical centers or community HIV practices in US. The study will be conducted over a 
period of 36 weeks, including upto 8-week screening period, 24-week treatment period and 
4-week safety follow-up period (Figure 1 and Section 2 Schedule of Assessments). 
Participants will be evaluated at the study sites for 10 scheduled visits. 
• Screening: Week -8 (Visit 1) and Week -6 (Visit 2); Screening period will last up to 8 weeks. 
Visit 2 must occur at least 14 days after Visit 1. 
• Randomization: Day 1 (Visit 3) can occur at any time point after visit 2 but within 8 weeks 
of screening period and participant can be randomized upon confirmation of eligibility 
criteria. 
• Treatment Period: Week 0 (Visit 3), Week 2 (Visit 4), Week 4 (Visit 5), Week 8 (Visit 6), 
Week 12 (Visit 7), Week 16 (Visit 8), Week 24/EOT (Visit 9) 
• Safety Follow-up: Week 28 (Visit 10)  
Eligibility of subject will be confirmed as per local reading of MRI-PDFF. Baseline and Week 
24/EOT MRI-PDFF assessment for Primary endpoint will be read by central laboratory. Details 
will be mentioned in Imaging manual. All laboratory investigations will be performed with at 
least 8-hours fasting blood samples. Participants will be monitored during the study at every visit 
for development of any AEs, including treatment emergent AEs and DILI. 
10.2 
STUDY PROCEDURES AT EACH VISIT 
10.2.1 Screening Period 
Visit 1: Screening: screening data collection (may occur over more than 1 calendar day) (-8 
Weeks [-56 Days]) 
Before signing the consent, study procedures and all possible risks will be explained to the 
potential participant. After providing the written informed consent, the following study 
procedures will be performed: 
• Check inclusion/exclusion criteria. 
• Demographics (age, gender, race, ethnicity). 
• Medical history. 
• Concomitant medication. 
• Hip circumference and minimum waist circumference. 


 
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• Weight, height, BMI, and vital signs measurement. 
• Complete physical examination. 
• Serum pregnancy test for all female participants of childbearing potential 
• Fasting laboratory evaluations 
• Biospecimen banking (plasma, serum). 
• Optional biospecimen banking if consent given: stool specimen for microbiome 
assessment.  
• FibroScan®/VCTE for LSM and CAP 
• MRI-PDFF 
• AUDIT alcohol history 
• Monitoring of diet, exercise, avoidance of alcohol, and other hepatotoxic agents (Refer 
Appendix 8). 
• Serology tests (HAV IgM, HBsAg and HCV RNA) 
• Urinalysis. 
• AE assessments. 
Visit 2: Screening: [-6 Weeks (-42 Days), +1 Week] 
• Confirm inclusion/exclusion criteria 
• Weight and BMI 
• Targeted physical examination 
• Vital signs measurement. 
• Concomitant medication  
• Fasting laboratory evaluations 
• Urine Pregnancy test for all female participants of childbearing potential 
• AE assessments. 
10.2.2 Visit 3: Randomization Visit: [0 Week. Day 1, +3 days) 
• Check inclusion/exclusion criteria  
• Concomitant medication. 
• Weight, BMI, and vital signs measurement. 
• Hip circumference and minimum waist circumference. 
• Targeted physical examination. 
• AUDIT alcohol history 
• Fasting laboratory evaluations 
• Biospecimen banking (plasma, serum) 
• AE assessments. 
• Urine pregnancy test for all female participants of child-bearing potential. 
• Randomize, administer, and dispense study medication. 
• SF-36 questionnaire (Refer Appendix 4)  


 
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• Monitoring of diet, exercise, avoidance of alcohol, and other hepatotoxic agents (Refer 
Appendix 8). 
10.2.3 Treatment and Follow-up Period: Week 2 to Week 28 
Participants will return for follow-up visits at Weeks 2, 4, 8, 12, 16, 24 and 28 after 
randomization. The window period of all the visits are as mentioned in Section 2 Schedule of 
Assessments. The specific study procedures will be performed at each follow-up visit as 
described below: 
Visit 4: Week 2 visit (Day 15 ± 3 days) 
• Concomitant medication 
• AUDIT alcohol history (Refer Appendix 5 for AUDIT Questionnaire) 
• Monitoring of diet, exercise, avoidance of alcohol, and other hepatotoxic agents (Refer 
Appendix 8). 
• Weight and BMI.  
• Vital signs measurement. 
• Study medication administration and compliance monitoring.  
• Targeted physical examination. 
• Fasting laboratory evaluations 
• Urine pregnancy test for all female participants of child bearing potential. 
• AE assessments. 
Visit 5: Week 4 visit (Day 29 ± 3 days) 
• Concomitant medication 
• AUDIT alcohol history (Refer Appendix 5 for AUDIT Questionnaire) 
• Monitoring of diet, exercise, avoidance of alcohol, and other hepatotoxic agents (Refer 
Appendix 8). 
• Weight and BMI.  
• Vital signs measurement. 
• Study medication administration and compliance monitoring 
• Targeted physical examination.  
• Fasting laboratory evaluations 
• Biospecimen banking (plasma, serum). 
• Urine pregnancy test for all female participants of child bearing potential. 
• AE assessments. 
Visit 6: Week 8 visit (Day 58 ± 3days 
• Concomitant medication 


 
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• AUDIT alcohol history (Refer Appendix 5 for AUDIT Questionnaire). 
• Monitoring of diet, exercise, avoidance of alcohol, and other hepatotoxic agents (Refer 
Appendix 8). 
• Weight and BMI. 
• Vital signs measurement. 
• Study medication administration and compliance monitoring  
• Targeted physical examination.  
• Fasting Laboratory evaluations 
• Urine pregnancy test for all female participants of child bearing potential. 
• AE assessments. 
Visit 7: Week 12 visit (Day 85 ± 3 days) 
• Concomitant medication 
• AUDIT alcohol history (Refer Appendix 5 for AUDIT Questionnaire) 
• Monitoring of diet, exercise, avoidance of alcohol, and other hepatotoxic agents (Refer 
Appendix 8). 
• Weight, BMI, hip circumference and minimum waist circumference. 
• Vital signs measurement. 
• Study medication administration, dispensing, and compliance monitoring 
• Targeted physical examination. 
• Fasting Laboratory evaluations 
• Biospecimen banking (plasma, serum). 
• FibroScan®/VCTE  
• SF-36 questionnaire (Refer Appendix 4) 
• Urine pregnancy test for all female participants of child bearing potential. 
• Urinalysis. 
• AE assessments. 
Visit 8: Week 16 visit (Day 113 ± 3 days) 
• Concomitant medication 
• AUDIT alcohol history (Refer Appendix 5 for AUDIT Questionnaire). 
• Monitoring of diet, exercise, avoidance of alcohol, and other hepatotoxic agents (Refer 
Appendix 8). 
• Weight, BMI.  
• Vital signs measurement. 
• Study medication administration and compliance monitoring.  
• Targeted physical examination. 
• Fasting Laboratory evaluations 
• Urine pregnancy test for all female participants of child bearing potential. 


 
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• AE assessments. 
Visit 9: Week 24/EOT visit (Day 169 ± 3 days) 
• Concomitant medication 
• AUDIT alcohol history (Refer Appendix 5 for AUDIT Questionnaire). 
• Weight, BMI, hip circumference and minimum waist circumference.  
• Vital signs measurement.  
• Study medication administration and compliance monitoring 
• Complete physical examination.  
• Fasting Laboratory evaluations 
• Biospecimen banking (plasma, serum) 
• Optional biospecimen banking if consent given: stool specimen for microbiome 
assessment 
• FibroScan®/VCTE 
• MRI-PDFF 
• Monitoring of diet, exercise, avoidance of alcohol, and other hepatotoxic agents (Refer 
Appendix 8). 
• SF-36 questionnaire (Refer Appendix 4). 
• Serum pregnancy test for all female participants of child bearing potential. 
• Urinalysis. 
• AE assessments. 
10.2.4 Safety Follow-up Period: Visit 10: Week 28 visit (Day 197 ± 3 days) 
Following assessment will be performed at the end of study visit (Week 28): 
• Urine pregnancy test for all female participants of child bearing potential. 
• Vital signs measurement. 
• Targeted physical examination 
• Weight and BMI 
• Fasting Laboratory evaluations 
• Concomitant medication 
• AE assessment. 
• Biospecimen banking (plasma) 
• Study completion 
10.2.5 Early Termination (ET) visit 
Participants prematurely discontinued from the study would be encouraged to complete an ET 
visit within 30 days of last dose. The investigator should make every effort to perform 
following assessments at the early termination visit in case if any participant discontinues from 


 
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the study prior to completion of his/her study treatment period (i.e. termination prior to Week 
24 visit):  
• Complete physical examination 
• Vital signs measurement. 
• AE assessment. 
• Concomitant medication review 
• Monitoring of diet, exercise, avoidance of alcohol, and other hepatotoxic agents (Refer 
Appendix 8). 
• Compliance review for study medication 
• Weight, Hip and waist minimal circumference measurements 
• Fasting Laboratory evaluations 
• Serum pregnancy test for all female participants of child bearing potential. 
10.3 
STANDARDIZED QUESTIONNAIRES 
Alcohol Use Disorders Identification Test (AUDIT) is a 10-item questionnaire with a simple 
scoring scale. The purpose of the questionnaire is to ascertain whether there is significant alcohol 
consumption prior to enrollment or after randomization. (Appendix 5). 
36-Item Short Form Health Survey (SF-36) is an easily administered questionnaire that will be 
used to patient-reported health-related quality of life. (Appendix 4). 
10.4 
ADHERENCE TO PROTOCOL 
The investigator and the site staff shall strictly adhere to the protocol and International Council for 
Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All participants will be 
encouraged to strictly follow the instructions given to them as per this protocol. For any deviation 
or violation from protocol considered serious, the participant may be withdrawn from the study at 
the discretion of the sponsor or the investigator. 
10.5 
 DATA AND SAFETY MONITORING BOARD 
External oversight for this trial will be provided by an unblinded DSMB. An unblinded DSMB 
may meet regularly as per the DSMB charter to review interim data. The primary responsibility of 
the DSMB is to protect the safety and welfare of the participants participating in this clinical trial 
and to ensure the integrity of the clinical trial. 
Specifically, for this study, the DSMB will be responsible for: 
• Examining accumulated safety data and compliance data in order to make 
recommendations concerning continuation, termination, or modification of the trial based 
on the safety of the interventions under study. 


 
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• Reviewing major trial design modifications proposed by Sponsor or the investigator(s) 
prior to implementation of those modifications. 
• The DSMB may review the safety data at any time as warranted by emerging results. Based 
on review of the safety data, the DSMB can recommend continuation of the study 
unchanged, study interruption, study termination, modification of the trial, or alteration in 
the DSMB monitoring plan. 
Further information regarding the DSMB review process will be provided in the DSMB charter. 
10.6 
PROTOCOL DEVIATIONS 
For the purposes of this study, no distinction will be made between protocol violation and 
deviation. Deviation may be categorized as minor protocol deviation or major protocol deviation. 
Classification of protocol deviations as major or minor will be assessed at the blinded data review 
meeting prior to database lock. Minor protocol deviation includes any deviation that do not 
necessarily influence the results/outcome of primary endpoints or participant safety. Minor 
protocol deviation does not require immediate notification to the IRB unless otherwise specified 
by IRB requirements. All minor protocol deviations will be noted in monitoring reports and discuss 
with investigator/site personal. Major protocol deviation includes any violation, which may 
influence the results/outcome of primary endpoints or participant safety. Major protocol deviation 
must be reported immediately to the IRB, as specified by the IRB requirements. All major protocol 
deviations will be reported to the sponsor immediately (Note: persistent non-compliance of minor 
protocol deviations may rise to the level of major protocol deviations). As a result of protocol 
deviations, corrective actions are to be developed and implemented promptly. 
The sponsor reserves the right to terminate the study at a given center in the event of monitoring 
and/or auditing findings of serious or persistent non-compliance with the protocol, Standard 
Operating Procedures (SOPs), GCP, and/or applicable regulatory requirement(s) by an 
investigator/Institution. In all cases of site closure due to protocol deviations, the IRB and 
regulatory authority will be informed. The clinical study report (CSR) will provide a list of protocol 
deviations/violations in a separate section. The results will be analyzed for all participants 
regardless of protocol deviation occurrence. 
Protocol deviations/violations will include but are not limited to the following:  
• Violations of inclusion and exclusion criteria at randomization. 
• Participants who met the withdrawal criteria but were not withdrawn. 
• Participants who received the wrong treatment or incorrect dose. 
• Participants who received an excluded medication. 
• Serious non-compliance with regulatory or GCP guidelines. 


 
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11. 
STATISTICAL CONSIDERATIONS 
11.1 
GENERAL CONSIDERATIONS 
A separate Statistical Analysis Plan (SAP) will be prepared and finalized before database lock. 
SAP will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. The SAP will serve as a compliment to the protocol 
and supersedes it in case of differences. 
The statistical evaluation will be performed using SAS® software version 9.4 or higher (SAS 
Institute, Cary, NC). All data will be listed and summary tables will be provided. Summary 
statistics will be presented by treatment group. Continuous variables will be summarized for the 
measured values and change from baseline values using the number of observations, mean, 
standard deviation, median, minimum, and maximum. Categorical variables will be summarized 
with counts and percent for each category.  
11.2 
PARTICIPANT EVALUABILITY 
Assignment to all analysis populations, including decisions made on inclusion/exclusion for the 
per-protocol population and other data handling issues will be agreed on and documented in a 
blinded data review meeting, to occur (with report finalized) prior to breaking the blinded 
treatment assignment code and locking the database. Protocol deviations and their impact on 
analysis populations will be listed for all randomized participants. 
11.3 
ANALYSIS POPULATIONS 
The following analysis populations are defined: 
All Enrolled Population: includes all participants who signed an ICF. This analysis population 
will be used to summarize participant disposition and pre-treatment AEs. 
Safety Population: includes all participants who received at least one dose of study drug (full or 
partial). Participants in the safety analysis population will be analyzed according to the treatment 
received. This analysis population will be used for all safety analyses. 
Intent-to-treat (ITT) Population: includes all participants who are randomized and receive at 
least one dose of the study drug (full or partial). Participants in the ITT population will be analyzed 
according to the treatment group they are assigned at randomization. The ITT population will be 
the primary analysis population for all efficacy analyses. 
Per-Protocol (PP) Population: includes all participants in the ITT population, received at least 
one dose of study drug, who are compliant with the study protocol with no major protocol 
deviations that are expected to affect the assessment of efficacy at Week 24/EOT. 






 
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o Hypothetical strategy: the approach allows for the assessment of the treatment effect in an 
alternative, hypothetical setting where 1) all participants take the assigned study treatment 
without discontinuation/interruption, and 2) prohibited medication was not available to 
participants for the study duration. Available data occurring on or after the ICE will be set 
to missing, and multiple imputed by a MNAR application of SAS Proc MI based on the 
distribution of data for each treatment arm where all participants do not experience an ICE. 
11.5.3 Statistical Hypotheses 
o The superiority hypotheses for comparing Saroglitazar Magnesium 4 mg to Placebo are 
o H0: μp 3 μs f 0  
o H1: μp 3 μs > 0  
o Where μs is the change from baseline to Week 24 in liver fat content for Saroglitazar 4 mg 
arm and μp is the change from baseline to Week 24 in liver fat content for placebo arm. 
11.5.4 Statistical Methods 
Comparison of change from baseline in hepatic fat content between Saroglitazar 4 mg and placebo 
will be evaluated using mixed models for repeated measures (MMRM) including visit and 
treatment as factors, baseline value as a covariate and an interaction term treatment x visit. The p-
value for the treatment differences (Saroglitazar Magnesium versus Placebo), estimate of 
LSMEANS treatment difference (Saroglitazar Magnesium 3 Placebo), and the two-sided 90% 
confidence interval of the LSMEANS difference will be generated from the MMRM model. 
Observed values and changes from baseline will be summarized descriptively at each visit for all 
continuous parameters. The primary endpoint will be analyzed based on the ITT population. 
11.5.5 Subgroups 
The following subgroup populations will be investigated for the main estimand using ITT 
population: 
• 
Age category (< 65 years and g 65 years) 
• 
Gender (male and female). 
• 
Race 
• 
Ethnicity 
• 
Baseline Type 2 Diabetes. 
11.5.6 Handling of Missing Data 
Every effort will be made to prevent participants early terminating the study and for participants 
who discontinue study drug, every effort will be made to continue to collect data after 










 
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11.9.3 Concomitant Therapies 
All medications recorded during the study will be coded using the World Health Organization 
(WHO) Drug Dictionary (latest version). A summary will be provided for the frequency and 
percent of participants who had concomitant therapy/medications. Summaries will be provided by 
Anatomical Therapeutic Chemical (ATC) classification level 3 term and Preferred Name. 
11.9.4 Safety Parameters 
The following safety parameters will be descriptively analyzed: 
• Frequency and severity of treatment emergent AEs, serious AEs, and AESIs. 
• Changes in vital sign parameters (Systolic BP, diastolic BP, pulse rate, temperature, and 
respiratory rate) 
• Changes in clinical laboratory testing parameters (hematology, clinical chemistry, hormonal 
profile, and urinalysis) 
• Changes in physical examination assessments 
AESI includes DILI and weight gain, which would be closely monitored.  
AEs/SAEs will be coded using the MedDRA dictionary and presented by system organ class and 
preferred term. Treatment emergent AEs will be analyzed based on the number and percentage of 
participants with at least one AE in the category of interest. Additional summaries will be provided 
by severity and causality. SAEs and AEs leading to discontinuation of study treatment will also be 
summarized separately. Participant listings of all AEs will be provided. Deaths and other serious 
or clinically significant non-fatal AEs will be listed separately. 
Observed values and changes from baseline will be summarized for the laboratory data and vital 
signs. Laboratory values will be categorized as low/normal/high according to normal ranges, and 
shift tables versus baseline will be created to determine treatment-emergent abnormalities. DILI 
events, as well as important biological consideration events (per Section 7.6) will be categorized 
based on the relevant laboratory parameters, and summarized by treatment group. 
11.10 INTERIM ANALYSIS 
No interim analysis is planned for this study. 
11.11 SAMPLE SIZE DETERMINATION 
The primary efficacy endpoint is the mean change from baseline in hepatic fat content assessed by 
MRI-PDFF at Week 24/EOT in participants with NAFLD. In a previously conducted Phase 2 study 
in NAFLD participants, the mean change from baseline in hepatic fat content at Week 16 in 
Saroglitazar 4 mg group was -4.2 (SD=6.2) and in Placebo was -0.3 (SD=5.7).  


 
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Assuming a similar treatment effect on hepatic fat content in Saroglitazar 4 mg group at Week 
24/EOT in this study, a sample size of 102 participants (51 participants in each treatment arm) will 
provide 80% power to detect a treatment difference of at least 3 in change from baseline in hepatic 
fat content at Week 24 between Saroglitazar 4 mg and Placebo using a one-sided 5% level of 
significance based on two-sided t-test, assuming a common standard deviation of 6. 
Assuming a dropout rate of 15% at week 24, approximately 120 participants (60 participants in 
each treatment arm) will be randomized in a 1:1 ratio to receive either Saroglitazar 4 mg or placebo. 
11.12 COVID-19 CONSIDERATIONS 
Given the current COVID-19 pandemic, per regulatory guidance, a listing of participants either 
experiencing COVID-19 infection or at least possibly affected by COVID-19 related measures 
will be produced where applicable. Further details relating to additional populations and subgroup 
analyses, handling of protocol deviations, handling of missing data (including use of virtual 
assessments and/or switches from local to centralized labs), and any other considerations related 
to COVID-19 infection and related measures will be detailed further in the SAP, finalized before 
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12. 
ADMINISTRATIVE MATTERS 
The study will be carried out in compliance with the protocol, in accordance with the ICH GCP 
and other applicable regulatory guidelines. 
12.1 
ETHICS 
12.1.1 Institutional Committee Review and Communications 
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent, and any accompanying material to be provided to the participant to 
the IRB. The trial will not be initiated before the protocol and informed consent, and any 
accompanying material have been reviewed and have received approval/favorable opinion from 
the IRB. The study will use a single IRB (sIRB) for its IRB of record. Each site and the sIRB will 
have a fully signed IRB Authorization Agreement (IAA) in place for the duration of the study. 
Should a protocol amendment be written that requires IRB approval, the changes in the protocol 
will not be instituted until the amendment and revised informed consent (if appropriate) has been 
reviewed and received approval/favorable opinion from the sIRB. A protocol amendment intended 
to eliminate an apparent immediate hazard to participants may be implemented immediately 
providing that the appropriate regulatory authorities and sIRB are notified as soon as possible and 
an approval is requested. Protocol amendments only for logistical or administrative changes may 
be implemented immediately; however, both the sIRB and the Regulatory Authorities will be 
notified as soon as possible. 
The constitution of the IRB must comply with the requirements of the US Code of Federal 
Regulations (CFRs) or applicable regulatory agency. A list of the IRB members, with names and 
qualifications, will be requested. If such a list is unavailable, the investigator or designee must 
provide the name and address of the IRB along with a statement from the IRB that it is organized 
according to GCP and the applicable laws and regulations. The IRB must also perform all duties 
outlined by the requirements of the regulatory agencies. 
12.1.2 Informed Consent and Participant Information 
Prior to participation in the study, written informed consent will be obtained from each participant 
(or the participant9s legally accepted representative) according to the regulatory and legal 
requirements of the participating site. Virtual verbal consent may be allowed at certain sites per 
IRB approval with signatures obtained at the first screening visit. Each signature must be dated by 
each signatory. The informed consent and all study data forms will be retained by the investigator 
or designee as part of the study records. A signed copy of the informed consent and recruitment 
materials must be given to each participant or the participant9s legally authorized representative. 
A written informed consent will also be obtained from each participant for the optional banking 
assessments. A legally accepted representative of the participant is not permitted to consent for the 
optional banking assessments. 


 
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The participant must be informed that his/her medical records may be examined by authorized 
monitors or Clinical Quality auditors appointed by the sponsor, by appropriate IRB members and 
by inspectors from regulatory authorities. 
Should a protocol amendment be made, the participant informed consent form and recruitment 
materials may need to be revised to reflect the changes to the protocol. It is the responsibility of 
the investigator to ensure that an amended consent form is reviewed and has received 
approval/favorable opinion from the IRB and that it is signed by all participants subsequently 
entered in the study and those currently in the study, if affected by the amendment. 
12.1.3 Compensation and Insurance 
Participants will not be required to pay for the study medications and laboratory investigations, if 
they participate in this study. If the participants develop a medical condition as a result of 
participation in this study, including SAEs, he/she will receive emergency care; out-patient care 
or hospitalization including proper referral, as needed. Zydus Therapeutics Inc. is the sponsor of 
the study and has an insurance cover, which will pay the medical expenses for the treatment of 
such conditions. This insurance covers damages or injury or death resulting from participation in 
a study and which are mentioned during the participation in the study. Any injury or damages or 
death will be reported to the insurer. Participants should report any discomforts, problems, or 
research related injuries immediately to study Investigator or study staff. In case of injury 
occurring to participants during the clinical trial as a result of taking the study drug(s) or from the 
procedures done for the purpose of this study, the sponsor will pay for those medical expenses 
necessary to treat the injury that are not covered by the participant9s medical insurance or any other 
third-party coverage. 
12.2 
RECORD KEEPING 
12.2.1 Drug Accountability 
Drug supplies, which will be provided by the sponsor, must be kept in a secure, controlled access 
storage area under the 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 investigator/designee and/or pharmacist must maintain records of the product9s delivery to the 
study site, the inventory at the site, the dispensation to each participant 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 investigator or designee will maintain records, that document 
adequately, that the participants 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 investigator or designee 
must verify that all unused or partially used drug supplies have been returned by the study 
participants and that no remaining supplies are in the investigator9s or site9s possession. 


 
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12.2.2 Emergency Code Break (Unblinding) 
An emergency code break will be available to the Investigator and/or pharmacist. This code break 
must only be opened in emergency situations when the identity of the study medication must be 
known by the Investigator in order to provide appropriate medical treatment. If the code break for 
a participant is opened, Sponsor must be informed immediately. The reason for opening the code 
break must be documented along with the date and the initials of the person who broke the code. 
Participants whose treatment assignment becomes unblinded inadvertently, need not require to 
complete the scheduled evaluations and the participant will be withdrawn from the trial from that 
visit. 
12.2.3 Electronic Case Report Forms 
For each participant enrolled, the eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. The eCRF should 
be completed on the day of the participant visit to enable the sponsor to perform central monitoring 
of safety data, whenever possible. The eligibility criteria eCRF should be completed only after all 
data related to eligibility have been received and the participant has been enrolled. 
Prior to database lock (or any interim time points as described in the clinical data management 
plan), the investigator or designee will use his/her login credentials to confirm that the forms have 
been reviewed, and that the entries accurately reflect the information in the source documents. The 
eCRF captures the data required per the protocol Schedule of Assessments. System-generated or 
manual queries will be issued to the investigative site staff as data discrepancies are identified by 
the monitor or sponsor staff who routinely review the data for completeness, correctness, and 
consistency. The site coordinator or designee is responsible for responding to the queries in a 
timely manner, within the system, either by confirming the data as correct or updating the original 
entry, and providing the reason for the update (e.g., data entry error). 


 
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12.2.4 Data Management 
12.2.4.1 
Data Handling 
Detailed data management plan will be prepared for this study. Data will be recorded by the 
investigator or designee into CRFs 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. A CRF will be considered complete when all missing, incorrect and/or inconsistent 
data has been accounted for and the CRF is signed by the investigator. 
12.2.4.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
12.2.4.3 
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. 
12.2.4.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• Latest version of Medical Dictionary for Regulatory Activities (MedDRA) for AEs and 
medical history 
• Latest version of WHO Drug Dictionary for prior and concomitant medications. 
12.2.4.5 
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 CRFs must be reviewed and approved/signed by the investigator. 
12.2.5 Source Documents 
Source documents will be <all original documents, data, and records (e.g., hospital records, clinical 
and office charts, laboratory notes, memoranda, participants9 diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 


 
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certified after verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, participant files, and records kept at the pharmacy, at the 
laboratories and at medico-technical departments involved in the clinical trial)=. 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator9s site. Data reported 
in the EDC must be consistent with the source CRF documents or the discrepancies must be 
explained. 
The investigator or designee may need to request previous medical records from another 
institution, depending on the study; also, current medical records 3 not just shadow charts 3 must 
be available.  
The following data to be reported on the CRF should be included and derived from participant 
interview or source documents but not limited to: 
• Participant identification (gender, date of birth/age) 
• Participant participation in the trial (medication, trial number, participant number, date 
informed consent given) 
• Dates of participant9s visits 
• Medical/surgical/alcohol history 
• Medication history 
• AE onset and end date and time 
• SAE onset and end date and time 
• Originals or copies of laboratory results, VCTE/FibroScan® findings, and other results if 
applicable 
• Conclusion of a participant9s participation in the trial 
12.2.6 Direct access to Source Data/Documents 
The investigator/institution will permit Sponsor/Sponsor9s designee for trial-related monitoring 
and audits, IRB review and regulatory inspection, providing direct access to all related source 
data/documents. Source data is defined as <All information in original records and certified copies 
of original records of clinical findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial. Source data are contained in source documents 
(original records or certified copies)=.  
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 sponsor9s clinical trial 
monitor and inspection by the health authorities (e.g., FDA, or other applicable regulatory 
authorities). The monitor will review all CRFs, and written informed consents. The accuracy of 
the data will be verified by reviewing the documents described in the Section 12.2.4. 


 
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12.2.7 Trial Monitoring 
It is the responsibility of the investigator to ensure that the study is conducted in accordance with 
the protocol, US CFR applicable to clinical trials 45 CFR Part 46, and applicable regulatory 
requirements and that valid data are entered into the CRFs. 
To achieve this objective, the study monitor9s duties are to aid the investigator, and, at the same 
time, the sponsor in the maintenance of complete, legible, well-organized and easily retrievable 
data. Before the enrollment of any participant in this study, the sponsor or their designee will 
review with the investigator and site personnel the following documents: protocol, Investigator9s 
Brochure, CRFs, and procedures for their completion, informed consent process and the procedure 
for reporting SAEs. 
The investigator will permit the sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the CRFs will be verified against source documents 
and requests for clarification or correction may be made. After the CRF data is entered by the site, 
the monitor will review the data (through onsite monitoring visits and/or remote monitoring) for 
safety information, completeness, accuracy, and logical consistency. Computer programs that 
identify data inconsistencies may be used to help monitor the clinical study. If necessary, requests 
for clarification or correction will be sent to investigators. The investigator and his/her staff will 
be expected to cooperate with the monitor and provide any missing information. 
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. 
12.3 
QUALITY AUDITS 
Quality audits of this study may be conducted by the sponsor or sponsor9s designees. The quality 
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 study. 
12.4 
PROCEDURES 
12.4.1 Adverse Events 
Adverse event reporting will begin after the informed consent has been signed and will continue 
until end of the study (i.e., the safety follow-up). The National Cancer Institute9s CTCAE (Version 
5.0 or higher) will be used for reporting and grading AEs when possible. 


 
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12.4.1.1 
Definitions 
An AE is any unfavorable or unintended sign, symptom or disease temporally associated with the 
use of the study medication whether or not considered related to the study medication (21 CFR 
312.32 [a]).  
Adverse events may include:  
• Objective signs observed by the investigator or the study personnel 
• Subjective or objective signs/symptoms 
• Concomitant disease or accidents 
• Clinically relevant adverse changes in laboratory parameters observed in a participant in 
the course of a clinical study 
• Pre-existing conditions that worsen in severity or frequency or have new 
signs/symptoms associated with them 
Findings related to abnormal laboratory values and vital signs, which are not considered clinically 
significant, are not to be recorded on the AE reporting page; such events should instead be entered 
in the relevant CRF page. 
12.4.1.2 
Treatment-emergent Adverse Events 
Treatment-emergent AEs are defined as any AE that started after the first dose of the study 
medication or started before the first dose but increased in severity or frequency after 
administration of the initial dose of the study medication. 
12.4.1.3 
Collection of Adverse Events 
It is the responsibility of the investigator to collect all AEs (both serious and non-serious) derived 
by spontaneous, unsolicited reports of patients, by observation and by routine open questionings, 
e.g., "How have you felt since I saw you last?" AEs will be recorded on study data forms whether 
or not they are thought to be associated with the study or with the study drug. AEs may be 
discovered during regularly scheduled visits or through unscheduled patient contacts between 
visits. 
12.4.1.4 
Assessment of Adverse Events 
For AEs not included in the protocol defined grading system, the following guidelines will be used 
to describe severity. Each AE will be assessed by the investigator with regard to the following 
categories:  
Severity 


 
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The investigator will provide an assessment of the severity of each AE by recording a severity 
rating on the appropriate AE reporting page of the participant9s CRF. 
Severity will be assessed according to the following scale:  
• Mild: Event is usually transient and easily tolerated, requiring no special treatment and 
causing no disruption of the participant9s normal daily activities 
• Moderate: Event introduces a low level of inconvenience or concern to the participant 
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 participant9s normal daily activities and generally requires 
systemic drug therapy or other treatment. Severe events are usually incapacitating. Of 
note, the term <severe= does not necessarily equate to <serious=.  
• Fatal 
Causality  
For all AEs, the investigator will provide an assessment of causal relationship to the study 
medication. The causality assessment must be recorded on the appropriate AE reporting page of 
the participant9s CRF. 
Causal relationship will be classified according to the following criteria:  
• Definitely Related 3 There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or chemicals. 
The response to withdrawal of the study intervention (de-challenge) should be clinically 
plausible. The event must be pharmacologically or phenomenologically definitive, with 
use of a satisfactory re-challenge procedure if necessary. 
• Probably Related 3 There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time after administration of the study intervention, is unlikely 
to be attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (de-challenge). Re-challenge information is not 
required to fulfill this definition. 
• Potentially Related 3 There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant9s clinical 
condition, other concomitant events). Although an AE may rate only as <possibly related= 
soon after discovery, it can be flagged as requiring more information and later be upgraded 
to <probably related= or <definitely related=, as appropriate. 


 
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• Unlikely to be related 3 A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant9s clinical 
condition, other concomitant treatments). 
• Not Related 3 The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician. 
• Unknown 
Outcome 
Outcome of AEs will be defined according to the ICH topic E2B, ICH Guideline, as follows:  
• Recovered/Resolved  
• Recovered/Resolved with sequelae  
• Recovering/Resolving  
• Not Recovered/Not Resolved  
• Fatal  
• Unknown 
12.4.1.5 
Recording Adverse Events 
All AEs must be recorded on the appropriate AE CRF for the participant. All AEs must be reported 
whether or not considered causally related to the study medication. For every AE, the investigator 
will provide an assessment of the severity and causal relationship to the study medication, will 
document all actions taken with regard to the study medication, and will document any other 
treatment measures for the AE. If an outcome for an AE is not available at the time of the initial 
report, follow-up will proceed until an outcome is known. 
12.4.1.6 
Follow-up of Adverse Events 
All AEs experienced by a participant, irrespective of the suspected causality, will be monitored 
until the AE has resolved, any abnormal laboratory values have returned to baseline or stabilized 
at a level acceptable to the investigator and Medical Monitor, until there is a satisfactory 
explanation for the changes observed, until the participant is lost to follow-up or the participant 
has died. 
12.4.2 Serious Adverse Event 
An SAE is an event that: 


 
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• 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 participant and may require medical or surgical 
intervention to prevent one of the outcomes listed above 
Serious AEs also include events that are medically significant in the investigator9s judgment, 
including medically significant laboratory abnormalities, such as those that warrant stopping the 
study medication for individual participants, as specified in the Section 7.6 of the protocol. In 
general, medically significant events require medical/surgical intervention to prevent one of the 
outcomes listed above. 
12.4.2.1 
Reporting Serious Adverse Events 
The investigator must report any SAEs to the Sponsor/Service provider within 24 hours of 
becoming aware of the event. 
During SAE reporting, the reporting SAE, the investigator9s name, participants name and the 
telephone number with the protocol number and title will be recorded. Details regarding the safety 
management will be specified in safety management plan. 
The investigator and the sponsor (or sponsor9s designated personnel) will review each SAE report 
and the sponsor will evaluate the seriousness and the causal relationship of the event to the study 
medication. In addition, the sponsor (or sponsor9s designated personnel) will evaluate the 
expectedness according to the reference document (Investigator Brochure or Summary of Product 
Characteristics).  
Based on the investigator and sponsor9s assessment of the event, a decision will be made 
concerning the need for further action. All SAEs will be recorded from first dose of study 
medication until the end of the study (i.e., the safety follow-up). Information regarding SAEs will 
be transmitted to the sponsor using the SAE Form, which must be completed and signed by a 
member of the investigational staff, and transmitted to the sponsor within 24 hours. 
The study sponsor or designee will be responsible for notifying the FDA of any unexpected fatal 
or life-threatening suspected adverse reaction as soon as possible, but in no case later than 7 
calendar days after the sponsor's initial receipt of the information. In addition, the sponsor must 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety report 
of potential serious risks, from clinical trials or any other source, as soon as possible, but in no 
case later than 15 calendar days after the sponsor determines that the information qualifies for 


 
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reporting. If the FDA determines that a change to the investigator9s brochure, IND, or protocol is 
needed, the Sponsor will send a copy of the IND Safety Report to the IRB, and all clinical centers, 
with instructions to forward the report to their local IRB. 
12.4.3 Hepatic Safety Adjudication Committee 
A separate blinded HSAC will be established. The committee will review, monitor and adjudicate 
possible cases of DILI in the study. 
Participants will be categorized as those for whom DILI or worsening of hepatic function 
attributable to study drug could be excluded (e.g., a clear, alternative explanation exists); those for 
whom DILI or worsening of hepatic function attributable to study drug could not be excluded (e.g., 
no clear, alternative explanation exists); and those with insufficient data to make a determination. 
Potential cases of DILI will be adjudicated during the treatment period. 
Further information regarding the HSAC review process will be provided in the HSAC charter. 
12.4.4 Expected Adverse Events 
No Suspected Adverse Reactions are considered expected by the sponsor for the purpose of 
expedited reporting of Suspected Unexpected Serious Adverse Reactions. . 
12.4.5 Pregnancy 
From screening to end of study, every female participant will be investigated for child-bearing 
potential and need for urine pregnancy test. Participants shall be advised to not become pregnant 
during the trial and for at least one month after the end of the trial period. Adequate contraceptive 
measures should be taken to prevent pregnancy. Refer Appendix 3: Contraceptive Guidance. Even 
when contraceptive methods are used, there is a small risk that pregnancy might occur. In case a 
female participant becomes pregnant, the study medication will be stopped immediately. The 
participant will be withdrawn from the study drug and adequate monitoring of the participant will 
be performed.  
Women who become pregnant while on trial drug (and up to 4 weeks ± 3 days following active 
treatment), an adequate monitoring will be done as follows: 
a. If the woman wants to continue the pregnancy, she will be provided proper obstetrical care. 
b. The investigator should ensure that the participant has access to an obstetrician for the entire 
duration of her pregnancy and the delivery. The investigator should regularly follow up with the 
obstetrician regarding the health status of the participant. If the woman decides to terminate her 


 
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pregnancy, she will be provided proper gynecological care. The investigator should ensure that the 
participant has access to a gynecologist for the termination of her pregnancy. The investigator 
should regularly follow up with the gynecologist regarding the health status of the participant. 
Although pregnancy and lactation are not considered AEs, it is the responsibility of the 
investigators or their designees to report any pregnancy or lactation in a participant (spontaneously 
reported to them) that occurs during the trial to the Sponsor, IRB, and DMC within 3 business days 
and unblinding may be considered depending on the DMC9s input. All female participants 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. Such events must be reported within 24 hours to the sponsor as mentioned 
in the Section 12.4.2.1.Pregnancies that occur on study medication should be reported 
prospectively to The Antiretroviral Pregnancy Registry by the investigators. More information is 
available at www.apregistry.com.  
Address 
The Antiretroviral Pregnancy Registry 
301 Government Center Drive 
Wilmington, NC 28403 
US, Canada (toll-free): Phone: 800-258-4263 
Fax: 800-800-1052 
E-Mail: SM_APR@APRegistry.com 


 
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12.5 
UNANTICIPATED PROBLEMS 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria: 
1. 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
2. 
Related or possibly related to participation in the research (<possibly related= means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
3. 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
12.6 
RULES FOR AMENDING PROTOCOL 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IRB, in accordance with local legal and regulatory requirements. This protocol is to be 
followed exactly. To alter the protocol, amendments must be written, receive approval from the 
appropriate personnel, and receive the IRB approval before implementation (if appropriate). 
Following approval, the protocol amendment(s) will be submitted to the IND under which the 
study is being conducted. Refer Appendix 10 
Administrative changes (not affecting the patient benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
12.7 
FINANCIAL DISCLOSURE 
The investigators are required to provide financial disclosure information to the sponsor to permit 
the sponsor to fulfil its obligations. In addition, the investigators must commit to promptly update 
this information if any relevant changes occur during the study and for a period of one year after 
the completion of the study. 
12.8 
DISCONTINUATION OF THE TRIAL BY THE SPONSOR 
The sponsor reserves the right to discontinue this study at any time for failure to meet expected 
enrollment goals, for safety, or any administrative reasons. The investigator will be reimbursed for 
reasonable expenses incurred if it is necessary to terminate the study as per the agreement. 


 
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12.9 
STATEMENT OF CONFIDENTIALITY 
Individual participant 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 sponsor9s representatives, monitor, auditor, to the IRB and the 
regulatory health authorities as required under the law. Participant confidentiality will be further 
ensured by utilizing participant identification code numbers to correspond to treatment data in the 
computer files. 
Such medical information may be given to the participant9s personal physician or to other 
appropriate medical personnel responsible for the participant9s welfare. 
Data generated as a result of this study are to be available for inspection on request by the 
participating physicians, the sponsor9s representatives, by the IRB and the regulatory health 
authorities. 
12.10 FINAL REPORT AND PUBLICATION POLICY 
The Final Study Report will include the tabulated raw data, the biostatistical analysis, and 
interpretation of the study results. By signing the clinical study protocol, the investigator agrees 
with the use of the study results for the purposes of national and international registration, 
publication, and information for medical and pharmaceutical professionals. If necessary, the 
relevant authorities will be notified of the investigator9s name, address, qualifications and extent 
of involvement. An investigator shall not publish any data (poster, abstract, paper, etc.) without 
prior written permission of the sponsor. 
12.11 ARCHIVING 
Participant9s files, identification codes and other source data (including original reports of test 
results, dispensing logs, records of informed consent), IRB approval letter, correspondence and 
other documents pertaining to the conduct of the study will be kept as per the SOPs of the 
institution. According to ICH guidelines, essential documents should be retained for a minimum 
of 2 years after the last approval of a marketing application in an ICH region and until there are 
no pending or contemplated marketing applications in an ICH region or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational drug. 
However, these documents should be retained for a longer period if required by the applicable 
legal requirements. No document pertinent to the study shall be destroyed without prior written 
agreement between the sponsor and the investigator. 


 
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13. 
REFERENCES 
1. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic 
fatty liver disease: Practice guidance from the American Association for the Study of Liver 
Diseases. Hepatology. 2018;67(1):328-357. 
2. Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading 
etiology of liver disease among adults awaiting liver transplantation in the United States. 
Gastroenterology. 2015;148(3):547-555. 
3. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global 
epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, 
incidence, and outcomes. Hepatology. 2016;64(1):73-84 
4. Sarin SK, Kumar M, Eslam M, George J, Al Mahtab M, Akbar SMF, et al. Liver diseases 
in the Asia-Pacific region: Lancet Gastroenterology & Hepatology Commission [published 
correction appears in Lancet Gastroenterol Hepatol. 2020 Mar;5(3):e2]. Lancet 
Gastroenterol Hepatol. 2020;5(2):1673228. 
5. Duseja A, Singh SP, Saraswat VA, Acharya SK, Chawla YK, Chowdhury S, et al. 
Nonalcoholic Fatty Liver Disease and Metabolic Syndrome-Position Paper of the Indian 
National Association for the Study of the Liver, Endocrine Society of India, Indian College 
of Cardiology and Indian Society of Gastroenterology. J Clin Exp Hepatol. 2015;5(1):513
68.  
6. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring 
system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313-1321. 
7. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or Placebo for 
nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675-1685. 
8. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, Nonalcoholic steatohepatitis (FLINT): a multicentre, 
randomised, Placebo-controlled trial. Lancet. 2014. 
9. Vuppalanchi R, Siddiqui MS, Van Natta ML, et al. Performance characteristics of 
vibration-controlled transient elastography for evaluation of nonalcoholic fatty liver 
disease. Hepatology. 2018;67(1):134-144. 
10. Dunn W, Sanyal AJ, Brunt EM, et al. Modest alcohol consumption is associated with 
decreased prevalence of steatohepatitis in patients with Nonalcoholic fatty liver disease 
(NAFLD). J Hepatol. 2012;57(2):384-391. 
11. Crum-Cianflone NF. Editorial Commentary: Elevated Aminotransferase Levels Among 
HIV-Infected Persons: What's Lurking Under the Surface? Clinical infectious diseases : an 
official publication of the Infectious Diseases Society of America. 2015;60(10):1579-1581. 
12. Crum-Cianflone N, Dilay A, Collins G, et al. Nonalcoholic fatty liver disease among HIV-
infected persons. Journal of acquired immune deficiency syndromes (1999). 
2009;50(5):464-473. 
13. Price JC, Seaberg EC, Latanich R, et al. Risk factors for fatty liver in the Multicenter AIDS 
Cohort Study. Am J Gastroenterol. 2014;109(5):695-704. 
14. Li Vecchi V, Soresi M, Giannitrapani L, et al. Prospective evaluation of hepatic steatosis 
in HIV-infected patients with or without hepatitis C virus co-infection. International 


 
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journal of infectious diseases : IJID : official publication of the International Society for 
Infectious Diseases. 2012;16(5):e397-402. 
15. Pembroke T, Deschenes M, Lebouche B, et al. Hepatic steatosis progresses faster in HIV 
mono-infected than HIV/HCV co-infected patients and is associated with liver fibrosis. J 
Hepatol. 2017;67(4):801-808. 
16. Maurice JB, Patel A, Scott AJ, Patel K, Thursz M, Lemoine M. Prevalence and risk factors 
of nonalcoholic fatty liver disease in HIV-monoinfection. Aids. 2017;31(11):1621-1632. 
17. Morse CG, McLaughlin M, Matthews L, et al. Nonalcoholic Steatohepatitis and Hepatic 
Fibrosis in HIV-1-Monoinfected Adults with Elevated Aminotransferase Levels on 
Antiretroviral Therapy. Clinical infectious diseases: an official publication of the Infectious 
Diseases Society of America. 2015;60(10):1569-1578. 
18. Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban 
population in the United States: impact of ethnicity. Hepatology. 2004;40(6):1387-1395. 
19. Sterling RK, Contos MJ, Smith PG, et al. Steatohepatitis: Risk factors and impact on 
disease severity in human immunodeficiency virus/hepatitis C virus coinfection. 
Hepatology. 2008;47(4):1118-1127. 
20. Guaraldi G, Squillace N, Stentarelli C, et al. Nonalcoholic fatty liver disease in HIV-
infected patients referred to a metabolic clinic: prevalence, characteristics, and predictors. 
Clinical infectious diseases: an official publication of the Infectious Diseases Society of 
America. 2008;47(2):250-257. 
21. Sterling RK, Chiu S, Snider K, Nixon D. The prevalence and risk factors for abnormal liver 
enzymes in HIV-positive patients without hepatitis B or C coinfections. Dig Dis Sci. 
2008;53(5):1375-1382. 
22. Mohr R, Boesecke C, Dold L, et al. Return-to-health effect of modern combined 
antiretroviral therapy potentially predisposes HIV patients to hepatic steatosis. Medicine. 
2018;97(17):e0462. 
23. Stanley TL, Fourman LT, Feldpausch MN, et al. Effects of tesamorelin on non-alcoholic 
fatty liver disease in HIV: a randomised, double-blind, multicentre trial. Lancet HIV. 2019 
Dec;6(12):e821-e830 
24. Ajmera VH, Cachay E, Ramers C, et al. MRI Assessment of Treatment Response in HIV-
associated NAFLD: A Randomized Trial of a Stearoyl-Coenzyme-A-Desaturase-1 
Inhibitor (ARRIVE Trial). Hepatology. 2019 Nov;70(5):1531-1545. 
25. Sosale A, Saboo B, Sosale B. Saroglitazar for the treatment of hypertriglyceridemia in 
patients with type 2 diabetes: current evidence. Diabetes, metabolic syndrome and obesity: 
targets and therapy. 2015;8:189 
26. Jain MR, Giri SR, Bhoi B, Trivedi C, Rath A, Rathod R, Ranvir R, Kadam S, Patel H, 
Swain P, Roy SS. Dual PPAR α/γ agonist Saroglitazar improves liver histopathology and 
biochemistry in experimental NASH models. Liver International. 2018 Jun;38(6):1084-94. 
27. Siddiqui MS, Parmar D, Sheikh F, et al. Saroglitazar, a Dual PPAR α/γ Agonist, Improves 
Atherogenic Dyslipidemia in Patients With Non-Cirrhotic Nonalcoholic Fatty Liver 
Disease: A Pooled Analysis. Clin Gastroenterol Hepatol. 2023 Sep;21(10):2597-2605.e2.  
28. Deshpande A, Toshniwal H, Joshi S, Jani RH. A Prospective, Multicentre, Open-Label 
Single-Arm Exploratory Study to Evaluate Efficacy and Safety of Saroglitazar on 


 
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Hypertriglyceridemia in HIV Associated Lipodystrophy. PLoS One. 2016 Jan 
20;11(1):e0146222 
29. Saroglitazar [Investigator Brochure] V14 dated 24-Nov-2023.  
30. Gawrieh S, Noureddin M, Loo N, Mohseni R, Awasty V, Cusi K, Kowdley KV, Lai M, 
Schiff E, Parmar D, Patel P, Chalasani N. et al., Saroglitazar, a PPAR-α/γ Agonist, for 
Treatment of Nonalcoholic Fatty Liver Disease: A Randomized Controlled Double-Blind 
Phase 2 Trial. Hepatology. 2021 April 2. DOI:10.1002/hep.31843, PMID: 33811367  
31. Mohammad Shadab Siddiqui , Michael O Idowu, Deven Parmar, Brian B Borg, Douglas 
Denham , Nicole M Loo , Donald Lazas, Ziad Younes, Arun J Sanyal et al., A Phase 2 
Double Blinded, Randomized Controlled Trial of Saroglitazar in Patients With 
Nonalcoholic Steatohepatitis. Clinical Gastroenterology Hepatology, 2020 Nov 2;S1542-
3565(20)31509-3, DOI: 10.1016/j.cgh.2020.10.051, PMID: 33152542 
32. Pai V, Paneerselvam A, Mukhopadhyay S, et al., A Multicenter, Prospective, Randomized, 
Double-blind Study to Evaluate the Safety and Efficacy of Saroglitazar 2 and 4 mg 
Compared to Pioglitazone 45 mg in Diabetic Dyslipidemia (PRESS V). J Diabetes Sci 
Technol, 2014. 8(1): p. 132-141. 
33. Jani RH, Pai V, Jha P, et al., A multicenter, prospective, randomized, double-blind study 
to evaluate the safety and efficacy of Saroglitazar 2 and 4 mg compared with Placebo in 
type 2 diabetes mellitus patients having hypertriglyceridemia not controlled with 
atorvastatin therapy (PRESS VI). Diabetes Technol Ther, 2014. 16(2): 63-71 
34. Kumar DP, Caffrey R, Marioneaux J, Santhekadur PK, Bhat M, Alonso C, Koduru SV, et 
al. The PPAR α/γ Agonist Saroglitazar Improves Insulin Resistance and Steatohepatitis in 
a Diet Induced Animal Model of Nonalcoholic Fatty Liver Disease. Sci Rep 2020;10:9330. 
35. Manjunath Krishnappa , Kishor Patil, Krupi Parmar, Purav Trivedi, et al. Effect of 
saroglitazar 2 mg and 4 mg on glycemic control, lipid profile and cardiovascular disease 
risk in patients with type 2 diabetes mellitus: a 561week, randomized, double blind, phase 3 
study (PRESS XII study). Cardiovasc Diabetol 2020. DOI: 0.1186/s12933-020-01073-w 


 
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14. 
SIGNATURE PAGE(S) 
SPONSOR APPROVAL 
STUDY TITLE: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of 
Saroglitazar Magnesium, for the Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in 
People Living with Human Immunodeficiency Virus (HIV) in the US. 
I have read, understood and approve this protocol. 
I agree to comply with all requirements regarding the obligations of Sponsor and all other 
pertinent requirements of Declaration of Helsinki (Fortaleza, 2013) and ICH E6 the guidelines on 
Good Clinical Practice (GCP) and any other applicable regulatory requirements. 
 
 
_________________________________________________________ Date: ____________ 
AUTHORIZED SIGNATORY 
 
 
 
 
 
 
 
 
 


 
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APPROVAL FROM PROTOCOL CO-CHAIR 
STUDY TITLE: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of 
Saroglitazar Magnesium, for the Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in 
People Living with Human Immunodeficiency Virus (HIV) in the US. 
I have read, understood and approve this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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DECLARATION OF THE LEAD PRINCIPAL INVESTIGATOR 
STUDY TITLE: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of 
Saroglitazar Magnesium, for the Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in 
People Living with Human Immunodeficiency Virus (HIV) in the US. 
I, the undersigned, have read and understood this protocol and hereby agree to conduct the study 
in accordance with this protocol and to comply with all requirements regarding the obligations of 
Principal Investigator(s) and all other pertinent requirements of the ICH E6 8Guidelines on Good 
Clinical Practice9, Declaration of Helsinki (Fortaleza, 2013) and applicable regulatory 
authorities. 
All documentation for this study that is supplied to me, and that has not been previously published, 
will be kept in the strictest confidence. This documentation includes this study protocol, 
Investigator's Brochure, Case Report Forms and other scientific data. Copying, disclosing and 
publishing without written consent of Sponsor is prohibited. 
The study will not be commenced without the prior written approval of Regulatory Authorities and 
a properly constituted Institutional Review Board (IRB). No changes will be made to the study 
protocol without the prior written approval of the Sponsor and the IRB, except where necessary 
to eliminate an immediate hazard to the patients. 
I further agree to ensure that all associates assisting in the conduct of this study are well informed 
regarding their obligations and confirm to conduct this study under my direction at the following 
address: 
 
  
 
 
 
 
 
______________________________________  
Signature and Date 
Note: Please retain original page of the Investigator9s declaration at the site and send a copy of 
this page to the Sponsor. 


 
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DECLARATION OF PRINCIPAL INVESTIGATOR 
STUDY TITLE: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of 
Saroglitazar Magnesium, for the Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in 
People Living with Human Immunodeficiency Virus (HIV) in the US. 
I, the undersigned, have read and understood this protocol and hereby agree to conduct the study 
in accordance with this protocol and to comply with all requirements regarding the obligations of 
Principal Investigator(s) and all other pertinent requirements of the ICH E6 8Guidelines on Good 
Clinical Practice9, Declaration of Helsinki (Fortaleza, 2013) and applicable regulatory 
authorities. 
All documentation for this study that is supplied to me, and that has not been previously published, 
will be kept in the strictest confidence. This documentation includes this study protocol, 
Investigator's Brochure, Case Report Forms and other scientific data. Copying, disclosing and 
publishing without written consent of Sponsor is prohibited. 
The study will not be commenced without the prior written approval of Regulatory Authorities and 
a properly constituted Institutional Review Board (IRB). No changes will be made to the study 
protocol without the prior written approval of the Sponsor and the IRB, except where necessary 
to eliminate an immediate hazard to the patients. 
I further agree to ensure that all associates assisting in the conduct of this study are well informed 
regarding their obligations and confirm to conduct this study under my direction at the following 
address: 
Name of the Principal Investigator:  
 
Name and Address of the site:  
 
 
______________________________________  
Signature and Date 
Note: Please retain original page of the Investigator9s declaration at the site and send a copy of 
this page to the Sponsor. 




 
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15.2 APPENDIX 2: LIST OF KNOWN CYP2C8 INHIBITORS/SUBSTRATES 
Selected inducers, inhibitors and substrates of CYP2C8 
 
Substrates  
 
Inhibitors  
 
Inducers  
 
a. 
Amodiaquinea (antimalarial, 
anti-inflammatory)  
b. Cerivastatina (statin)  
c. 
Enzalutamide (antiandrogen)  
d. Paclitaxela(chemotherapeutic)  
e. 
Repaglinidea (antidiabetic)  
f. 
Torsemidea (loop diuretic)  
g. Sorafeniba (tyrosine kinase 
inhibitor)  
h. Rosiglitazone (antidiabetic) - 
converted to active 
metabolitesb 
i. 
Buprenorphine (semisynthetic 
opioid)  
j. 
Montelukast (leukotriene 
receptor antagonist)  
 
Strong  
a. 
Gemfibrozila(Hypolipidemic)  
 
Moderate  
a. 
Trimethoprima(Antibiotic)  
 
Unspecified potency  
a. 
Thiazolidinedionesa(antidiabet
ic)  
b. Montelukasta(leukotriene 
receptor antagonist)  
c. 
Quercetina(anti-inflammatory)  
 
Unspecified potency  
a. 
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 
 


 
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15.3 APPENDIX 3: CONTRACEPTIVE GUIDANCE 
In order to include women of childbearing potential (WOCBP) in any clinical study, certain 
precautions pertaining to pregnancy must be taken. These will include pregnancy urine and serum 
testing at screening and visits as defined in the protocol (Section 2 Schedule of Assessments) and 
as per local regulations. Pregnancy should be avoided by either complete abstinence or the use of 
an acceptable effective contraceptive measures for the duration of the study and for at least 1 month 
after the end of the study treatment. 
Female participants who become pregnant during a study will be withdrawn and adequately 
monitored until the outcome of the pregnancy. 
Definitions: 
•WOCBP: A woman is considered of childbearing potential, i.e. fertile, following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal 
state is defined as no menses for 12 months without an alternative medical cause. A high follicle 
stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-
menopausal state in women not using hormonal contraception or hormonal replacement therapy. 
However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
•A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Contraception Guidance: 
•Male Participants:  
Male participants with female partners of childbearing potential should agree to use one of the 
following: 
1.Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on 
a long-term and persistent basis) and agree to remain abstinent for duration of study.  
2.Agree to use condom or have their partner use of a contraceptive method as described below 
when having penile-vaginal intercourse with WOCBP who are not currently pregnant. 
Female participants: Female participants of childbearing potential should agree to use an 
acceptable effective method of contraception consistently and correctly for the duration of the 
study and for at least 1 month after the end of the study treatment.as described below 


 
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Highly Effective Contraceptive Methods (having a failure rate of less than 1% per year) 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation: 
Oral. 
Intravaginal. 
Transdermal. 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
Oral. 
Injectable. 
Implantable. 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
Intrauterine device. 
Intrauterine hormone-releasing system. 
Bilateral tubal occlusion. 
Vasectomized partner 
A vasectomized partner is a highly effective birth control method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. 
 
Acceptable Birth Control Methods (having a failure rate of more than 1% per year) 
• Progesterone-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action. 
• 
Condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository. Spermicides alone are inefficient at preventing 
pregnancy. Therefore, spermicides alone are not an acceptable method of 
contraception. 
Pregnancy Testing: 
Any WOCBP should only be included after a confirmed menstrual period and a negative serum 
and urine pregnancy test as defined in the protocol. Additional pregnancy testing will be done as 
specified in the protocol during the treatment period and as per local regulations (if any). 


 
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Pregnancy testing will also be performed whenever a menstrual cycle is missed or when pregnancy 
is otherwise suspected. 


 
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15.4 
APPENDIX 3: HEALTH-RELATED QUALITY OF LIFE ASSESSMENT 
QUESTIONNAIRE 
https://www.rand.org/health-care/surveys tools/mos/36-item-short-form/survey-instrument.html 
  
 


 
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15.5 
APPENDIX 4: AUDIT QUESTIONNAIRE 
The Alcohol Use Disorders Identification Test (AUDIT) is a 10-item screening tool developed by 
the World Health Organization (WHO) to assess alcohol consumption, drinking behaviors, and 
alcohol-related problems. 
A self-report version of the AUDIT is provided. Patients should be encouraged to answer the 
AUDIT questions in terms of standard drinks. A chart illustrating the approximate number of 
standard drinks in different alcohol beverages is included for reference in the link below. A score 
of 8 or more is considered to indicate hazardous or harmful alcohol use. The AUDIT has been 
validated across genders and in a wide range of racial/ethnic groups and is well suited for use in 
primary care settings.  
Detailed guidelines about use of the AUDIT have been published by the WHO and are available 
online in the link below:  
https://www.drugabuse.gov/sites/default/files/audit.pdf 


 
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15.6 
APPENDIX 6: CKD-EPI CALCULATOR 
This CKD-EPI equation calculator should be used when Scr is reported in µmol/L. This equation 
is recommended when eGFR values above 60 mL/min/1.73 m² are desired. 
 
GFR = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if African 
American] 
 
where: 
Scr is serum creatinine in µmol/L, 
κ is 61.9 for females and 79.6 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr/κ or 1, and 
max indicates the maximum of Scr/κ or 1 
The equation does not require weight because the results are reported normalized to 1.73 m² body 
surface area, which is an accepted average adult surface area. 
Please refer: https://www.niddk.nih.gov/health-information/professionals/clinical-tools-patient-
management/kidney-disease/laboratory-evaluation/glomerular-filtration-rate-calculators/ckd-epi-
adults-conventional-units 
 
 


 
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15.7 
APPENDIX 7: LIST OF STEATOGENIC MEDICATIONS OR SUPRA-
PHYSIOLOGIC HORMONAL THERAPIES OR MEDICATIONS THAT 
CAUSE SIGNIFICANT WEIGHT CHANGE 
Steatogenic Medications 
1. Amiodarone 
2. Tamoxifen 
3. Methotrexate 
4. Systemic glucocorticoids 
5. Anabolic steroids 
6. Tetracycline 
7. Vitamin A 
8. L-asparaginase 
9. Valproate 
10. Chloroquine 
11. Stavudine 
Supra-Physiologic Hormonal Therapies 
1. Estrogen in doses higher than used in oral 
contraceptives or post-menopausal hormone 
replacement therapy (except for transgender 
women on stable dosing) 
Medications that can cause significant weight 
change 
1. Phentermine 
2. Topiramate 
3. Orlistat  
4. Bupropion 
5. Naltrexone 
 
 


 
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15.8 APPENDIX 8: DIET AND EXERCISE GUIDANCE 
1. DIETARY INTAKE: 
a. Patients without diabetes will be instructed to follow the National Cholesterol 
Education Program (NCEP) Step 1 recommendations (Refer Table 1 of this appendix). 
These recommendations will include specific discussions on total caloric intake, the 
amount and type of fat consumed, and the amount of carbohydrate consumed. 
b. The importance of portion control will be discussed, especially in reference to eating 
at restaurants. Avoidance of calorie dense fast food and sugar sweetened beverages will 
be stressed. 
c. Patients with known or newly discovered type 2 diabetes will receive specific 
recommendations as promulgated by the American Diabetes Association (ADA) (Refer 
Table 2 of this appendix). 
d. Recommendations regarding the use of specific nutritional supplements are addressed 
below. 
e. Dietary guidelines may not apply to all participants or situations. 
2. WEIGHT LOSS 
a. Overweight participants (BMI >25 kg/m2) will be given a goal of losing and sustaining 
the loss of 5%-10% of body weight. This weight loss should be achieved at a rate of 1-
2 lbs per week per NHLBI guidelines (Refer Table 3 of this appendix). 
b. Patients will be instructed not to fast as a means of achieving weight loss. 
c. Alternative diet plans intended to promote weight loss will be considered individually 
based on nutritional completeness. 
3. ALCOHOL CONSUMPTION 
Patients will be instructed that total abstinence from alcohol is advisable. The Committee 
acknowledges the paucity of data regarding a minimal safe dose of alcohol in individuals 
with liver disease and consumption limited to <ceremonial use= or even amounts up to 10 
g per week (1 oz 80 proof liquor, 3.5 oz non-fortified wine, 8 oz beer) may be safe. 
4. EXERCISE 
Patients will be instructed to engage in a lifestyle that includes regular moderate exercise. 
The recommendations of the Institute of Medicine will be used: regular physical activity 
of at least one hour daily. 


 
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NCEP STEP 1 DIET (STANDARD RECOMMENDATION) 
The general dietary recommendations developed by the Institute of Medicine with the goal of 
promoting a healthy lifestyle will be reviewed for possible substitution for the NCEP guidelines 
below. 
The following dietary recommendations were stated by the [National Cholesterol Education 
Program (NCEP)] in their monograph entitled 8The Third Report of the Expert Panel on the 
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel 
III), or ATP III9. The primary goal of these recommendations is to provide a diet that would reduce 
the risk of coronary heart disease in individuals with high LDL cholesterol levels. A secondary 
target of risk reduction, which was new to this version of the report, was the metabolic syndrome 
or insulin resistance. 
Table 1: Nutrient Composition of the Therapeutic, Lifestyle Change, Diet, and Nutrient 
Recommended Intake 
Saturated fat a 
< 7% of total calories 
Polyunsaturated fat 
<10% of total calories 
Monounsaturated fat 
<20% of total calories 
Total fat 
25 - 35% of total calories 
Carbohydrate b 
50 - 60% of total calories 
Fiber 
20 - 30 g daily 
Protein 
Approximately 15% of total calories 
Cholesterol 
< 200 mg/day 
Total calories c 
Balance energy intake and expenditure to maintain 
desirable body weight/prevent weight gain. 
a. 
Trans fatty acids are another LDL-raising fat that should be kept at a low intake. 
b. Carbohydrates should be derived predominantly from foods rich in complex carbohydrates 
including grains, especially whole grains, fruits, and vegetables. 
c. 
Daily energy expenditure should include at least moderate physical activity (contributing 
approximately 200 Kcal per day). 


 
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AMERICAN DIABETES ASSOCIATION (ADA) DIET RECOMMENDATION 
Current evidence-based recommendations developed by the ADA are summarized in Table 2. 
Table 2: American Diabetes Association (ADA) Diet (for Patients with Type 2 Diabetes) 
Carbohydrates 
a. 
Choose whole grains, fruits, vegetables, low-fat milk. 
b. Amount of carbohydrate is more important than source. 
c. 
Non-nutritive sweeteners in usual doses 
Fats 
a. 
Limit to 10% or less of total calorie intake. 
b. Limit cholesterol to <300 mg per day 
Obesity and Weight 
Loss 
a. 
Modest weight loss by reduced calorie intake improves insulin 
resistance. 
b. Structured programs of lifestyle change can produce weight loss of 
5-7% calorie. 
c. 
Exercise and behavior modification are useful adjuncts to reduction 
of calorie intake. 
Older Adults 
a. 
Energy requirements decline with age. 
b. Encourage physical activity. 
Hypoglycemia 
Glucose is preferred treatment 
Hypertension 
a. 
Reduced sodium intake reduces blood pressure. 
b. Modest weight loss reduces blood pressure. 
 
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (NHLBI) STEP I DIET 
RECOMMENDATION 
Source: The Practice Guide. Identification, Evaluation, and Treatment of Overweight and 
Obesity in Adults. NHLBI, 2000, p 27.  
Table 3: NHLBI Step 1 Diet (for Weight Reduction) 
Nutrient 
Recommended intake 
Calories a 
Approximately 500 - 1,000 kcal/day reduction from usual state 
Total fat b 
30% or less of total calories 
Saturated fatty acids c 
8% - 10% of total calories 
Monounsaturated fatty acids 
Up to 15% of total calories 
Polyunsaturated fatty acids 
Up to 10% of total calories 
Cholesterol c 
< 300 mg/day 
Protein d 
Approximately 15% of total calories 


 
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Carbohydrate e 
55% or more of total calories 
Sodium chloride 
No more than 100 mmol/day (approximately 2.4 g of sodium or 
approximately 6 g of sodium chloride) 
Calcium f 
1,000 to 1,500 mg/day 
Fiber e 
20 - 30 g/day 
a. 
A reduction in calories of 500 to 1,000 kcal/day will help achieve a weight loss of 1 to 2 
pounds/week. Alcohol provides unneeded calories and displaces more nutritious foods. Alcohol 
consumption not only increases the number of calories in a diet but has been associated with obesity 
in epidemiologic studies as well as in experimental studies. The impact of alcohol calories on a 
person9s overall caloric intake needs to be assessed and appropriately controlled 
b. Fat-modified foods may provide a helpful strategy for lowering total fat intake but will only be 
effective if they are also low in calories and if there is no compensation by calories from other foods 
c. 
Patients with high blood cholesterol levels may need to use the Step II diet to achieve further 
reductions in LDL-cholesterol levels; in the Step II diet, saturated fats are reduced to less than 7 
percent of total calories, and cholesterol levels to less than 200 mg/day. All of the other nutrients 
are the same as in Step I. 
d. Protein should be derived from plant sources and lean sources of animal protein. 
e. 
Complex carbohydrates from different vegetables, fruits, and whole grains are good sources of 
vitamins, minerals, and fiber. A diet rich in soluble fiber, including oat bran, legumes, barley, and 
most fruits and vegetables, may be effective in reducing blood cholesterol levels. A diet high in all 
types of fiber may also aid in weight management by promoting satiety at lower levels of calorie 
and fat intake. Some authorities recommend 20 to 30 grams of fiber daily, with an upper limit of 35 
grams. 
f. 
During weight loss, attention should be given to maintaining an adequate intake of vitamins and 
minerals. Maintenance of the recommended calcium intake of 1,000 to 1,500. 
 
 


 
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15.9 
APPENDIX 9: INSTRUCTIONS FOR STANDARDIZED HIP CIRCUMFERENCE 
AND MINIMUM WAIST CIRCUMFERENCE MEASUREMENT 
General Information: 
Measurements should be taken after a fast of 8 or more hours (fasting measurements preferred, 
but non-fasting measurements will be accepted).  
1. Participant should undress to underwear, such that the portion of the torso below the nipples 
and above the knee is visible to the person taking the measurement. Any outer clothing 
covering this portion of the body should be removed. 
2. Use non-stretchable, cloth or vinyl measuring tape that measures in centimeters or millimeters 
and is at least one-half inch in width. 
3. Make sure the tape does not compress the body tissues during the measurement. 
4. Measuring tape should always be read at eye level at recorded to the nearest 0.1 cm. 
5. All measurements should be made in triplicate and averaged. If one measurement varies more 
than 10% from the other two, it should be discarded and the remaining two values averaged. 
6. Ask the participant not to hold in the stomach/to relax/exhale fully during the measurements. 
Hip Circumference: 
1. The participant should be standing erect but relaxed, with feet/ankles touching. 
2. Viewing the participant from the side, visually identify the widest width of the hip, which 
is generally where there is maximal protuberance of the buttocks.  
3. Measure circumference at that point, making sure the measuring tape is exactly parallel to 
the floor all the way around the body. Record the result in cm to the nearest 
millimeter/0.1 cm. 
4. Repeat this procedure twice, with the participant fully exhaling between each measurement, 
so that in all 3 measurements are performed.  
5. Follow instructions as per general information (Number 6), above. 
Waist Circumference: 
1. The participant should be standing erect but relaxed, with feet/ankles touching. 
2. All measurements should be made after the participant has fully exhaled. 
3. Viewing the participant from the front or rear, identify the smallest width of the waist; 
4. measure circumference at that point. In each case, the measuring tape should be parallel to 
the floor during the measurement. Record the result in cm to the nearest millimeter/0.1 cm. 
5. Repeat this procedure twice, with the participant fully exhaling between each measurement, 
so that in all 3 measurements are performed.  
6. Follow instructions as per general information (Number 6), above. 


 
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15.10 APPENDIX 10: PROTOCOL AMENDMENT TEMPLATE 
Amendment Details 
History of Amendments 
A total of two XX global amendments have occurred, as shown in the table below: 
Document  
Sponsor Approval Date 
(dd/mmm/yyyy)  
Approximate No Enrolled* 
 
 
 
 
 
 
 
 
 
*Subjects enrolled until the date of Sponsor approval date 
Current Amendment 
The table below provides an overview of the current amendment. 
Amendment Number:  
 
Approximate No Enrolled  
 
Summary of the Amendment:   
 
Summary of Changes in the Current Amendment: 
Section # and Name  Description of Change  Brief Rationale for Change  
 
 
 
 
 
 
 
 
 
 
 
 
 
Other changes made throughout protocol: 
➢ Editorial, grammatical, and typographical corrections were done in the text to provide 
better clarity to the readers. 
➢ Relevant changes are also reflected in the synopsis 


 
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RESPONSIBILITY 
NAME 
DATE AND 
SIGNATURE 
STUDY DIRECTOR: 
(SPONSOR’S 
REPRESENTATIVE) 
Deven V. Parmar MD, FCP 
 
 

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SAFETY DATA PLAN 
Protocol Number (Version 
no.)    
SARO.20.001 (Version 4.0) 
Study Title 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter 
Trial of Saroglitazar Magnesium for the Treatment of 
Nonalcoholic Fatty Liver Disease (NAFLD) in People Living with 
Human Immunodeficiency Virus (HIV) in the US. 
Clinical Phase 
2a 
Sponsor’s Signatory 
Version Number 
1.0 
Site for Safety Evaluation 
 finalization 
29/11/2024 
This Safety Data Plan is the property of Zydus Therapeutics Inc. and may not be amended without amending the master 
document held by the company. Under no circumstances should this plan be passed on, copied, reproduced or retrieved in 
other form in electronic media without expressed permission of Head, Zydus Therapeutics Inc.  
NCT05211284


 
 
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Table of Contents 
Table of Contents ..................................................................................................................... 2 
List of Abbreviations: ............................................................................................................. 3 
Introduction: ............................................................................................................................ 4 
1 
Objectives: ....................................................................................................................... 4 
2 
Study Design: .................................................................................................................. 4 
3 
Schedule of Assessments ................................................................................................ 6 
4 
Protocol Deviations/ Violations/ Changes from Protocol: .......................................... 9 
5 
Concomitant Therapy: ................................................................................................... 9 
6 
Analysis Populations: ................................................................................................... 10 
7 
Demographic and Baseline Characteristics: .............................................................. 10 
8 
Disposition of Subjects: ................................................................................................ 10 
9 
Medical History ............................................................................................................ 10 
10 
Data handling methodology: ....................................................................................... 10 
10.1 Derived and Transformed Data: ................................................................................. 10 
10.2 Decimal Precision: ........................................................................................................ 11 
10.3 Coding Dictionaries: ..................................................................................................... 11 
10.4 Values of Clinical Significance: ................................................................................... 11 
11 
Handling of Drop-outs/ Premature Withdrawal: ...................................................... 11 
12 
Statistical Methods and Analysis: ............................................................................... 11 
13 
Safety Analysis: ............................................................................................................. 11 
13.1 Adverse Events: ............................................................................................................ 11 
13.2 Laboratory Evaluations: .............................................................................................. 12 
13.3 Physical examinations: ................................................................................................. 12 
13.4 Vital Signs: .................................................................................................................... 12 
14 
Revision History: .......................................................................................................... 12 
15 
Reference: ...................................................................................................................... 12 
16 
Appendix: ...................................................................................................................... 12 
 
 
 
 


 
 
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List of Abbreviations: 
AE 
: Adverse Event 
ALT 
: Alanine Aminotransferase 
AST 
: Aspartate transaminase 
BP 
: Blood Pressure 
CRF 
: Case Report Form 
CSR 
: Clinical Study Report 
eGFR 
: Estimated Glomerular Filtration Rate 
ICH 
: International Council on Harmonization 
IP 
: Investigational product 
MedDRA 
: Medical Dictionary for Regulatory Activities 
PI 
: Principal investigator 
PLWH 
: People Living with Human Immunodeficiency Virus 
PT 
: Preferred Term 
R&D 
: Research and development 
SAE 
: Serious Adverse Event 
SAS 
: Statistical Analysis Software 
SOC 
: System Organ Class 
TEAE 
: Treatment Emergent Adverse Event 
WHODD 
: WHO Drug Dictionary 
 
 
 


 
 
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 Introduction: 
The purpose of this document is to provide a description of the methods and procedures to be implemented 
for the presentation of safety data from Saroglitazar Magnesium 4 mg tablet, for trial SARO.20.001 version 
4.0. This document is based on protocol dated 17th Nov 2023. Any revisions to this plan will be made prior 
to final analysis and reasons for such revisions will be described in the final Clinical Study Report.  This 
study is terminated by sponsor’s discretion and no primary efficacy endpoint data has been collected for any 
subject, hence no formal statistical analysis will be done for any efficacy endpoints. Hence, this safety data 
plan includes only data of screened and four subjects who were randomized in the study. 
 
1 Objectives: 
Safety Objectives: 
1. To evaluate the safety and tolerability of Saroglitazar Magnesium 4 mg. 
 
 
2 Study Design: 
This phase 2a study is a randomized, placebo-controlled, double-blind, multicenter parallel-arm trial to 
evaluate the safety and efficacy of Saroglitazar Magnesium 4 mg compared with placebo in NAFLD in 
PLWH. 
 
Number of Subjects: 
In total, approximately 120 participants (60 participants in each treatment arm) were planned to receive 
either Saroglitazar 4 mg or placebo.   
Randomization 
 
Participants were randomized in a 1:1 ratio to receive Saroglitazar Magnesium 4 mg once daily orally or 
Placebo. The randomization scheme will be stratified by clinical center. Treatment assignments are 
double masked throughout the study until all data collection for the trial has been completed (i.e., after 
completion of the post-trial follow-up for all participants). The block randomization schedule was 
generated using SAS® software (Version: 9.4 or higher; SAS Institute Inc., USA). 
Blinding and Un-blinding 
The study is a double blind study with  randomized subjects being treated with Saroglitazar Magnesium 
4 mg, or Placebo. The essential aim of blinding is to prevent identification of the treatments by the 
investigator, subject, and others associated with the conduct of the study until all such opportunities for 
bias have passed.  
All members of the clinical study team, investigators and site staff will be blinded to treatment 
assignments while the study is in progress. In addition, Biostatistics staff who are directly involved in 
the analysis of the study results will remain blinded to treatment assignment while the study is in 
progress.  
If necessary, the Sponsor may be required to unblind a subject if an adverse event (AE) meets criteria of 
a Suspected Unexpected Serious Adverse Reaction (SUSAR) in order to fulfil expedited regulatory 
reporting requirements. In this event, the Sponsor Medical Expert will not divulge the treatment code to 


 
 
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any other personnel involved in reporting, obtaining, and/or reviewing the clinical evaluations. This level 
of blinding will be maintained throughout the conduct of the study. 
In the event of a medical emergency during the study where the knowledge of subject treatment is 
required, an individual Principal Investigator will have the ability to unmask the treatment assignment 
for a specific subject. The Investigator should notify the Sponsor prior to unmasking a subject if there is 
sufficient time. Further, the Sponsor must be informed whenever the randomization code is broken. The 
reason for unblinding should be clearly and fully documented by the Investigator. 
Once all study data have been verified, validated, and the database is locked, individual subjects will be 
unmasked to their treatment. 
During this study, no unblinding done due to any safety reason. 
 
 
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4 Protocol Deviations/ Violations/ Changes from Protocol: 
Protocol deviation will be included in CSR. 
For the purposes of this study, no distinction will be made between protocol violation and deviation. 
Deviation may be categorized as minor protocol deviation or major protocol deviation. Classification 
of protocol deviations as major or minor will be assessed at the blinded data review meeting prior to 
database lock. Minor protocol deviation includes any deviation that do not necessarily influence the 
results/outcome of primary endpoints or participant safety. Minor protocol deviation does not require 
immediate notification to the IRB unless otherwise specified by IRB requirements. All minor protocol 
deviations will be noted in monitoring reports and discuss with investigator/site personal. Major 
protocol deviation includes any violation, which may influence the results/outcome of primary 
endpoints or participant safety. Major protocol deviation must be reported immediately to the IRB, as 
specified by the IRB requirements. All major protocol deviations will be reported to the sponsor 
immediately (Note: persistent non-compliance of minor protocol deviations may rise to the level of 
major protocol deviations). As a result of protocol deviations, corrective actions are to be developed 
and implemented promptly. 
 
The sponsor reserves the right to terminate the study at a given center in the event of monitoring and/or 
auditing findings of serious or persistent non-compliance with the protocol, Standard Operating 
Procedures (SOPs), GCP, and/or applicable regulatory requirement(s) by an investigator/Institution. 
In all cases of site closure due to protocol deviations, the IRB and regulatory authority will be 
informed. The clinical study report (CSR) will provide a list of protocol deviations/violations in a 
separate section. The results will be analyzed for all participants regardless of protocol deviation 
occurrence. 
 
Protocol deviations/violations will include but are not limited to the following: 
 
• Violations of inclusion and exclusion criteria at randomization. 
• Participants who met the withdrawal criteria but were not withdrawn. 
• Participants who received the wrong treatment or incorrect dose. 
• Participants who received an excluded medication. 
• Serious non-compliance with regulatory or GCP guidelines. 
 
5 Concomitant Therapy: 
All medications recorded during the study will be coded using the World Health Organization (WHO) 
Drug Dictionary (latest version). A summary will be provided for the frequency and percent of 
participants who had concomitant therapy/medications. Summaries will be provided by Anatomical 
Therapeutic Chemical (ATC) classification level 3 term and Preferred Name. 
 
Refer the protocol section 8.8 Concomitant Medications in detailed for the previous and concomitant 
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6 Analysis Populations:  
All Enrolled Population: includes all participants who signed an ICF. This analysis population will 
be used to summarize participant disposition. 
 
Safety Population: includes all participants who received at least one dose of study drug. Participants 
in the safety analysis population will be analysed according to the treatment received. This analysis 
population will be used for all safety analyses. 
 
7 Demographic and Baseline Characteristics: 
Demographic and baseline characteristics include age in years, gender, ethnicity, race, height (cm), 
weight (kg), body mass index (kg/m2), hip (cm) and waist circumference (cm).  
Demographic and baseline characteristics will be summarized for safety populations.  
All the continuous variables (i.e., age, height etc.) will be summarized by n, mean, standard deviation, 
minimum, median and maximum values. All the categorical variables (i.e., gender) will be summarized 
as frequency and percentage. 
8   Disposition of Subjects: 
The number of subjects treated will be summarized. 
The following summaries (number and/or percentage) will be included in the disposition table:  
All enrolled subjects 
Subjects in safety population  
Subjects who completed the study 
Subjects who discontinued from the study with reason for discontinuation 
 
9 
Medical History  
The frequency count and percentage of patients experiencing any medical conditions will be tabulated 
by system organ classifications (SOC) and preferred term (PT) of MedDRA for all patients. The 
denominators for calculating the percentages will be based on number of patients in Safety Population. 
A data listing of medical history including medical and surgical history will be provided for Safety 
Population. 
 
10 Data handling methodology: 
Listing of subject data and tabulation of descriptive statistics be performed primarily using SAS® 
(version 9.4 or higher; SAS Institute Inc., USA).  
The continuous variables will be summarized by n, mean, standard deviation, minimum, median and 
maximum. Categorical variables will be summarized with frequency and percentage. 
10.1 Derived and Transformed Data: 
Baseline: 
In general, baseline will be defined as the last available, non-missing assessment prior to the 
administration of study assigned treatment.  


 
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10.2 Decimal Precision: 
Unless otherwise noted, mean, median, standard deviation, minimum, maximum, percentage and any 
corresponding confidence interval will be presented to two decimal places. 
 
10.3 Coding Dictionaries: 
Adverse Events will be coded using the latest Medical Dictionary for Regulatory Activities 
(MedDRA). 
The actual dictionary versions used will be presented in the Clinical Study Report. 
 
10.4 Values of Clinical Significance: 
Reference ranges for all laboratory parameters collected throughout the study are provided by the 
respective laboratory. A laboratory value that is outside of the reference range is considered either 
high abnormal (value above the upper limit of the reference range) or low abnormal (value below the 
lower limit of the reference range).  
Note: a high abnormal or low abnormal laboratory value is not necessarily of clinical significance.  
The laboratory reference ranges will be provided on the listings of standardized laboratory data with 
out of range values flagged (low or high). 
 
11 Handling of Drop-outs/ Premature Withdrawal: 
All data compiled up to the point of discontinuation will be used for the data presentation. All withdrawals 
will be included in all analyses up to the time of withdrawal. Subjects who are withdrawn prematurely 
from study treatment will be included in all analyses regardless of the duration of treatment.  
   
12  Statistical Methods and Analysis: 
The data collected from CRF and laboratory test reports will be analyzed for demographics and safety. 
All data in the database will be presented in the data listings. Unless otherwise stated, all listings will be 
presented by treatments and sorted by subject number and assessment date/time. 
Demographic and baseline characteristics will be summarized by treatment. Subject disposition and 
reason for withdrawal will be listed 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 frequency and percentage.  
The change from baseline will be determined as: 
Change = (last observed post dose value – pre dose). 
 
13 Safety Analysis: 
Subjects in safety population will be considered for the safety analysis.  
13.1 Adverse Events: 
Adverse Events will be coded using the MedDRA dictionary. Adverse Events will be grouped by SOC 
and PT and summarized by study treatment. 


 
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The summary tables will include the number of subjects and the number of events. For summaries by 
SOC and PT, a subject will be counted once at the SOC level and once at each PT within the SOC level. 
• Relationships of definitely related, probably related, potentially related and Unknown will be judged as 
being treatment-related for the summary tables. Assessment of safety will be based on the frequency of 
TEAEs. All TEAEs seen during the study period will be listed. Separate listing will be provided for 
TEAE leading to discontinuation/other clinically significant non-fatal AE. Incidence of all TEAEs 
reported during the study in either of the group will be summarized by causality, severity and 
seriousness. Summaries for SAEs if any will also be provided.  
The following AE tables will be provided: 
• Overall Summary of Adverse Events by treatment 
• Summary of Treatment Emergent Adverse Events by system organ class and preferred term 
• Summary of Treatment Emergent Adverse Events by system organ class and preferred term by 
Severity. 
13.2 Laboratory Evaluations: 
Listings of individual subject laboratory results will be provided. Laboratory results and change from 
pre-dose values for lab tests will be summarized, at scheduled visits.  
For summary purposes, laboratory values that are listed as above or below particular thresholds will be 
numerically listed as above or below that threshold, respectively, by the minimum measured amount for 
that parameter. For example, if a parameter is measured to two decimal places, and has a result of “> 6” 
then, for summary purposes, the value of 6.01 will be used. Values with “<” or “>” will be classified as 
Low or High, respectively, unless such classifications aren’t applicable for that parameter, in which case 
they will be classified as Normal. 
13.3 Physical examinations: 
All the physical examination will be listed by Subject no. by treatment. 
13.4 Vital Signs: 
 
Vital signs (systolic/diastolic blood pressure, heart rate, respiratory rate and body temperature) will be 
listed at each protocol scheduled visit. 
 
All the vital signs will be listed by Subject no. by treatment.  
 
14 Revision History: 
Version No. 
Revision History 
Reason for change 
Not Applicable 
Not Applicable 
Not Applicable 
 
15 Reference: 
Protocol: SARO.20.001 (Version 4.0). 
 
16 Appendix: 
Appendix-01: Tables, Listings and Figures specifications