Phase 2A, Double-blind, Randomized Clinical Trial to Evaluate the Efficacy and Safety of Saroglitazar Mg 4 mg Tablet Vs Placebo for Treating Nonalcoholic Fatty Liver Disease (NAFLD) in Women With Polycystic Ovary Syndrome (PCOS)
Phase: PHASE2
Conditions: Non-alcoholic Fatty Liver Disease in Women With PCOS
Sponsor: Zydus Therapeutics Inc.

 
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Saroglitazar Magnesium – Phase 2A 
SARO.17.009 
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Approved by: 
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Protocol No. SARO.17.009 
Version No.: 5.0 
 
Protocol No. 
SARO.17.009 
Version No. and dated 
5.0, dated 06 February 2020 
Superseded Version and Date 
SARO.17.009.04 PROTOCOL Version 4.0,  21 June 2019 
Investigational Product(s) 
Saroglitazar Magnesium 4 mg Tablets 
IND Number 
IND 138351 
Study/Scientific Title 
A Phase 2A, Double-blind, Randomized, Placebo-Controlled 
Clinical Trial to Evaluate the Efficacy and Safety of 
Saroglitazar Magnesium 4 mg Tablets for Treating Non-
alcoholic Fatty Liver Disease (NAFLD) in Women With 
Polycystic Ovary Syndrome (PCOS). 
Public Title 
Saroglitazar Magnesium 4 mg for the treatment of NAFLD in 
Women With PCOS. 
Clinical Phase 
Phase 2A 
Sponsor 
Zydus Discovery DMCC  
  
 
  
 
 
Study Director 
(Sponsors Representative) 
Dr Deven V Parmar MD, FCP 
Senior Director & Head – Clinical R & D 
 
 
  
 
 
 
 
 
Sponsors Medical Experts 
Dr. Deven V Parmar, MD, FCP  
Senior Director & Head – Clinical R & D 
 
 
  
 
 
 
 
 
 
  
  
   
   
  
 

 
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Saroglitazar Magnesium – Phase 2A 
SARO.17.009 
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Approved by: 
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Protocol No. SARO.17.009 
Version No.: 5.0 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This protocol is the property of Zydus Discovery DMCC and 
may not - in full or in part - be retrieved, passed on, 
reproduced, published or otherwise used without the express 
permission of Zydus Discovery DMCC. 
 

 
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Protocol No. SARO.17.009 
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STUDY PROTOCOL SUMMARY 
Name of Sponsor 
Zydus Discovery DMCC  
  
 
  
 
 
Name of the Test Product 
Saroglitazar Magnesium 4 mg Tablets  
Name of Active Ingredient of Test 
Product 
Saroglitazar Magnesium 4 mg 
Name of the Reference Drug 
Placebo Tablet 
Name of Active Ingredient of Reference 
Product 
Placebo 
Study Population 
Non-alcoholic Fatty Liver Disease (NAFLD) in 
women with Polycystic Ovary Syndrome (PCOS) 
Study Subjects 
Patients of PCOS with NAFLD 
Number of Subjects 
90 
Planned Study Period 
34 weeks  
Study Title: A Phase 2A, Double-blind, Randomized, Placebo-Controlled Clinical Trial to Evaluate 
the Efficacy and Safety of Saroglitazar Magnesium 4 mg Tablets for Treating NAFLD in Women 
With PCOS. 
Background: Polycystic ovarian syndrome is the most common endocrine disorder of women of 
reproductive age, affecting 9-18% of women aged 27-34 years. Polycystic ovarian syndrome is 
diagnosed when women present with two of the three following features: (a) ovarian dysfunction or 
anovulation (commonly oligomenorrhea), (b) hyperandrogenemia and (c) polycystic ovaries after 
excluding hyperprolactinemia, thyroid disease or congenital adrenal hyperplasia. 
 
Polycystic ovarian syndrome can present as one of the four phenotypes based on the number and 
pattern of criteria that are fulfilled; phenotype 1 where all three criteria are met, phenotype 2 where 
patients have anovulation and hyperandrogenism, phenotype 3 where patients have polycystic 
ovaries and hyperandrogenism and phenotype 4 where patients have anovulation and polycystic 
ovaries. There are a number of important knowledge gaps in the field of PCOS and NAFLD. These 
can be broadly categorized into (a) there is high prevalence of NAFLD and perhaps Non-alcoholic 
steatohepatitis (NASH); (b) there is higher likelihood of advanced fibrosis prematurely and at an 
earlier age; (c) mechanistic basis for prevalence and severity of NAFLD; and (d) novel treatments. 
 
Effective therapies for NAFLD/NASH in this population are missing. The Dual Peroxisome 
Proliferator-Activated Receptor Alpha/Gamma (PPAR- α/γ) agonist, Saroglitazar Magnesium, has 
demonstrated lipid and glucose lowering effects through its PPAR α and γ activation. It is already 
approved for treatment of dyslipidemia in patients with diabetes in some countries and to date 
exhibited excellent tolerability and safety. It also reduces fasting blood glucose and hemoglobin A1c 
in these patients. Being predominantly a PPAR α agonist, with weaker γ stimulating effects, it has 
the advantage of inducing fewer side effects than previously identified with PPAR γ activation, such 

 
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as weight gain and peripheral edema. 
 
Saroglitazar Magnesium improved hepatic steatosis, inflammation and fibrosis in rodent models of 
NAFLD and NASH. Saroglitazar Magnesium resulted improvement in the lipoproteins and 
triglyceride levels as well as measures of insulin sensitivity. 
 
In this phase 2A pilot trial, we will test the efficacy and safety of Saroglitazar Magnesium on 
NAFLD patients with PCOS. If efficacy and safety are shown, that will provide a strong basis for 
long term evaluation of decreasing the disease burden for patients with PCOS and NAFLD. 
Objectives:  
Objective: 
The purpose of this study is to evaluate the efficacy and safety of Saroglitazar Magnesium 4 mg 
Tablets once-daily in women with well characterized PCOS diagnosed with NAFLD. 
Primary Objective: 
To evaluate the effect on hepatic fat content, measured as proton-density fat-fraction (PDFF) by 
magnetic resonance imaging (MRI), of once-daily Saroglitazar Magnesium 4 mg Tablets for 24 
weeks vs placebo. 
Secondary Objectives:  
To assess the effect of a 24-week treatment regimen of once-daily Saroglitazar Magnesium 4 mg 
Tablets on the following parameters in patients of PCOS with NAFLD: 
 
1. Liver enzymes/LFTs. 
2. Insulin resistance (IR) measured by Homeostasis Model Assessment (HOMA). 
3. Liver stiffness measurement obtained via transient elastography/FibroScan®. 
4. Controlled attenuation parameter obtained via transient elastography/ FibroScan®. 
5. Body weight, body mass index (BMI) and waist circumference. 
6.  MRI-derived total liver fat index and total liver volume. 
7. Serum lipid profile and lipoproteins. 
8. Sex hormone binding globulin. 
9. Ovarian function. 
10. Free androgen index. 
11. Pharmacokinetics of Saroglitazar following first dose and last dose. 
Criteria for Safety: 
1. Vitals: blood pressure (BP) (sitting BP after 05 min rest; systolic and diastolic BP), pulse rate, 
oral temperature and respiratory rate (at Visit 1 [Screening] and at Visit 3 through Visit 8 
[End-of-Treatment]). 
2. Body mass index (BMI) at Screening Visit (Visit 1), at 12 weeks (Visit 6) and at the Week 24 
End-of-Treatment visit (Visit 8). 
3. Waist measurements at Screening Visit, at Visit 6 and at the End-of-Treatment visit. 

 
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4. The physical examination will consist of an evaluation of the head, neck, eyes, ears, nose, 
throat, pelvic, breast, chest, heart, lungs, abdomen, skin, extremities, neurological systems, 
musculoskeletal systems and weight measurement. Investigator should also evaluate the 
patients for hirsutism and virilizing signs (upper lip, chin, chest, upper abdomen, lower 
abdomen, thighs, back, arm and buttocks). Note: Breast examination will be done as part of 
screening. Pelvic examination will be performed as part of screening, if not performed within 6 
months of randomization. 
5. Laboratory assessment 
a. Hematology: Hematocrit, hemoglobin, mean corpuscular hemoglobin concentration 
(MCHC), mean corpuscular volume (MCV), platelet count, mean platelet volume, red 
blood cell (RBC) count, white blood cell (WBC) count, differential WBC count. 
b. Liver enzymes/liver function tests (LFTs): aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (with conjugated 
bilirubin), gamma glutamyltransferase (GGT), serum protein and albumin. 
c. Renal function tests (RFTs): blood urea nitrogen (BUN), creatinine and estimated 
glomerular filtration rate (eGFR). Estimated glomerular filtration rate will be 
calculated by using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation. 
d. Inflammatory marker: high sensitivity C-reactive protein (hs-CRP). 
e. Lipid profile and lipoproteins: triglyceride (TG), total cholesterol (TC), high-density 
lipoprotein (HDL), low-density lipoprotein (LDL), small dense low-density 
lipoprotein 
(sdLDL), 
very 
low 
density 
lipoprotein 
(VLDL), 
free 
fatty 
acids, apolipoprotein A and apolipoprotein B. 
f. Urine examination: physical examination (appearance, color, specific gravity and pH); 
microscopy (epithelial cells, red blood cells, pus cells, cast and crystals) and chemical 
examination (protein, glucose, bilirubin, urobilinogen, ketone bodies and nitrite). 
g. T3, T4 and thyroid stimulating hormone (TSH) 
h. Serum pregnancy test 
i. 
Urine pregnancy test 
j. 
Serology: human immunodeficiency virus (HIV) type 1 and type 2, hepatitis A virus 
(HAV), anti-hepatitis B virus surface antigen (HBsAg) and hepatitis C virus (HCV) (at 
Visit 1). 
k. International normalized ratio (INR) and prothrombin time (PT) 
l. 
Cytokeratin 18 
m. Free androgen index and Sex hormone binding globulin level 

 
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n. Total testosterone and free testosterone 
o. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels 
p. 17-hydroxyprogesterone 
q. Estradiol 
r. Creatine Kinase (CK) 
s. Cardiac function: 12-lead-electrocardiogram (ECG) 
t. 
Glycemic control: Fasting plasma glucose (FPG), HbA1c and plasma insulin levels 
u. B-type natriuretic peptide (BNP) and aminoterminal fragment of BNP prohormone 
(NT-proBNP) 
v. Papanicolaou (PAP) test 
w. Cardiac troponin, creatine kinase-muscle/brain (CK-MB) 
x. Lipase and amylase 
y. Uric acid 
6. Adverse event(s): Frequency and severity of adverse event (AE) /serious adverse events 
(SAEs), drop-outs due to AEs/SAEs for all subjects enrolled will be recorded. All AEs, will be 
assessed using Council for International Organizations of Medical Sciences (CIOMS) criteria 
using:  
a. Causality  
b. Severity 
c. Seriousness 
d. Expectedness 
 
Note: Efficacy assessments and laboratory assessments (liver fat content by MRI-PDFF [MRI-
PDFF will be performed during screening phase, screening phase results will be used as the 
baseline assessment], controlled attenuation parameter, hormonal profile, fasting plasma glucose, 
lipid and lipoprotein profiles, MRI-derived total liver fat index and total liver volume [MRI-
derived total liver fat index and total liver volume assessment will be performed during screening 
phase, screening phase results will be used as the baseline assessment], plasma insulin levels, 
homeostasis model assessment (insulin resistance [HOMA-IR]), liver stiffness by transient 
elastography/FibroScan®, ovarian function, liver enzymes/LFTs, hematology, coagulation test 
(PT/INR), renal function test, CK, hs-CRP, BNP, NT-proBNP, cardiac troponin, CK-MB, lipase 
and amylase, TNFα, uric acid, TSH, T3 and T4, serology, HIV type 1 and type 2, HAV,  anti-
HBsAg, HCV, serum pregnancy test, urine microscopy and urine chemistry) which will be done at 
Visit 1 will be considered for baseline visit. PAP test, endometrial biopsy and mammography will 
be performed as per Time and Events Schedule. 

 
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Criteria for Inclusion/Exclusion 
Inclusion criteria: 
1. Females, 18 to 45 years of age. 
2. Previously confirmed diagnosis of PCOS by Rotterdam criteria (at least 2 of 3):  
1) oligo-and/or anovulation; 
2) hyperandrogenism (clinical and/or biochemical) ; 
3) polycystic ovary morphology on ultrasonography (either 12 or more follicles 
measuring 2–9 mm in diameter or an increased ovarian volume >10 cm3). 
3. Evidence of NAFLD within 6 months prior to the Screening Visit (Visit 1). The 
diagnosis of NAFLD is made according to the American Association for the Study of 
Liver Diseases (AASLD) criteria. 
 
a) hepatic steatosis by imaging or histology,  
b) no significant alcohol consumption,  
c) no competing etiologies for hepatic steatosis, and  
d) no co-existing causes for chronic liver disease. 
4. Alanine transaminase ≥ 38 U/L at Visit 1. Visit 2 ALT must not increase >30% from 
Visit 1. 
5. Hepatic fat fraction ≥10% by MRI-PDFF. 
6. Willingness to participate in the study. 
7. Ability to understand and give informed consent for participation. 
8. A normal pelvic examination within past 6 months before randomization. 
9. A normal breast examination at screening (If Mammogram has been done in the 
preceding 12 months it will be documented. If patient is not up to date with standard 
breast cancer screening guidelines and is willing to receive screening, mammogram 
will be offered prior to enrollment as part of standard care). 
10. A normal Papanicolaou (PAP) test within past 6 months before randomization (If 
PAP test has not been performed within 6 months of the screening visit, it must be 
performed during screening). 
11. Woman who agrees to use the following contraceptive methods: 
a. Combination hormonal contraceptives (including pills, patches and vaginal 
rings). 
For the following conditions, the usage of the combination hormonal 
contraceptives should be based upon a discussion with the subject and the 
investigators’ clinical judgment. 
i. 
Women greater than 35 years of age who also smoke fewer than 15 cigarettes 
per day 
ii. 
Adequately controlled hypertension 
iii. 
Properly taken blood pressure above a systolic 140-159 mm Hg or diastolic 
90- 99 mm Hg 

 
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iv. 
Known hyperlipidemia 
v. 
Diabetes associated with vascular disease, including neuropathy, retinopathy 
and nephropathy. 
vi. 
Diabetes duration greater than 20 years. 
b. Women with the following conditions should use effective methods other than 
combined 
hormonal 
contraceptives 
(for 
e.g., 
Progestogen-only 
oral 
contraceptives or progestogen-containing intrauterine devices (IUD), Non-
hormonal IUD, Double-barrier contraception [e.g., condom plus diaphragm]): 
i. 
Women greater than 35 years of age who also smoke 15 or more 
cigarettes per day 
ii. 
Properly taken blood pressure above systolic ≥ 160 mm Hg or diastolic ≥ 
100 mm Hg 
iii. 
Known hyperlipidemia 
iv. 
Vascular disease, including neuropathy, retinopathy and nephropathy 
v. 
Diabetes duration greater than 20 years. 
Exclusion criteria: 
1. Presence of other chronic liver diseases (hepatitis B or C, autoimmune hepatitis, 
cholestatic liver disease, Wilsons disease, hemochromatosis, etc.).  
2. Average alcohol consumption ≥ 7 drinks per week for women in the 6 months prior to 
enrollment. Subjects will be required to have an “Alcohol Use Disorder Identification 
Test” (AUDIT) score of <8. 
3. Clinical, imaging, or histological evidence of cirrhosis  
4. Any of the following laboratory values:  
a. Hemoglobin <10 g/dL  
b. White blood cell count <4 x 109/L  
c. Neutrophil count <1.5 × 103/µL  
d. Abnormal baseline platelet counts (<150 x 103 uL). 
e. Total serum bilirubin greater than the ULN (>1.3 mg/dL) (except in 
patient with known Gilbert Syndrome where TB up to 2.5 mg/dL is 
allowed)  
f. Albumin <3.2 g/dL  
g. Serum ALT or AST >250 IU/L 
h. Lipase or amylase more than the ULN at baseline. 
i. 
Serum creatinine ≥1.5 mg/dL 
j. 
Renal impairment as demonstrated by baseline estimated glomerular 
filtration rate (eGFR) < 60 mL/min/1.73 m2 (calculated using the 
CKD-EPI equation). 
k. Total creatine kinase level more than the ULN at baseline. 
5. Patient with INR >1.3 
6. Patients who have used  medications known to cause hepatic steatosis (e.g., 
corticosteroids, amiodarone, methotrexate, tetracycline, tamoxifen, anabolic steroids, 
or valproic acid) for more than 2 weeks in the past year.  
7. Prior bariatric surgery. 
8. Weight loss of more than 5% in the 3 months preceding screening. 
9. Severe co-morbidities (e.g., advanced cardiac, renal, pulmonary, or psychiatric 
illness). 

 
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10. Known allergy, sensitivity or intolerance to Saroglitazar Magnesium, comparator or 
formulation ingredients (Saroglitazar Magnesium Micronized, Magnesium Oxide 
Light, Microcrystalline Cellulose, Anhydrous Lactose, Croscarmellose Sodium, 
Povidone k 30, Talc (luzena c), Colloidal Silicon Dioxide and Magnesium Stearate). 
11. Use of antidiabetic and lipid lowering medications if the dose is not stable for at least 
the 3 months preceding screening. 
12. Intake of Vitamin E (>100 IU/day) or multivitamins containing Vitamin E (>100 
IU/day) 3 months before enrollment. 
13. Use of drugs with potential effect on NAFLD/NASH such as S-adenosylmethionine 
(SAM-e), Betaine, Pentoxifylline, Thiazolidinediones (Pioglitazone, Rosiglitazone), 
Obeticholic Acid or Milk Thistle in the 3 months prior to screening. 
14. Changing doses of statins (Simvastatin, Pravastatin, Atorvastatin, Fluvastatin, 
Lovastatin, Rosuvastatin) or Fibrates (Clofibrate, Fenofibrate) in the 3 months prior to 
enrollment.  
15. Illicit substance abuse within the past 12 months.  
16. Pregnant or breast-feeding females. 
17. Poorly controlled diabetes with HbA1c >8.5%. 
18. Use of total parenteral nutrition in the 6 months preceding enrollment. 
19. Women with known Cushing syndrome or hyperprolactinemia. 
20. Late onset congenital adrenal hyperplasia, androgen-producing tumors. 
21. Refusal or inability to comply with the requirements of the protocol, for any reason, 
including scheduled clinic visits and laboratory tests. 
22. History of myopathies or evidence of active muscle diseases. 
23. History or current significant cardiovascular disease, including: 
i. 
Unstable angina (i.e., new or worsening symptoms of coronary heart disease 
within the past 3 months before screening), acute coronary syndrome within the 
past 6 months before screening, acute myocardial infarction in the past 3 months 
or heart failure of New York Heart Association class (III-IV) or worsening 
congestive heart failure, or coronary artery intervention, within the past 6 
months before screening. 
ii. 
History or current unstable cardiac dysrhythmias within prior 3 months before 
screening. 
iii. 
Uncontrolled hypertension (systolic blood pressure > 160 mmHg and/or 
diastolic blood pressure > 100 mmHg). 
iv. 
Stroke or transient ischemic attack prior 6 months before screening visit. 
24. History of malignancy in the past 5 years and/or active neoplasm with the exception of 
resolved superficial nonmelanoma skin cancer.  
25. History of bladder disease other than urinary tract infection or cystitis. Previous or 
current hematuria due to etiologies other than urinary tract infection or kidney stones. 
Methodology: 
 
This is a multicenter, phase 2A, randomized, double-blind, placebo-controlled study designed 
to evaluate the efficacy and safety of Saroglitazar Magnesium in women with well 
characterized PCOS, 18-45 years of age diagnosed with NAFLD according to the AASLD 
criteria within 6 months preceding the Screening Visit (Visit 1). Six patients in each group 
are planned for pharmacokinetic assessment therefore a total of 12 patients will be included. 
Additional patients may be enrolled into the study to ensure the pharmacokinetic assessment 
is performed on at least 6 completed patients in each treatment arm. 

 
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Protocol No. SARO.17.009 
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 
Eligible subjects will be screened within 4 weeks prior to randomization. During the Visit 1, 
subject will be seen by the investigator or designated study personnel and an AUDIT 
questionnaire will be administered. Inclusion and exclusion criteria will be verified during 
Visit 1 and Visit 3. 
 
Eligible subjects will be enrolled into either of the two treatments arms: Saroglitazar 
Magnesium 4 mg Tablets and matching placebo tablets in a 1:1 ratio. 
 
The study will be conducted over a period of up to 34 weeks. Subjects will be evaluated at 
study sites for 8 scheduled visits: at screening visits (Visit 1: Day [-28], Visit 2: Day [-14 to -
7]), randomization (Visit 3: Week 1, Day 1), Visit 4 (Week 2, Day 14), Visit 5 (Week 8, Day 
56), Visit 6 (Week 12, Day 84), Visit 7 (Week 16, Day 112) Visit 8 (Week 24, Day 168). 
After completion of the study treatment period, the subjects will be followed for an 
additional period of 6 weeks without study medication until Visit 9 (Week 30, Day 210).  
 
Subjects will be monitored during the study and in every visit for development of any 
adverse events including drug induced liver injury. In addition to physical examination, 
laboratory data and ECGs done during the study period will be monitored to detect any 
treatment emergent adverse events. The schedule of assessments is presented in Table 1 
(Time and Events Schedule). 
Pre-screening Visit: An informed consent will be obtained from the potential subjects before any 
pre-screening evaluations. The study sites may identify potential subjects by conducting a laboratory 
evaluation of the ALT levels. This optional pre-screening can be conducted before the actual study 
screening. A subject with an ALT ≥38 U/L may be considered for the actual study screening. Also, 
along with the evaluation of the ALT levels, in those potential subjects who do not have a 
documented diagnosis of NAFLD through any imaging method, an optional abdominal ultrasound or 
Fibroscan® may be performed during the pre-screening. 
In addition, an optional lab evaluation for diagnosis of PCOS through lab or ultrasound may be 
performed during pre-screening.  The evaluation of the ALT levels during the pre-screening will be 
done at the local laboratory, whereas the laboratory evaluations during the screening and the 
treatment phase will be done at the central laboratory. 
Screening Phase 
Visit 1 (Day -28): In this study, the screening phase will consist of 28 days. Unless otherwise 
specified, screening procedures may be completed at any time during the screening period. Before 
each patient is enrolled to the study, informed consent will be obtained from the patient (or her 
legally authorized representative) according to the regulatory and legal requirements of the 
participating country. Patient eligibility for participation in the study will be assessed. Current 
social, medical and ovarian dysfunction history will be obtained and physical examination, vital 
signs, ECGs, laboratory evaluations (including serology, hematology, lipid and lipoprotein profiles, 
liver enzymes/LFTs, BNP, NT-proBNP, cardiac troponin, CK-MB, lipase and amylase, hormonal 
profile and urinalysis) will be performed. PAP test, endometrial biopsy and mammography will be 
performed as per Time and Events Schedule. Patients will undergo a serum pregnancy test. 

 
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Visit 2 (Day -14 to -7): Liver function tests (AST, ALT, ALP, GGT, total-protein, albumin, total 
bilirubin (with conjugated bilirubin) will be re-measured approximately 2 weeks from Day -28 to 
determine eligibility. 
Alanine transaminase ≥ 38 U/L at Visit 1. Visit 2 ALT must not increase >30% from Visit 1.  
Randomization and Treatment Phase 
 
The randomization and treatment phase will include 6 outpatient visits (Visit 3 to Visit 8) 
over a period of 24 weeks including the randomization visit. 
 
All the eligible subjects will be randomly assigned into either of the two treatments arms: 
Saroglitazar Magnesium 4 mg Tablets and matching placebo tablets in a 1:1 ratio.  
 
Efficacy assessments will be conducted at 12 (hormonal profile, lipid and lipoprotein 
profiles, ovarian function and liver enzymes/LFTs) and 24 weeks (liver fat content by MRI-
PDFF, hormonal profile, lipid and lipoprotein profiles, MRI-derived total liver fat index and 
total liver volume, homeostasis model assessment [insulin resistance (HOMA-IR)], liver 
stiffness by transient elastography/FibroScan®, controlled attenuation parameter, ovarian 
function and liver enzymes/LFTs).  
 
In addition, subjects will be monitored during the study and at every visit for development 
of any adverse events including drug induced liver injury. 
 
In addition to physical examination, laboratory data and ECGs done during the study period 
will be monitored to detect any treatment emergent adverse events. Detailed efficacy and 
safety assessments are provided in Table 1 (Time and Events Schedule). 
End-of-treatment Visit (Visit 8): An end-of-treatment visit will occur at 24 weeks for clinical 
assessment, reconciliation of study drug, and measurements of efficacy and safety endpoints. 
Detailed efficacy and safety assessments are provided in Table 1 (Time and Events Schedule). 
Safety follow-up visit (Visit 9): A final post-treatment visit will occur 6 weeks (±3 days) after the 
end-of-treatment visit for safety monitoring. A telephonic follow-up visit will be performed to assess 
any AE or SAE after the end-of-treatment visit for safety monitoring. 
Patient Withdrawal: 
Patients may withdraw from the entire study at any time without penalty and for any reason without 
prejudice to her future medical care. A patient’s withdrawal of consent and agreement to undergo a 
final examination will be documented on the electronic case report form. As far as possible, all 
assessments scheduled for end-of-treatment must be performed on all patients who receive the study 
drug but do not complete the study according to protocol. 
Discontinuation of Patients from the Study or Study Drug: 
A patient may be discontinued from the study for any of the following reasons: 
 
Noncompliance to the protocol requirements. 
 
Occurrence of a serious or intolerable AE and based upon the Investigators’ clinical 

 
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judgment. 
 
 The Sponsor or PI terminates the study. 
 
Either the PI or the Sponsor decides that discontinuing the study or discontinuing the patient 
is in the patient’s best interest. 
 
For reasons related to safety. 
 
The patient is lost to follow-up. 
 
A patient may also be discontinued from study drug/study by the Sponsor, Regulatory 
Authorities or Institutional Review Board (IRB) or Independent Ethics Committee (IEC). 
 
If the patient becomes pregnant. 
Concomitant medications: 
All the permitted and excluded concomitant medications will be recorded in this study. 
Total Enrollment: 
Ninety patients are planned to be enrolled in this study. Patients 
will be randomly assigned to receive active drug (Saroglitazar 
Magnesium 4 mg) or placebo in a 1:1 ratio. 
Six patients in each group are planned for pharmacokinetic 
assessment therefore a total of 12 patients will be included. 
Test Product: 
Dose: 
Mode of Administration: 
Saroglitazar Magnesium tablet (Zydus) 
4 mg  
Oral (once daily in the morning before breakfast without food) 
Reference/Placebo Therapy: 
Mode of Administration: 
Placebo tablet 
Oral (once daily in the morning before breakfast without food) 
Duration of Treatment:  
24 weeks 
Criteria for Efficacy 
Primary Efficacy Endpoint: 
Change in hepatic fat content from baseline following 24 weeks of treatment as measured by 
MRI-PDFF. 
Secondary Efficacy Endpoints: 
1. Changes from baseline to Week 12 and Week 24 in liver enzymes/LFTs: ALT, AST, ALP, 
GGT, serum protein, albumin and total bilirubin. 
2. Changes from baseline to Week 12 and Week 24 in IR as measured by HOMA.  
3. Changes from baseline to Week 24 in markers of liver injury and fibrosis including CK-18, 
high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor α (TNFα), and liver 
stiffness measured by transient elastography/FibroScan®. 
4. Changes from baseline to Week 24 in controlled attenuation parameter measured by 
transient elastography/FibroScan®. 
5. Changes from baseline to Week 12 and Week 24 in body weight, BMI and waist 
circumference. 
6. Changes from baseline to Week 24 in MRI-derived measures of total liver fat index and 
total liver volume.  
7. Changes from baseline to Week 12 and Week 24 in lipid and lipoprotein levels: TG, TC, 

 
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HDL, LDL, sdLDL, VLDL, apolipoprotein A and apolipoprotein B. 
8. Changes from baseline to Week 12 and Week 24 in sex hormone binding globulin (SHBG) 
level. 
9. Changes from baseline to Week 12 and Week 24 in ovarian function (Total testosterone, 
17-hydroxyprogesterone, free testosterone, luteinizing hormone, follicle-stimulating 
hormone, LH-to-FSH ratio and estradiol). 
10. Changes from baseline to Week 12 and Week 24 in free androgen index. 
11. Pharmacokinetics of Saroglitazar following first dose and last dose. 
Criteria for Safety 
1. Frequency and severity of AEs and serious AEs. 
2. Clinical laboratory testing (hematology, clinical chemistry, hormonal profile and 
urinalysis). 
3. Twelve-lead electrocardiogram. 
4. Vital signs. 
5. Physical examination. 
Statistical Methods: 
General data analysis: 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 and baseline characteristics will be summarized by treatment and population set. 
Subject disposition and reason for withdrawal will be summarized and presented.  
Unless otherwise stated, all the continuous variables will be summarized using descriptive statistics 
such as n, mean, standard deviation, minimum, median and maximum. Categorical variables will be 
summarized using frequencies and percentages. 
Efficacy analysis: All efficacy analysis will be based primarily on the Per Protocol (PP) population 
and analysis based on modified intent-to-treat (mITT) population will be considered as supporting 
analyses for this proof of concept study. The PP population is a subset of mITT population. The PP 
population will consist of all randomized patients completing the treatment phase and have not 
deviated from or violated the protocol in such a way that could affect efficacy outcome (i.e., had 
both baseline and end-of-treatment MRI & has taken ≥80% and ≤120% of the study drug).The mITT 
population will consist of all randomized patients who received at least one dose of the study drug 
and have at least one post-baseline efficacy data. Last observation carried forward method will be 
used as an imputation method for post-baseline missing values for mITT analysis. 
Primary efficacy analysis: The primary analysis for primary efficacy endpoint will be based on PP 
population. The primary efficacy endpoint in this study is the change in hepatic fat content from 
baseline following 24 weeks of treatment as measured by MRI-PDFF. The change from baseline of 
hepatic fat will be determined as (Week 24 value – Baseline value). The change from baseline at 
Week 24 in hepatic fat content between treatments will be evaluated using analysis of covariance 
(ANCOVA) model with treatment as fixed effect and baseline value as covariate. Treatment effects 
will be estimated using the least square means, standard error and 95% confidence interval (CI) from 
the ANCOVA model. The two treatment groups, i.e., Saroglitazar Magnesium 4 mg Tablets versus 
Placebo, will be compared using difference in least-square means and p-values from the ANCOVA 
model. 
 
Secondary efficacy analysis: All secondary efficacy endpoints will be analyzed using the same 
statistical methods as primary efficacy endpoint. 

 
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Descriptive statistics will be provided for all pharmacokinetic parameters. 
 
Safety analysis: Safety analysis will be based on the safety population which will consist of all 
randomized patients who received at least 1 dose of study drug. All patients in the safety population 
will be analysed according to the actual treatment received. All safety endpoints (AEs, clinical 
laboratory testing, ECGs, body weight, physical examination and vital signs) will be summarized by 
treatment group using the following descriptive statistics: N, mean, median, standard deviation, 
minimum and maximum for continuous variables, frequencies and percentages for categorical 
variables. 

 
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ABBREVIATIONS 
Abbreviation 
Definition 
AEs 
Adverse events 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
AASLD 
American Association for the Study of Liver Diseases 
AST 
Aspartate aminotransferase 
ANCOVA 
Analysis of covariance 
AUDIT 
Alcohol Use Disorder Identification Test 
BP 
Blood pressure 
BMI 
Body mass index 
BNP 
B-type natriuretic peptide 
BUN 
Blood urea nitrogen 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CIOMS 
Council for International Organization of Medical Sciences 
CI 
Confidence interval 
CTCAE 
Common Terminology Criteria for Adverse Event 
CRA 
clinical research associate 
CK 
Creatine Kinase 
CK-MB 
Creatine kinase-muscle/brain 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
FA 
Fatty acids 
FDA 
Food and Drug Administration 
FPG 
Fasting plasma glucose 
FSH 
Follicle stimulating hormone  
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyltransferase 
HAV 
Hepatitis A virus 
HbA1c 
Glycated hemoglobin 
HCV 
Hepatitis C virus 

 
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HBsAg 
Hepatitis B virus surface antigen  
HDL 
High density lipoprotein 
HOMA 
Homeostasis Model Assessment  
HIV 
Human immunodeficiency virus 
hs-CRP 
High sensitivity C-reactive protein 
INR 
International Normalized ratio 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IR 
Insulin resistance 
IRB 
Institutional Review Board 
LDL 
Low density lipoprotein 
LFT 
Liver function test 
LPL 
Lipoprotein lipase 
LH 
luteinizing hormone 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
mITT 
 
Modified intent-to-treat  
MRI 
Magnetic resonance imaging 
MS 
Metabolic syndrome 
NAFLD 
Non-alcoholic fatty liver disease 
NASH 
Non-alcoholic steatohepatitis 
PAP 
Papanicolaou 
PT 
Prothrombin time 
PI 
Principal Investigator 
PCOS 
Polycystic ovarian syndrome 
PDFF 
Proton-density fat-fraction 
MPV 
Mean platelet volume 
PPAR 
Peroxisome proliferator-activated receptor 
PP 
Per protocol 
QD 
Quarter-in-die  
RBC 
Red blood cell 
RFT 
Renal function test 
SAE 
Serious adverse event 

 
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SAM-e 
S adenosylmethionine 
sdLDL 
small dense low-density lipoprotein 
SHBG 
Sex hormone binding globulin  
SAP 
Statistical analysis plan 
SOPs 
Standard operating procedures 
TC 
Total Cholesterol 
T2DM 
Type 2 diabetes mellitus 
TG 
Triglyceride 
TSH 
Thyroid stimulating hormone 
TZD 
Thiazolidinediones 
VLDL 
Very low density lipoprotein 
WBC 
White blood cell 
 

 
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TABLE OF CONTENTS 
 
Contents 
STUDY PROTOCOL SUMMARY ...................................................................................................................... 3 
ABBREVIATIONS ............................................................................................................................................. 22 
TABLE OF CONTENTS .................................................................................................................................... 25 
1 
STUDY FLOW CHART ............................................................................................................................. 28 
2 
INTRODUCTION ....................................................................................................................................... 29 
2.1 
BACKGROUND ................................................................................................................................. 29 
2.2 
RATIONALE FOR CONDUCTING THE TRIAL ............................................................................. 30 
2.3 
DRUG PROFILE ................................................................................................................................ 31 
2.4 
RISK AND BENEFIT ......................................................................................................................... 33 
3 
STUDY OBJECTIVES ............................................................................................................................... 35 
3.1 
PRIMARY OBJECTIVE .................................................................................................................... 35 
3.2 
SECONDARY OBJECTIVES ............................................................................................................ 35 
3.3 
SAFETY ASSESSMENT ................................................................................................................... 35 
4 
STUDY POPULATION ............................................................................................................................. 39 
4.1 
NUMBER OF SUBJECTS PLANNED .............................................................................................. 39 
4.2 
INCLUSION CRITERIA .................................................................................................................... 39 
4.3 
EXCLUSION CRITERIA ................................................................................................................... 40 
4.3.1 
Screen Failures ............................................................................................................................ 42 
4.4 
PATIENT WITHDRAWAL ............................................................................................................... 42 
4.4.1 
Discontinuation of Patients from the Study or Study Drug ......................................................... 43 
4.4.2 
Patients Lost to Follow-up .......................................................................................................... 43 
4.5 
STOPPING CRITERIA FOR INDIVIDUAL PATIENTS ................................................................. 43 
4.6 
TERMINATION OF THE CLINICAL STUDY ................................................................................. 45 
5 
STUDY TREATMENTS / INVESTIGATIONAL PRODUCT MANAGEMENT .................................... 46 
5.1 
TREATMENTS TO BE COMPARED ............................................................................................... 46 
5.1.1 
Investigational Product Description ............................................................................................ 46 
5.1.2 
Comparator Drug Description ..................................................................................................... 47 
5.2 
DOSAGE AND TREATMENT SCHEDULE .................................................................................... 47 
5.3 
PACKAGING, LABELLING AND SUPPLY .................................................................................... 48 
5.4 
STORAGE CONDITIONS AND STABILITY .................................................................................. 48 
5.5 
BLINDING ......................................................................................................................................... 48 
5.6 
METHOD OF ASSIGNING PATIENTs TO the TREATMENT GROUPs ....................................... 49 
5.7 
SELECTION OF DOSES ................................................................................................................... 49 
5.8 
CONCOMITANT THERAPY ............................................................................................................ 49 
5.8.1 
Subjects on Concomitant Anti-diabetic Medication .................................................................... 50 

 
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5.8.2 
Previous and Concomitant Medications ...................................................................................... 51 
5.8.3 
Excluded Concomitant Medications ............................................................................................ 51 
5.8.4 
Other Restrictions ........................................................................................................................ 52 
5.9 
OVER DOSE AND DRUG INTERACTION ..................................................................................... 53 
5.10 
TREATMENT COMPLIANCE .......................................................................................................... 53 
6 
OBSERVATIONS ...................................................................................................................................... 54 
6.1 
EFFICACY ......................................................................................................................................... 54 
6.1.1 
Primary Endpoint ........................................................................................................................ 54 
6.1.2 
Secondary Endpoints ................................................................................................................... 54 
6.2 
SAFETY .............................................................................................................................................. 54 
6.2.1 
Abnormal Laboratory Findings ................................................................................................... 55 
6.2.2 
Appropriateness of Measurement ................................................................................................ 55 
7 
INVESTIGATIONAL PLAN ..................................................................................................................... 56 
7.1 
STUDY DESIGN AND PLAN ........................................................................................................... 56 
7.2 
STUDY PROCEDURES AT EACH VISIT ....................................................................................... 56 
7.3 
PHARMACOKINETIC ASsESSMENT ............................................................................................. 58 
7.4 
ADHERENCE TO PROTOCOL ........................................................................................................ 59 
7.5 
PROTOCOL DEVIATION ................................................................................................................. 59 
8 
DATA MANAGEMENT AND BIOSTATISTICS .................................................................................... 60 
8.1 
DATA MANAGEMENT .................................................................................................................... 60 
8.1.1 
Data Handling ............................................................................................................................. 60 
8.1.2 
Computer Systems ....................................................................................................................... 60 
8.1.3 
Data Entry ................................................................................................................................... 60 
8.1.4 
Medical Information Coding ....................................................................................................... 60 
8.1.5 
Data Validation ........................................................................................................................... 60 
8.2 
STATISTICAL DESIGN .................................................................................................................... 61 
8.3 
NULL AND ALTERNATIVE HYPOTHESIS ................................................................................... 61 
8.4 
STUDY POPULATION PLANNED ANALYSIS ............................................................................. 61 
8.4.1 
Population.................................................................................................................................... 61 
8.4.2 
Planned Analysis ......................................................................................................................... 62 
8.4.3 
Safety Analysis ............................................................................................................................ 64 
8.4.4 
Baseline Characteristics .............................................................................................................. 64 
8.4.5 
Interim Analysis .......................................................................................................................... 64 
8.5 
Handling of Missing Data ................................................................................................................... 64 
8.6 
DETERMINATION OF SAMPLE SIZE ............................................................................................ 64 
8.7 
RANDOMIZATION ........................................................................................................................... 65 
9 
ADMINISTRATIVE MATTERS ............................................................................................................... 66 
9.1 
ETHICS ............................................................................................................................................... 66 

 
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9.1.1 
Institutional/independent Committee Review and Communications .......................................... 66 
9.1.2 
Informed Consent and Subject Information ................................................................................ 66 
9.2 
RECORDS .......................................................................................................................................... 67 
9.2.1 
Drug Accountability .................................................................................................................... 67 
9.2.2 
Emergency code break (Unblinding) ........................................................................................... 67 
9.2.3 
Case Report Forms ...................................................................................................................... 68 
9.2.4 
Source documents........................................................................................................................ 68 
9.2.5 
Direct Access to Source Data / Documents ................................................................................. 68 
9.2.6 
Trial Monitoring .......................................................................................................................... 69 
9.2.7 
Query Handling and Error Management ..................................................................................... 69 
9.3 
QUALITY CONTROL AND QUALITY ASSURANCE AUDIT ..................................................... 69 
9.4 
PROCEDURES ................................................................................................................................... 70 
9.4.1 
Adverse Events ............................................................................................................................ 70 
9.4.2 
Serious Adverse Event ................................................................................................................ 72 
9.4.3 
Expected Adverse Events ............................................................................................................ 73 
9.4.4 
Emergency procedures ................................................................................................................ 73 
9.4.5 
Pregnancy .................................................................................................................................... 73 
9.5 
RULES FOR AMENDING PROTOCOL ........................................................................................... 75 
9.6 
DISCONTINUATION OF THE TRIAL BY THE SPONSOR........................................................... 75 
9.7 
STATEMENT OF CONFIDENTIALITY .......................................................................................... 75 
9.8 
FINAL REPORT AND PUBLICATION POLICY ............................................................................ 75 
9.9 
ARCHIVING ...................................................................................................................................... 76 
10 
REFERENCES ........................................................................................................................................ 77 
11 
APPENDICES ......................................................................................................................................... 79 
11.1 
Appendix 1: List of Known CYP2C8 Inhibitors/Substrates ................................................................ 79 
11.2 
Appendix 2: Declaration of Helsinki ................................................................................................... 79 
12 
PROTOCOL SIGNATURE .................................................................................................................... 80 
 

 
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2 INTRODUCTION 
2.1 
BACKGROUND 
Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of women of 
reproductive age, affecting 9-18% of women aged 27-34 years.1,2 Polycystic ovarian syndrome is 
diagnosed when women present with two of the three following features: (a) ovarian dysfunction 
or anovulation (commonly oligomenorrhea), (b) hyperandrogenemia and (c) polycystic ovaries 
after excluding hyperprolactinemia, thyroid disease or congenital adrenal hyperplasia.3 
 
Polycystic ovarian syndrome can present as one of the four phenotypes based on the number and 
pattern of criteria that are fulfilled; phenotype 1 where all three criteria are met, phenotype 2 
where patients have anovulation and hyperandrogenism, phenotype 3 where patients have 
polycystic ovaries and hyperandrogenism and phenotype 4 where patients have anovulation and 
polycystic ovaries. Polycystic ovarian syndrome phenotype 1 has been shown to be more 
commonly associated with insulin resistance (IR) compared to the rest.4 Insulin resistance state is 
also believed to contribute to hyperandrogenism; excess insulin in such states increases 
sensitivity of pituitary to gonadotropic hormone releasing hormone thus increasing 
steroidogenesis in the ovaries; insulin also appears to stimulate 17- hydroxylase and 3- 
hydroxysteroid dehydrogenase, increasing adrenal androgen secretion while inhibiting sex 
hormone binding globulin. Subjects, males and females with metabolic syndrome (MS) were 
found to have low sex hormone binding globulin (SHBG).5Among patients with PCOS, those 
with MS  also showed low SHBG levels compared to those without metabolic syndrome.6 But 
the levels were no longer different after adjusting for body mass index (BMI) and insulin 
resistance (IR).6 In a prospective study where patients with PCOS were compared to those 
without PCOS, we learn that subjects with MS have similar homeostatic model assessment 
(HOMA)-IR compared to those who do not regardless of PCOS diagnosis. Subjects with PCOS 
and MS had higher serum androgen levels compared to those without PCOS and metabolic 
syndrome. Almost two thirds of patients with PCOS have insulin resistance.7 Up to 67% patients 
with IR have non-alcoholic fatty liver disease (NAFLD).8 This suggests that patients with PCOS 
are at higher risk of NAFLD. In fact, patients with PCOS have been shown to have high 
prevalence of NAFLD, diagnosed based on imaging and clinical criteria.9 Some studies 
suggested that women with PCOS and NAFLD may have more advanced hepatic histology. 
While there are numerous clinical trials ongoing for non-alcoholic steatohepatitis 
NASH/NAFLD in the general population there are no studies targeting women with PCOS. 
Arguably, women with PCOS and NAFLD are an important subgroup of patients needing 
specific attention because of their risk for advanced fibrosis and potentially different mechanistic 
basis. 
 
There are a number of important knowledge gaps in the field of PCOS and NAFLD.  These can 
be broadly categorized into (a) prevalence and clinical risk factors for NAFLD in women with 
well characterized PCOS; (b) spectrum of liver disease severity, characterized non-invasively 

 
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and when possible invasively; (c) mechanistic basis for prevalence and severity of NAFLD; and 
(d) novel treatments. 
However, effective therapies for NAFLD/NASH in this population are missing. The Dual 
Peroxisome Proliferator-Activated Receptor Alpha/Gamma (PPAR- α/γ) agonist, Saroglitazar 
Magnesium, has demonstrated lipid and glucose lowering effects through its PPAR α and γ 
activation.10, 11 It is already approved in India for treatment of hyperlipidemia in patients with 
diabetes. It also reduces fasting blood glucose and hemoglobin A1c in these patients.10 Being 
predominantly a PPAR α agonist, with weaker γ stimulating effects, it has the advantage of 
inducing fewer side effects than previously identified with PPAR γ activation, such as weight 
gain and peripheral edema.12 
2.2 
RATIONALE FOR CONDUCTING THE TRIAL 
The Dual Peroxisome Proliferator-Activated Receptor Alpha/Gamma agonist, Saroglitazar 
Magnesium, has demonstrated lipid and glucose lowering effects through its PPAR α and γ 
activation.10, 11 It is already approved in India for treatment of hyperlipidemia in patients with 
diabetes. It also reduces fasting blood glucose and hemoglobin A1c in these patients.10 Being 
predominantly a PPAR α agonist, with weaker γ stimulating effects, it has the advantage of 
inducing fewer side effects than previously identified with PPAR γ activation, such as weight 
gain and peripheral edema.12 More recently, an exploratory open label study of Saroglitazar 
Magnesium was conducted in human immunodeficiency virus (HIV) infected patients with HIV 
lipo-dystrophy related hypertriglyceridemia.13 Fifty subjects were on stable antiretroviral therapy 
(ART) regimen at least for 8 weeks prior enrolling in the 12-week trial. Saroglitazar Magnesium 
showed improvements in the lipoproteins and triglycerides (TG) levels as well as measures of 
insulin sensitivity. 
Non-alcoholic fatty liver disease is a spectrum of clinical–pathological conditions that can 
manifest as simple steatosis, characterized by accumulation of lipids in the liver parenchyma, or 
NASH, characterized by hepatocyte injury, inflammation, and fibrosis. The worldwide 
prevalence of NAFLD has been estimated to range from 2.8% to 46% depending on the 
diagnostic method used. The disease is strongly associated with obesity, diabetes mellitus, IR, 
and MS.14, 15 
Another element strongly associated with IR and MS is PCOS, which is a common endocrine 
abnormality in women of reproductive age, and is characterised by chronic anovulation and 
hyperandrogenism. Insulin resistance is one of the core pathophysiologies of this syndrome, and 
although the prevalence varies across populations with different backgrounds, obesity is also 
prevalent (20–70%) in women with PCOS.16 
The prevalence of NAFLD within the PCOS population is now estimated to be anywhere 
between 15% and 55%, depending on the diagnostic index used for both NAFLD and PCOS. 
The pathogenesis of NAFLD is multifactorial, but obesity, MS and IR appear to be pivotal 
contributing factors. Given that central obesity, MS and IR are shared features in both PCOS and 
subjects with NAFLD, there is an increasing evidence of higher NAFLD prevalence in women 

 
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with PCOS. Since insulin resistance, obesity and MS are common features of both NAFLD and 
PCOS, We hypothesize that PCOS and NAFLD may coexist. The present study is a phase 2 A, 
proof-of-concept study, the purpose of the present study is to evaluate the concept of efficacy of 
Saroglitazar Magnesium 4 mg Tablets once-daily in women with well characterized PCOS 
diagnosed with NAFLD. Data on safety and tolerability of Saroglitazar Magnesium 4 mg Tablets 
in PCOS patients diagnosed with NAFLD will also be collected. 
2.3 
DRUG PROFILE 
Saroglitazar, [benzenepropanoic acid, α-ethoxy-4-[2-[2-methyl-5-[4-(methylthio) phenyl]-1H- 
pyrrol-1-yl]ethoxy]-, magnesium salt (2:1), (αS)], is a novel PPAR agonist with dual PPAR 
agonistic properties – it is a potent and predominant PPARα agonist with moderate PPARγ 
agonistic activity. 
Peroxisome proliferator-activated receptors are nuclear lipid-activated transcription factors that 
regulate the expression of various genes involved in the control of lipid and lipoprotein 
metabolism, glucose homeostasis and inflammatory processes. The pharmacological effects of 
Saroglitazar Magnesium were extensively evaluated in various preclinical models. Saroglitazar 
Magnesium showed both antidyslipidemic and antidiabetic effects, mainly mediated via 
activation of PPARα and PPARγ, respectively. 
Pre-clinical Experience 
Saroglitazar Magnesium is a novel predominately PPAR agonist and moderate PPARγ agonist. 
Pre-clinical studies with Saroglitazar Magnesium using various animal models wherein, EC50 of 
PPARα: PPARγ>300; favorably modulated the lipid and glucose profile. Extensive preclinical 
safety pharmacology, pharmacokinetics and toxicological studies of Saroglitazar Magnesium 
showed favorable results. It was found to have superior or equivalent safety and efficacy profile 
compared to marketed fibrates or thiazolidinediones (TZDs) in pre-clinical studies. 
PPARα activation by Saroglitazar Magnesium increases the hepatic oxidation of fatty acids (FA) 
and reduces the synthesis and secretion of TG. This, in turn, increases diversion of FA from 
peripheral tissues (e.g., skeletal muscle and fat tissue) to the liver, thereby decreasing both FA 
synthesis and delivery of TG to peripheral tissues. In addition, Saroglitazar Magnesium causes 
increased lipolysis and elimination of TG-rich particles from plasma by activating lipoprotein 
lipase (LPL) and reducing production of apolipoprotein C-III (an inhibitor of LPL activity). 
Consistent with the above mechanism, Saroglitazar Magnesium was also found to reduce plasma 
LDL cholesterol. PPARα activation by Saroglitazar Magnesium also induces an increase in the 
synthesis of apolipoproteins, A-I, A-II and HDL cholesterol. 
Although Saroglitazar Magnesium is predominantly a PPARα agonist, it also causes activation of 
PPARγ and regulates the transcription of insulin-responsive genes involved in the control of 
glucose production, transport and utilization. Saroglitazar Magnesium increases the expression of 
numerous PPARγ-responsive genes involved in carbohydrate and lipid metabolism, including 

 
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adiponectin, adipocyte fatty-acid-binding protein (aP2), LPL, fatty acid transport protein and 
fatty acid translocase. By increasing the expression of these genes, Saroglitazar Magnesium 
decreases the post-prandial rise of plasma free fatty acids, improves postabsorptive insulin-
mediated suppression of hepatic glucose output, reduces the metabolic burden on liver and 
muscle and promotes glucose utilization. Robust antidiabetic and insulin sensitizing effects of 
Saroglitazar Magnesium were observed in preclinical models, in which hyperglycemia and/or 
impaired glucose tolerance is a consequence of insulin resistance in target tissues. 
Furthermore, two pre-clinical studies were conducted in letrozole induced PCOS animal models. 
In first study, female Wistar rats of 11-12 weeks were used. Wistar rats develop obesity, 
hyperglycemia, hyperinsulinemia and PCOS when manipulated using drugs, surgery or by 
environmental changes. Therefore, this model proves to be suitable for predicting the likely 
therapeutic benefit of novel treatment for PCOS in humans.  
Following observation was recorded after treatment with Saroglitazar in letrozole-induced PCOS 
in female Wistar rats: 
1. After 28 days repeated dose of Saroglitazar (4 mg/kg, PO) significantly reduced number of 
cystic follicles in Letrozole-treated female rats when compared with vehicle control. 
In second study, female Zucker fa/fa rats of 13-15 weeks were used. Zucker fa/fa rats are 
genetically obese, hyperinsulinemic and hyperlipidemic. PCOS can be developed when 
manipulated surgically or by environmental modifications. Therefore, this model proves to be 
suitable for predicting the likely therapeutic benefit of novel treatment for PCOS in humans. 
Following observations were recorded after repeated dose treatment with Saroglitazar in 
letrozole-induced PCOS in Zucker fa/fa rats. 
1. Saroglitazar significantly improved insulin tolerance. 
2. Saroglitazar significantly increased serum FSH levels, with little change in LH levels and 
reduced LH/FSH ratio. 
3. Saroglitazar significantly decreased serum testosterone levels. 
4. Saroglitazar significantly normalized ovary weight. 
In conclusion, repeated dose oral treatment with Saroglitazar at 4 mg/kg resulted in 
significantly improved insulin sensitivity, increased serum FSH, decreased LH/FSH ratio, 
decreased serum testosterone and normalized ovary weight. 
 
 

 
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Clinical Experience 
Maximum Tolerated Dose in Phase 1 was 16 mg/day for 10 days and it was found to be well 
tolerated. In Phase 1 trials in healthy human volunteers, Saroglitazar Magnesium was found to be 
well tolerated in single 12 and multiple dose studies without any safety concern. Several Phase 2 
studies were conducted to evaluate the safety and efficacy of Saroglitazar Magnesium in 
dyslipidemic subjects without diabetes, diabetes and subjects with impaired glucose tolerance 
test. 
In dyslipidemic subjects with diabetes mellitus, Saroglitazar Magnesium showed favorable 
results in all the expected endpoints (fasting plasma glucose: (FPG) and lipid profile). 
Saroglitazar Magnesium, especially 2 mg Saroglitazar Magnesium and 4 mg Saroglitazar 
Magnesium seemed to be comparable to Pioglitazone and Rosiglitazone and showed clinically 
relevant reduction in the triglyceride-cholesterol (TG-C), total cholesterol and FPG levels. 
A Phase 3 study of 24-week duration to evaluate the efficacy and safety of Saroglitazar 
Magnesium in diabetic dyslipidemic patients as compared to Pioglitazone revealed that there is 
statistically significant reduction in the TG-C levels at all visits as compared to baseline in 
Saroglitazar Magnesium 2 mg and 4 mg groups. There was statistically significant reduction 
(45%) in the TG-C levels in Saroglitazar Magnesium 4 mg Tablets as compared to Pioglitazone 
45 mg (15.5%). Similarly there was statistically significant reduction (45.5%) in the very-low-
density lipoprotein (VLDL) cholesterol and total cholesterol levels (7.7%) as compared to 
Pioglitazone.10 
A Phase 3 study of 12-week duration to evaluate the efficacy and safety of Saroglitazar 
Magnesium in diabetic dyslipidemic patients not controlled with atorvastatin 10 mg revealed 
statistically significant reduction (>45%) in the TG-C levels as compared to placebo. Statistically 
significant reduction in the LDL cholesterol (>27.5%), total cholesterol (>22%) and apo B 
(>27%) levels with Saroglitazar Magnesium 4 mg Tablets was observed as compared to baseline. 
Thus far, Saroglitazar Magnesium clinical studies have shown efficacy in patients with mild to 
moderate dyslipidemia and showed favorable effects.11 
Saroglitazar Magnesium has been the first glitazar granted marketing authorization in India and 
is indicated for treatment of diabetic dyslipidemia. The drug was developed with an expectation 
to achieve optimum antidyslipidemic and antihyperglycemic effects, while avoiding adverse 
events (AEs) such as peripheral edema, weight gain, cardiovascular events, renal and/or liver 
toxicity, etc., which are commonly seen with other dual PPAR or PPARα agonists. 
2.4 
RISK AND BENEFIT 
The safety and tolerability of Saroglitazar Magnesium is well defined on the basis of pre-clinical 
and clinical studies (Phase 1 to Phase 3). 
 
Saroglitazar Magnesium is approved in India at the doses of 
2 mg and 4 mg QD for treatment of “diabetic dyslipidemia” and “hypertriglyceridemia with type 
2 diabetes mellitus (T2DM) not controlled by statin therapy”. In addition, since insulin 
resistance, obesity and MS are common features of both NAFLD and PCOS, it is very likely that 

 
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NAFLD and PCOS coexist in a given set of patients. There are a number of important 
knowledge gaps in the field of PCOS and NAFLD. These can be broadly categorized into (a) 
prevalence and clinical risk factors for NAFLD in women with well characterized PCOS; (b) 
spectrum of liver disease severity, characterized non-invasively and when possible invasively; 
(c) mechanistic basis for prevalence and severity of NAFLD; and (d) novel treatments. However, 
very limited clinical data are available in patients of PCOS with NAFLD. This proof-of-concept 
phase 2A study will evaluate the concept of efficacy of Saroglitazar Magnesium 4 mg Tablets 
once-daily in women with well characterized PCOS diagnosed with NAFLD. If efficacy and 
safety are shown, that will provide a strong basis for long term evaluation of decreasing the 
disease burden for patients with PCOS and NAFLD. 

 
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3 STUDY OBJECTIVES 
Objective:  
 
The purpose of this study is to evaluate the efficacy and safety of Saroglitazar Magnesium 4 mg 
Tablets once-daily in women with well characterized PCOS diagnosed with NAFLD. 
3.1 
PRIMARY OBJECTIVE 
To evaluate the effect on hepatic fat content, measured as proton-density fat-fraction (PDFF) by 
magnetic resonance imaging (MRI), of once-daily Saroglitazar Magnesium 4 mg Tablets for 24 
weeks vs placebo. 
3.2 
SECONDARY OBJECTIVES 
 To assess the effect of a 24-week treatment regimen of once-daily Saroglitazar 
Magnesium 4 mg Tablets on the following parameters in patients of PCOS with NAFLD: 
 
1. Liver enzymes/LFTs. 
2. Insulin resistance measured by Homeostasis Model Assessment (HOMA). 
3. Liver stiffness measurement obtained via transient elastography/FibroScan®. 
4. Controlled attenuation parameter obtained via transient elastography/FibroScan®.  
5. Body weight, BMI and waist circumference. 
6. MRI-derived total liver fat index and total liver volume. 
7. Serum lipid profile and lipoproteins. 
8. Sex hormone binding globulin. 
9. Ovarian function. 
10. Free androgen index. 
11. Pharmacokinetics of Saroglitazar following first dose and last dose. 
3.3 
SAFETY ASSESSMENT 
Criteria for Safety: 
1. Vitals: blood pressure (BP) (sitting BP after 05 min rest; systolic and diastolic BP), pulse 
rate, oral temperature and respiratory rate (at Visit 1[Screening] and at Visit 3 through Visit 
8 [End-of-Treatment]). 
2. Body mass index at Screening Visit (Visit 1), at 12 weeks (Visit 6) and at the Week 24 
End-of-Treatment visit (Visit 8). 
3. Waist measurements at Screening Visit, at Visit 6 and at the End-of-Treatment visit. 
4. The physical examination will consist of an evaluation of the head, neck, eyes, ears, nose, 
throat, pelvic, breast, chest, heart, lungs, abdomen, skin, extremities, neurological systems, 

 
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musculoskeletal systems and weight measurement. Investigator should also evaluate the 
patients for hirsutism and virilizing signs (upper lip, chin, chest, upper abdomen, lower 
abdomen, thighs, back, arm and buttocks). Note: Breast examination will be done as part of 
screening. Pelvic examination will be performed as part of screening, if not performed 
within 6 months of randomization. 
5. Laboratory assessment: 
a. Hematology: Hematocrit, hemoglobin, mean corpuscular hemoglobin concentration 
(MCHC), mean corpuscular volume (MCV), platelet count, mean platelet volume, 
red blood cell (RBC) count, white blood cell (WBC) count, differential WBC count. 
b. Liver enzymes/LFTs: aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase (ALP), total bilirubin (with conjugated bilirubin), 
gamma glutamyltransferase (GGT), serum protein and albumin. 
c. Renal function tests (RFTs): blood urea nitrogen (BUN), creatinine and estimated 
glomerular filtration rate (eGFR). Estimated glomerular filtration rate will be 
calculated by using Chronic Kidney Disease Epidemiology Collaboration (CKD-
EPI) equation. 
d. Inflammatory marker: high sensitivity C-reactive protein (hs-CRP). 
e. Lipid profile and lipoproteins: triglyceride (TG), total cholesterol (TC), high-density 
lipoprotein (HDL), low-density lipoprotein (LDL), small dense low-density 
lipoprotein (sdLDL), very low density lipoprotein (VLDL), free fatty 
acids, apolipoprotein A and apolipoprotein B. 
f. Urine examination: physical examination (appearance, color, specific gravity and 
pH); microscopy (epithelial cells, red blood cells, pus cells, cast and crystals) and 
chemical examination (protein, glucose, bilirubin, urobilinogen, ketone bodies and 
nitrite). 
g. T3, T4 and thyroid stimulating hormone (TSH) 
h. Serum pregnancy test 
i. Urine pregnancy test 
j. Serology: HIV type 1 and type 2, hepatitis A virus (HAV), anti-hepatitis B virus 
surface antigen (HBsAg) and hepatitis C virus (HCV) (at Visit 1). 
k. International normalized ratio (INR) and prothrombin time (PT) 
l. Cytokeratin 18 

 
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m. Free androgen index and SHBG level 
n. Total testosterone and free testosterone 
o. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels 
p. 17-hydroxyprogesterone 
q. Estradiol 
r. Creatine Kinase (CK) 
s. Cardiac function: 12-lead-electrocardiogram (ECG) 
t. Glycemic control: FPG, HbA1c and plasma insulin levels. 
u. B-type natriuretic peptide (BNP) and aminoterminal fragment of BNP prohormone 
(NT-proBNP) 
v. Papanicolaou (PAP) test 
w. Cardiac troponin, creatine kinase-muscle/brain (CK-MB) 
x. Lipase and amylase 
y. Uric acid 
6. Adverse event(s): Frequency and severity of AE /serious adverse events (SAEs), drop-outs 
due to AEs/SAEs for all subjects enrolled will be recorded. All AEs, will be assessed using 
Council for International Organizations of Medical Sciences (CIOMS) criteria using:  
a. Causality  
b. Severity 
c. Seriousness 
d. Expectedness 
 
Note: Efficacy assessments and laboratory assessment (liver fat content by MRI-PDFF [MRI-
PDFF will be performed during screening phase, screening phase results will be used as the 
baseline assessment], controlled attenuation parameter, hormonal profile, fasting plasma glucose, 
lipid and lipoprotein profiles, MRI-derived total liver fat index and total liver volume [MRI-
derived total liver fat index and total liver volume assessment will be performed during screening 
phase, screening phase results will be used as the baseline assessment], plasma insulin levels, 
homeostasis model assessment (insulin resistance [HOMA-IR]), liver stiffness by transient 
elastography/FibroScan®, ovarian function, liver enzymes/LFTs, hematology, coagulation test 
(PT/INR), renal function test, CK, hs-CRP, BNP , NT-proBNP, cardiac troponin, CK-MB, lipase 
and amylase, TNFα, uric acid, TSH, T3 and T4, serology, HIV type 1 and type 2, HAV,  anti-

 
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HBsAg, HCV, serum pregnancy test, urine microscopy and urine chemistry) which will be done 
at Visit 1 will be considered for baseline visit. PAP test, endometrial biopsy and mammography 
will be performed as per Time and Events Schedule. 

 
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4  STUDY POPULATION 
Patients of PCOS with NAFLD will be recruited for this study. 
4.1 
NUMBER OF SUBJECTS PLANNED 
A total 90 subjects (including 20% dropouts), will be enrolled across USA and Mexico in a ratio 
of 1:1 to have 45 subjects in each treatment arm i.e., Saroglitazar Magnesium 4 mg Tablets and 
placebo. Additional patients will be enrolled if the dropout rate is more than 20%. 
 
Six patients in each group are planned for pharmacokinetic assessment therefore a total of 12 
patients will be included. Additional patients may be enrolled into the study to ensure that the 
pharmacokinetic assessment is performed on at least 6 completed patients in each treatment arm. 
4.2 
INCLUSION CRITERIA 
1. Females, 18 to 45 years of age. 
2. Previously confirmed diagnosis of PCOS by Rotterdam criteria17 (at least 2 of 3): 
1) oligo-and/or anovulation; 
2) hyperandrogenism (clinical and/or biochemical); 
3) polycystic ovary morphology on ultrasonography (either 12 or more follicles 
measuring 2–9 mm in diameter or an increased ovarian volume >10 cm3). 
3. Evidence of NAFLD within 6 months prior to the Screening Visit (Visit 1). The 
diagnosis of NAFLD is made according to the American Association for the Study of 
Liver Diseases criteria.18 
 
a) hepatic steatosis by imaging or histology,  
b) no significant alcohol consumption,  
c) no competing etiologies for hepatic steatosis, and  
d) no co-existing causes for chronic liver disease. 
4. Alanine transaminase ≥ 38 U/L at Visit 1. Visit 2 ALT must not increase >30% from 
Visit 1.  
5. Hepatic fat fraction ≥10% by MRI-PDFF. 
6. Willingness to participate in the study. 
7. Ability to understand and give informed consent for participation. 
8. A normal pelvic examination within past 6 months before randomization. 
9. A normal breast examination at screening (If Mammogram has been done in the 
preceding 12 months it will be documented. If patient is not up to date with standard 
breast cancer screening guidelines and is willing to receive screening, mammogram 

 
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will be offered prior to enrollment as part of standard care). 
10. A normal Papanicolaou (PAP) test within past 6 months before randomization (If PAP 
test has not been performed within 6 months of the screening visit, it must be 
performed during screening). 
11. Woman who agrees to use the following contraceptive methods: 
a. Combination hormonal contraceptives (including pills, patches and vaginal rings). 
For the following conditions, the usage of the combination hormonal 
contraceptives should be based upon a discussion with the subject and the 
investigators’ clinical judgment. 
i. 
Women greater than 35 years of age who also smoke fewer than 15 cigarettes 
per day 
ii. 
Adequately controlled hypertension 
iii. 
Properly taken blood pressure above a systolic 140-159 mm Hg or diastolic 90- 
99 mm Hg 
iv. 
Known hyperlipidemia 
v. 
Diabetes associated with vascular disease, including neuropathy, retinopathy 
and nephropathy. 
vi. 
Diabetes duration greater than 20 years. 
b. Women with the following conditions should use effective methods other than 
combined hormonal contraceptives (e.g., Progestogen-only oral contraceptives or 
progestogen-containing intrauterine devices (IUD), Non-hormonal IUD, Double-
barrier contraception [e.g., condom plus diaphragm]): 
i. 
Women greater than 35 years of age who also smoke 15 or more cigarettes per day 
ii. 
Properly taken blood pressure above systolic ≥ 160 mm Hg or diastolic ≥ 100 mm 
Hg 
iii. 
Known hyperlipidemia 
iv. 
Vascular disease, including neuropathy, retinopathy and nephropathy 
v. 
Diabetes duration greater than 20 years. 
4.3 
EXCLUSION CRITERIA 
1. Presence of other chronic liver diseases (hepatitis B or C, autoimmune hepatitis, 
cholestatic liver disease, Wilsons disease, hemochromatosis, etc.).  
2. Average alcohol consumption ≥ 7 drinks per week for women in the 6 months prior to 
enrollment. Subjects will be required to have an “Alcohol Use Disorder Identification 
Test” (AUDIT) score of <8. 
3. Clinical, imaging, or histological evidence of cirrhosis. 
4. Any of the following laboratory values:  
a. Hemoglobin <10 g/dL  
b. White blood cell count <4 x 109/L 
c. Neutrophil count <1.5 × 103/µL  
d. Abnormal baseline platelet counts (<150 x 103 uL). 

 
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e. Total Serum bilirubin greater than the ULN (>1.3 mg/dL) (except in patient with 
known Gilbert Syndrome where TB up to 2.5 mg/dL is allowed) 
f. Albumin <3.2 g/dL  
g. Serum ALT or AST >250 IU/L  
h. Lipase or amylase more than the ULN at baseline. 
i. Serum creatinine ≥1.5 mg/dL 
j. Renal impairment as demonstrated by baseline estimated glomerular filtration rate 
(eGFR) < 60 mL/min/1.73 m2 (calculated using the CKD-EPI equation). 
k. Total creatine kinase level more than the ULN at baseline. 
5. Patient with INR >1.3 
6. Patients who have used medications known to cause hepatic steatosis (e.g., 
corticosteroids, amiodarone, methotrexate, tetracycline, tamoxifen, anabolic steroids, or 
valproic acid) for more than 2 weeks in the past year. 
7. Prior bariatric surgery.  
8. Weight loss of more than 5% in the 3 months preceding screening. 
9. Severe co-morbidities (e.g., advanced cardiac, renal, pulmonary, or psychiatric illness). 
10. Known allergy, sensitivity or intolerance to Saroglitazar Magnesium, comparator or 
formulation ingredients (Saroglitazar Magnesium Micronized, Magnesium Oxide Light, 
Microcrystalline Cellulose, Anhydrous Lactose, Croscarmellose Sodium, Povidone k 
30, Talc (luzena c), Colloidal Silicon Dioxide and Magnesium Stearate). 
11. Use of antidiabetic and lipid lowering medications if the dose is not stable for at least 
the 3 months preceding screening. 
12. Intake of Vitamin E (>100 IU/day) or multivitamins containing Vitamin E (>100 
IU/day) 3 months before enrollment. 
13. Use of drugs with potential effect on NAFLD/NASH such as S-adenosylmethionine 
(SAM-e), Betaine, Pentoxifylline, Thiazolidinediones (Pioglitazone, Rosiglitazone), 
Obeticholic Acid or Milk Thistle in the 3 months prior to screening. 
14. Changing doses of statins (Simvastatin, Pravastatin, Atorvastatin, Fluvastatin, 
Lovastatin, Rosuvastatin) or Fibrates (Clofibrate, Fenofibrate) in the 3 months prior to 
enrollment.  
15. Illicit substance abuse within the past 12 months.  
16. Pregnant or breast-feeding females. 
17. Poorly controlled diabetes with HBA1c >8.5% 
18. Use of total parenteral nutrition in the 6 months preceding enrollment. 
19. Women with known Cushing syndrome or hyperprolactinemia. 
20. Late onset congenital adrenal hyperplasia, androgen-producing tumors. 
21. Refusal or inability to comply with the requirements of the protocol, for any reason, 
including scheduled clinic visits and laboratory tests. 
22. History of myopathies or evidence of active muscle diseases. 
23. History or current significant cardiovascular disease, including: 
i. 
Unstable angina (i.e., new or worsening symptoms of coronary heart disease within 
the past 3 months before screening), acute coronary syndrome within the past 6 
months before screening, acute myocardial infarction in the past 3 months or heart 

 
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failure of New York Heart Association class (III-IV) or worsening congestive heart 
failure, or coronary artery intervention, within the past 6 months before screening. 
ii. 
History or current unstable cardiac dysrhythmias within prior 3 months before 
screening. 
iii. 
Uncontrolled hypertension (systolic blood pressure > 160 mmHg and/or diastolic 
blood pressure > 100 mmHg). 
iv. 
Stroke or transient ischemic attack prior 6 months before screening visit. 
24. History of malignancy in the past 5 years and/or active neoplasm with the exception of 
resolved superficial nonmelanoma skin cancer.  
25. History of bladder disease other than urinary tract infection or cystitis. Previous or 
current hematuria due to etiologies other than urinary tract infection or kidney stones. 
4.3.1 Screen Failures 
Patients who fail the screening criteria will not be rescreened unless approved by the Sponsor or 
its designee. Screening laboratory tests may be repeated following the approval of Sponsor or its 
designee if the laboratory test results seem implausible or inaccurate. 
A screen failure occurs when a patient who has signed the informed consent form (ICF) does not 
meet all the entry criteria outlined in this protocol and has not been randomized or received study 
drug. No study procedures (including end-of-treatment procedures) will be performed for these 
patients. For patients who fail to meet the inclusion criteria or who meet 1 or more of the 
exclusion criteria, the Principal Investigator (PI) (or designee) will document on a screening log 
the reason for the screening failure. 
4.4 
PATIENT WITHDRAWAL 
Patients may withdraw from the entire study at any time without penalty and for any reason 
without prejudice to her future medical care. Although a patient is not obliged to give her reason 
for withdrawing prematurely, the PI will make a reasonable effort to obtain the reason while 
fully respecting the patient’s rights. If there is a medical reason for withdrawal, the patient will 
remain under the supervision of the PI for follow-up of AE(s) as detailed in Section 9.4.1.6. 
Every effort will be made to continue clinical and/or laboratory follow-up, as appropriate, in 
patients who wish to withdraw from the study drug (Investigational product or placebo) and 
reasonable efforts will be made to contact a patient who fails to attend any follow-up 
appointments, in order to ensure that she is in satisfactory health. A patient’s withdrawal of 
consent and agreement to undergo a final examination will be documented on the electronic case 
report form (e-CRF).  
As far as possible, all assessments scheduled for end-of-treatment must be performed on all 
patients who receive the study drug but do not complete the study according to protocol. In 
addition, if patient withdraws from the study, any data collected during the period of time will 
maintained as part of the study data. 

 
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4.4.1 Discontinuation of Patients from the Study or Study Drug 
A patient may be discontinued from the study for any of the following reasons:  
 Noncompliance to the protocol requirements. 
 Occurrence of a serious or intolerable AE and based upon the Investigators’ clinical 
judgment. 
 The Sponsor or PI terminates the study (Section 4.6). 
 Either the PI or the Sponsor decides that discontinuing the study or discontinuing the 
patient is in the patient’s best interest. 
 For reasons related to safety as specified in Section 4.5. 
 The patient is lost to follow-up. 
 A patient may also be discontinued from study drug/study by the Sponsor, Regulatory 
Authorities or Institutional Review Board (IRB) or Independent Ethics Committee (IEC). 
 If the patient becomes pregnant. 
A study completion eCRF, which includes the reason for discontinuation, must be completed for 
all patients who are discontinued from the study. If the patient is discontinued prematurely, the 
study completion eCRF should clearly indicate the reason for discontinuation. If the patient 
discontinues due to an AE, an AE eCRF must be completed. The AE must be followed by 
medical attention to satisfactory resolution and all study data related to the patient will be 
reported. 
Every effort will be made to continue clinical and laboratory follow-up, as appropriate, in 
patients who are withdrawn or in whom the study drug is stopped by the PI or per individual 
stopping rules (Section 4.5). 
4.4.2 Patients Lost to Follow-up 
Every attempt must be made to have all patients complete the visit schedule. A patient will not 
be considered lost-to-follow-up unless all efforts to obtain compliance are unsuccessful. Study 
sites should attempt to contact these patients in order to maintain study visit compliance and all 
contact attempts should be documented in the patient’s medical records. At a minimum, the site 
should make 2 attempts (at least 3 to 5 days apart and during both business and nonbusiness 
hours) to contact the patient; once by phone and once by certified mail. 
4.5 
STOPPING CRITERIA FOR INDIVIDUAL PATIENTS 
The following clinical events warrant discontinuation of study drug; however, the patient will 
continue to be followed for safety, hormonal profile, liver function tests and lipid levels until the 
event has resolved, i.e., clinical laboratory value(s) has/have returned to baseline or is/are no 
longer of clinical significance. Discontinuation of study drug will only occur if mandated by 
safety events as defined below:  

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

 
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 Total CK > 5X ULN 
 Amylase or lipase > ULN 
 eGFR < 60 ml/min/1.73 m2 and where the value is reconfirmed after 24 
hours. Additionally, any subject who requires renal replacement therapy 
should also be discontinued from drug. 
 Complete Blood Counts: Hemoglobin < 10 g/dL or HCT < 30%; platelets < 
100,000/microL; WBC < 4 x 109/L. 
4.6 
TERMINATION OF THE CLINICAL STUDY 
If the Investigator, the Sponsor or the Medical Monitor becomes aware of conditions or events 
that suggest a possible hazard to patients 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 Sponsor’s discretion in the absence of such a finding. Conditions 
that may warrant termination of the clinical study include, but are not limited to: 
 The discovery of an unexpected, relevant or unacceptable risk to the patients enrolled in the 
clinical study;  
 Three patients develop the same AE of CTCAE grade 3, considered to be at least probably 
related to study drug; 
 Two patients develop any AE of CTCAE grade 4, considered to be at least probably related 
to study drug; 
 One patient develops an AE of CTCAE grade 5, considered to be at least probably related to 
study drug; 
 Failure to enroll patients at the required rate;  
 A decision of the Sponsor to suspend or discontinue development of the study drug. 
Should the study be terminated and/or the site closed for whatever reason, a copy of all 
documentation pertaining to the study and study drugs must be returned to the Sponsor. All the 
site specific documents will be archived at study site. 

 
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5 STUDY TREATMENTS / INVESTIGATIONAL PRODUCT 
MANAGEMENT 
Saroglitazar Magnesium 4 mg Tablets or placebo will be administered in patients of PCOS with 
NAFLD once daily in the morning before breakfast without food, for a period of 24 weeks. 
5.1 
TREATMENTS TO BE COMPARED 
5.1.1 Investigational Product Description 
The products that will be used in this study are outlined in Table 2. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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0* 
*Round-up quantity 
5.1.2 Comparator Drug Description 
Placebo will be used as comparator, which will be formulated as tablets, and will contain above 
mentioned excipients without Saroglitazar Magnesium Micronized (Refer section 5.1.1 for 
excipients details). The IP will be manufactured following current-Good Manufacturing Practice 
(cGMP) guideline. 
5.2 
DOSAGE AND TREATMENT SCHEDULE 
Patients will receive either 4 mg Saroglitazar Magnesium or placebo orally once each morning 
before breakfast without food, for 24 weeks during the double-blinded treatment period. 
However, on scheduled visits patients will have the IP administered on site after the blood 
sample collection. The drug dose during the treatment phase, this will be checked and verified 
with study medication compliance by using drug accountability form. 

 
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5.3 
PACKAGING, LABELLING AND SUPPLY 
Study drug will be packaged by the Sponsor according to all local legal requirements. 
 
 
 
 
 
 
An adequate quantity of study drug will be shipped to each site. The PI will maintain an accurate 
record of the receipt of the study drug, including the date received. Until dispensed to the 
patients, the study drug will be stored at room temperature (20°C to 25°C or 68°F to 77°F) in a 
dry place at the study site or pharmacy that can be securely locked and that is accessible to 
authorized personnel only. 
5.4 
STORAGE CONDITIONS AND STABILITY 
Investigational product will be stored at room temperature (20°C to 25°C or 68°F to 77°F) and in 
dry place, protected from light. If the IP temperature extends outside the 20-25°C range, a 
temperature excursion must be documented in IP specific temperature log. If the excursion is 
within 15-30°C, quarantine is not required, and the IP is acceptable for use. If the excursion is 
outside of the 15-30°C range, the IP must be quarantined until a decision on the stability of the 
IP is made by the Sponsor. If the excursion goes beyond the range of 15-30o C it will be 
considered as a protocol deviation. Storage condition will be maintained during shipment. All IP 
supplies in the study will be stored in a secure location with access limited to the Site Pharmacist 
or the Investigator designated site staff. 
Refer to the pharmacy manual/site investigational product manual for additional guidance on 
study drug preparation, handling and storage. 
5.5 
BLINDING 
The study will be performed in a double-blind manner. All study drug will be supplied in 
identical packages and study drug kits. The study drug tablets will be similar in color, smell, 
taste and appearance, thereby maintaining double-blind conditions. 
The study blind should not be broken except in a medical emergency where knowledge of the 
study drug received would affect the treatment of the emergency. 
The blind must only be broken following a discussion on a case-by-case basis, at the discretion 
of the Sponsor/Medical Expert. If an emergency unblinding becomes necessary, the PI should 
notify the Sponsor/Medical Expert, if possible, before unblinding. If it is determined that 
unblinding is necessary, a scratchcard will be decoded to reveal the treatment received by the 
patient. All cases resulting in an unblinding event will be documented and reported to the 

 
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Medical Expert and the Sponsor. If the blind is broken, the date, time and reason must be 
recorded in the patient’s eCRF/source document and any associated AE report completed. 
The overall randomization code will be broken only for reporting purposes. This will occur once 
all final clinical data have been entered into the database, all data queries have been resolved, 
and the assignment of patients to the analysis sets has been completed. 
5.6 
METHOD OF ASSIGNING PATIENTS TO THE TREATMENT GROUPS 
Patients will be randomly assigned in a 1:1 ratio to Saroglitazar Magnesium 4 mg Tablets and 
placebo. The block randomization schedule will be generated using SAS® software (Version: 9.4 
or higher; SAS Institute Inc., USA). 
5.7 
SELECTION OF DOSES 
Saroglitazar Magnesium is known to safely and effectively improve dyslipidemia by reducing 
TG, LDL cholesterol, very low-density lipoprotein (VLDL) cholesterol, non-high-density 
lipoprotein (non-HDL) cholesterol and increasing HDL cholesterol. In addition, Saroglitazar 
Magnesium can improve glycemic indices in diabetic patients by reducing fasting serum glucose 
and glycated hemoglobin. Considering the association between insulin resistance, dyslipidemia 
and the development of NASH, Saroglitazar Magnesium could potentially benefit patients with 
NAFLD including those with NASH and PCOS. 
 
Saroglitazar Magnesium 4 mg Tablets have favorably modified the lipid profile in dyslipidemic 
and hypertriglyceridemic patients during previously conducted Phase 2 and 3 studies.10, 13 Based 
on these results, Saroglitazar Magnesium 4 mg dose has been selected for this study. 
5.8 
CONCOMITANT THERAPY 
All medications received by the subject at any time prior to the Screening Visit and taken within 
3 months before the Screening Visit, during the interval between the Screening Period and 
Randomization and those taken throughout the trial will be recorded on the appropriate section of 
the eCRF. The site may rely on subject reports for this information. All subjects must be 
questioned about concomitant medication at each visit. All concomitant medication, both 
prescribed and over-the-counter, must be recorded in the eCRF. This includes drugs used on a 
chronic and as needed basis. Medications that are indicated as prohibited in the Exclusion 
Criteria must not be used after the Screening Visit during the interval between the screening 
period and randomization or during the trial. 
The following treatment/drugs will be allowed during the study. 
 Treatment for common illness during the study may be allowed. 

 
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 Stable antidiabetic and lipid lowering medications at least for the 3 months preceding 
screening. 
 Stable doses of metformin or any treatment of PCOS at least for the 3 months preceding 
screening. 
 For any required concomitant medication, the patient must be on a stable dose for 3 
months at study entry and patients must continue with their current drug regimen without 
any change in dosage. 
5.8.1 Subjects on Concomitant Anti-diabetic Medication 
Subjects on anti-diabetic medication shall also be assessed at scheduled visits for 
hyperglycemia/hypoglycemia; rescue medication will also be permitted, if required. Patients on 
concomitant anti-diabetic medication will be provided with a glucometer and instructions for 
use. All point of care (POC) glucose measurements by the patient during the study period should 
be performed on the study provided glucometer. The investigational site will download/record 
the data from glucometer for assessment of glucose levels since the prior visit. 
The patients should monitor their glucose levels as follows: 
 Fasting blood glucose should be measured on at least two days in a week. These 
measurements should be done in the morning before having breakfast and when the 
subject has been fasting for a minimum of 10 hours. 
 Spontaneous measurements of the blood glucose should be done in the event the patient 
suffers from suspected hypoglycemia. The investigator should inform the patients on 
recognizing the symptoms of hypoglycemia (i.e. palpitations, tremor, diaphoresis, hunger 
and/or cognitive impairment) and instruct them on the actions to be taken in accordance 
with standard-of-care. 
The American Diabetes Association (ADA) recommends the following treatment for non-severe 
hypoglycemia during which a patient is safety willing and able to consume oral treatment.  
1. Consume 15-20 grams of glucose or simple carbohydrates 
2. Recheck your blood glucose after 15 minutes 
3. If hypoglycemia continues, repeat #1 & #2 
4. Once your blood glucose returns to a normal level, consume a small snack if your next 
planned snack or meal is greater than 1 hour in the future 
 

 
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Examples provided by the ADA of items containing 15 grams of simple carbohydrates include: 
 Glucose tablets (follow instructions on the package) 
 Gel tube (follow instructions on the package) 
 2 tablespoons of raisins 
 4 ounces (1/2 cup) of juice or regular (non-diet) soda 
 1 tablespoon of sugar, honey or corn syrup 
 8 ounces of nonfat or 1% milk 
 Hard candy, gumdrops or jellybeans (read package for amount to consume) 
In the event of severe hypoglycemia when a patient is unconscious and possibly seizing, and/or 
unable to safely ingest carbohydrates, do not attempt oral treatment. If glucagon is available, this 
should be administered as soon as possible. If glucagon is not available, it is not able to be 
administered or persons witnessing the event do not feel able to handle the situation, emergency 
medical personnel should be summoned via calling 911. 
Investigators shall advise subjects to report any/all hypoglycemic episodes occurring during the 
course of the trial as they will be recorded in the eCRF. 
Treatment for such conditions should be initiated as soon as the need for treatment is identified 
by the investigator, in accordance with treatment guidelines and standard of care, and should be 
adjusted as necessary to treat the subject’s condition(s). All treatment with these drugs must be 
recorded in the eCRF. 
5.8.2 Previous and Concomitant Medications 
Any medication the patient takes other than the study drug, including herbal and other 
nontraditional remedies, is considered a concomitant medication. All concomitant medications 
and any changes in the dosage or regimen of a concomitant medication for the 3 months 
preceding visit 1 until the end of the study (i.e., the safety telephone call) must be recorded in the 
eCRF. 
5.8.3 Excluded Concomitant Medications 
Patients are not permitted to take the following medications: 
 Zileuton, parenteral nutrition and Vitamin E (>100 IU/day)  
 Other drugs with potential effect on NAFLD such as Ursodeoxycholic acid, SAM-e, 
Betaine, Pentoxifylline, or Milk Thistle. 
 Thiazolidinediones (pioglitazone, rosiglitazone), chemotherapy or other investigational 
medications during the study duration. 

 
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 
Patients are not permitted to take medications which causes hepatic steatosis (e.g., 
corticosteroids, amiodarone, methotrexate, tetracycline, tamoxifen, anabolic steroids, or 
valproic acid). 
 The known CYP2C8 inhibitors/substrates are not permitted during the study (Appendix 
1: List of Known CYP2C8 Inhibitors/Substrates). 
 Patients are not permitted to take medications such as digoxin, warfarin, quinidine, 
prazosin, etc. 
 Patients also should not take any non-allowed over-the-counter medications or 
complementary and/or alternative medications believed to have a potential impact that 
would affect the ability to evaluate the study data. 
The doses of statins (simvastatin, pravastatin, atorvastatin, fluvastatin, lovastatin, rosuvastatin) or 
fibrates (clofibrate, fenofibrate) should remain stable throughout the study period as much as 
possible. 
5.8.3.1 Permitted Concomitant Medications 
With the exception of excluded concomitant medications, other medications that patients have 
been taking at stable dosages for at least 3 months preceding visit 1, i.e., lipid lowering drugs and 
drugs for glycemic control, will be permitted as concomitant medications, including antidiabetic 
drugs such as metformin, sulfonylureas, dipeptidyl peptidase 4 inhibitors and insulin. To the 
extent possible, patients should continue with their current regimen of medication without any 
change throughout the study. Allowed over-the-counter medications include acetaminophen 
(maximum 1 gram/day), ibuprofen (maximum 800 mg/day) or naproxen (maximum 440 mg/day) 
or antacids such as H2 receptor blockers or proton-pump inhibitors for shorter duration as per 
investigator discretion. 
The PI should be alerted if, during the course of the study, a patient requires a new medicine or 
therapy or a change to an established dosing regimen. All medications that target NAFLD with 
PCOS or NASH, or have been suggested to target the underlying causes of NAFLD with PCOS 
or NASH, should be reviewed and agreed by the PI, Medical Monitor and Sponsor before being 
taken by the patient. 
5.8.4 Other Restrictions 
5.8.4.1 Alcohol  
Patients are encouraged to stop alcohol consumption entirely during the trial. They are not 
permitted to consume ≥7 drinks per week of alcohol before 6 months prior to enrollment and 
during the study. Alcohol consumption will be recorded throughout the study period. 

 
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5.9 
OVER DOSE AND DRUG INTERACTION 
No incidence of overdose with Saroglitazar Magnesium has been reported. In case of overdose 
with Saroglitazar Magnesium, general supportive care of the patient is indicated, including 
monitoring of vital signs and observation of clinical status. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.10 TREATMENT COMPLIANCE 
Saroglitazar Magnesium 4 mg Tablets or placebo will be administered by qualified staff at 
scheduled site visits and the details administration will be recorded in the eCRF. 
Investigator or designated study personnel will maintain a log of all study drugs dispensed to a 
study patient and returned to the site by the study patient into the eCRF for the purpose of drug 
supply management and accountability. If Saroglitazar Magnesium 4 mg Tablets or placebo will 
be administered outside of the study site (at-home use/self-administration), subjects will be 
instructed regarding storage of study drug at-home use/ self-administration. In addition, all 
unused study drug shipped back to the Sponsor/drug suppliers will be captured on a drug 
accountability form, of which a copy will be included with the shipment and a copy retained in 
the study records. Although 100% compliance to study drug is desired and should be encouraged 
throughout the treatment phase, a compliance of ≥80% and ≤120% will be considered 
acceptable. 

 
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6 OBSERVATIONS 
6.1 
EFFICACY 
6.1.1 Primary Endpoint 
Change in hepatic fat content from baseline following 24 weeks of treatment as measured by 
MRI-PDFF. 
6.1.2 Secondary Endpoints 
1. Changes from baseline to Week 12 and Week 24 in liver enzymes/LFTs: ALT, AST, 
ALP, GGT, serum protein, albumin and total bilirubin. 
2. Changes from baseline to Week 12 and Week 24 in insulin resistance as measured by 
HOMA.  
3. Changes from baseline to Week 24 in markers of liver injury and fibrosis including CK-
18, hs-CRP, TNFα, and liver stiffness measured by transient elastography/FibroScan®. 
4. Changes from baseline to Week 24 in controlled attenuation parameter measured by 
transient elastography/ FibroScan®. 
5. Changes from baseline to Week 12 and Week 24 in body weight, BMI and in waist 
circumference. 
6. Changes from baseline to Week 24 in MRI-derived measures of total liver fat index and 
total liver volume. 
7. Changes from baseline to Week 12 and Week 24 in lipid and lipoprotein levels: TG, TC, 
HDL, LDL, sdLDL, VLDL, apolipoprotein A and apolipoprotein B. 
8. Changes from baseline to Week 12 and Week 24 in SHBG level. 
9. Changes from baseline to Week 12 and Week 24 in ovarian function (Total 
testosterone, 17-hydroxyprogesterone, free testosterone, luteinizing hormone, follicle-
stimulating hormone, LH-to-FSH ratio and estradiol). 
10. Changes from baseline to Week 12 and Week 24 in free androgen index. 
11. Pharmacokinetics of Saroglitazar following first dose and last dose. 
6.2 
SAFETY  
1. Adverse event(s): frequency and severity of AE/SAEs, drop-outs due to AEs/SAEs for 
all subjects enrolled will be recorded. All AEs, will be assessed using CIOMS criteria 
which includes: 
 Causality 
 Severity 
 Seriousness 
 Expectedness 
2. Clinical laboratory testing (hematology, clinical chemistry, hormonal profile and 
urinalysis). 
3. Twelve-lead ECG. 

 
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4. Vital signs. 
5. Physical examination (Physical examination will consist of an evaluation of the  head, 
neck, eyes, ears, nose, throat, pelvic, breast, chest, heart, lungs, abdomen, skin, 
extremities, neurological systems, musculoskeletal systems and weight measurement. 
Investigator should also evaluate the patients for hirsutism and virilizing signs (upper lip, 
chin, chest, upper abdomen, lower abdomen, thighs, back, arm and buttocks). Note: 
Breast examination will be done as part of screening. Pelvic examination will be 
performed as part of screening, if not performed within 6 months of randomization. 
6.2.1 Abnormal Laboratory Findings 
In addition, a clinically significant value outside the normal or reference range in a routine safety 
assessment, such as clinical laboratory, vital signs or ECGs, may signify an adverse finding. 
Additional examinations or repetition of test will be performed as medically indicated. If the 
Investigator considers the abnormality as of major 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), then this diagnosis should be recorded as AE. The criteria for determining whether an 
abnormal objective test finding should be reported as an AE are as follows:  
1. Test result is associated with accompanying symptoms, and/or  
2. Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or  
3. Test result leads to change in study dosing or discontinuation from the 
study, significant additional concomitant drug treatment or other therapy, and/or  
4. Test result leads to any of the outcomes included in the definition of SAE, and/or  
5. Test result is considered to be an AE by the Investigator. 
For any abnormal test result that meets one of the above conditions except for the last condition, 
the Investigator will provide a justification for not reporting the abnormal test finding as an AE. 
Each AE shall be evaluated for the severity, duration, resolution, action taken and its association 
with the study treatment. The study participant may be withdrawn or terminated from the study 
depending on the seriousness of the adverse effects. 
6.2.2 Appropriateness of Measurement 
The endpoints chosen for the given study [safety and efficacy] are appropriate for the assessment 
of outcome of the study.  

 
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7 INVESTIGATIONAL PLAN 
7.1 
STUDY DESIGN AND PLAN 
This is a multicenter, phase 2A, randomized, double-blind, placebo-controlled study designed to 
evaluate the efficacy and safety of Saroglitazar Magnesium in women with well characterized 
PCOS, 18-45 years of age diagnosed with NAFLD. A total 90 subjects (including 20% 
dropouts), will be enrolled across USA and Mexico in a ratio of 1:1 to have 45 subjects in each 
arm i.e., Saroglitazar Magnesium 4 mg Tablets and placebo. Six patients in each group are 
planned for pharmacokinetic assessment therefore a total of 12 patients will be included. 
The study will be conducted over a period of up to 34 weeks. Subjects will be evaluated at study 
sites for 8 scheduled visits: (Visit 1: Day [-28]), Visit 2: Day [-14 to -7]), randomization (Visit 3: 
Week 1, Day 1), Visit 4 (Week 2, Day 14), Visit 5 (Week 8, Day 56), Visit 6 (Week 12, Day 84), 
Visit 7 (Week 16, Day 112) Visit 8 (Week 24, Day 168). After completion of the study treatment 
period, the subjects will be followed for an additional period of 6 weeks without study 
medication until Visit 9 (Week 30, Day 210). 
7.2 
STUDY PROCEDURES AT EACH VISIT 
Time and Events Schedule for the trial is given in Table 1. 
Pre-screening Visit: An informed consent will be obtained from the potential subjects before 
any pre-screening evaluations. The study sites may identify potential subjects by conducting a 
laboratory evaluation of the ALT levels. This optional pre-screening can be conducted before the 
actual study screening. A subject with an ALT ≥38 U/L may be considered for the actual study 
screening. Also, along with the evaluation of the ALT levels, in those potential subjects who do 
not have a documented diagnosis of NAFLD through any imaging method, an optional 
abdominal ultrasound or Fibroscan® may be performed during the pre-screening. 
In addition, an optional lab evaluation for diagnosis of PCOS through lab or ultrasound may be 
performed during pre-screening. The evaluation of the ALT levels during the pre-screening will 
be done at the local laboratory, whereas the laboratory evaluations during the screening and the 
treatment phase will be done at the central laboratory. 
Screening Phase  
 
Visit 1 (Day -28): In this study, the screening phase will consist of 28 days. Unless otherwise 
specified, screening procedures may be completed at any time during the screening period. 
Before each patient is enrolled to the study, informed consent will be obtained from the patient 
(or her legally authorized representative) according to the regulatory and legal requirements of 
the participating country. Patient eligibility for participation in the study will be assessed. 
Current social, medical and ovarian dysfunction history will be obtained and physical 
examination, vital signs, ECGs, laboratory evaluations (including serology, hematology, lipid 
and lipoprotein profiles, liver enzymes/LFTs, BNP, NT-proBNP, cardiac troponin, CK-MB, 
lipase and amylase, hormonal profile and urinalysis) will be performed. PAP test, endometrial 

 
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biopsy and mammography will be performed as per Time and Events Schedule. Patients will 
undergo a serum pregnancy test. During this visit, subject will be seen by the investigator or 
designated study personnel and an AUDIT questionnaire will be administered. 
Visit 2 (Day -14 to -7): Liver function tests (AST, ALT, ALP, GGT, total  protein, albumin, 
total bilirubin (with conjugated bilirubin) will be re-measured approximately 2 weeks from Day -
28 to determine eligibility. 
Alanine transaminase ≥ 38 U/L at Visit 1. Visit 2 ALT must not increase >30% from Visit 1. 
Randomization and Treatment Phase 
Visit 3 to Visit 8: The randomization and treatment phase will include 6 outpatient visits (Visit 3 
to Visit 8) over a period of 24 weeks including the randomization visit. All the eligible subjects 
will be randomly assigned into either of the two treatments arms: Saroglitazar Magnesium 4 mg 
Tablets and matching placebo tablets in a 1:1 ratio. Efficacy assessments will be conducted at 12 
(hormonal profile, lipid and lipoprotein profiles, ovarian function and liver enzymes/LFTs) and 
24 weeks visits (liver fat content by MRI-PDFF, hormonal profile, lipid and lipoprotein profiles, 
MRI-derived total liver fat index and total liver volume, homeostasis model assessment [insulin 
resistance (HOMA-IR)], liver stiffness by transient elastography/FibroScan®, controlled 
attenuation parameter, ovarian function and liver enzymes/LFTs). In addition, subjects will be 
monitored during the study and at every visit for development of any adverse events including 
drug induced liver injury. In addition to physical examination, laboratory data and ECGs done 
during the study period will be monitored to detect any treatment emergent adverse events. 
 
Visit 3 (Week 1, Day 1): Patients will be randomly assigned to receive Saroglitazar Magnesium 
4 mg Tablets or placebo orally once-daily, starting on Day 1 of a 24-week outpatient treatment 
period. 
 
Visits 4, 5, 6, 7 and 8: Patients will visit the study site at Week 2 (Visit 4), Week 8 (Visit 5) 
Week 12 (Visit 6), Week 16 (Visit 7) and Week 24 (Visit 8) for clinical assessment, dispensation 
and reconciliation of study drug, measurements of efficacy endpoints and assessment of AEs. 
 
Detailed efficacy and safety assessments are provided in Table 1 (Time and Events Schedule). 
Safety follow-up visit (Visit 9): A final post-treatment visit will occur 6 weeks (±3 days) after 
the end-of-treatment visit for safety monitoring. A telephonic follow-up visit will be performed 
to assess any AE or SAE after the end-of-treatment visit for safety monitoring. As far as 
possible, all assessments scheduled for end-of-treatment must be performed on all patients who 
receive the study drug but do not complete the study according to protocol. 

 
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7.3 
PHARMACOKINETIC ASSESSMENT 
Twelve subjects will be included in the pharmacokinetic assessment. On study visit 3 (Day 1), 
and study visit 8 (Day 168) subjects will be asked to remain at the clinic for 10 hours after 
dosing. In addition, subjects may be remained in-house as per investigator discretion for a 
pharmacokinetic assessment. On these days, blood samples will be collected at the following 
timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 10.0 hours. Subjects will be asked 
to return to the clinic the following day for another collection approximately 24 hours after study 
drug administration on visit 3 (Day 1) and visit 8 (Day 168). In addition to these collections, pre-
dose sample will be collected at visits 4 (Day 14), 5 (Day 56), 6 (Day 84) and 7 (Day 112). A 
detail pharmacokinetic laboratory manual will be prepared separately. 
 
The following pharmacokinetic parameters will be evaluated at the first and last dose: 
 
The pharmacokinetic parameters will be evaluated using Phoenix® WinNonlin® professional 
software (Version 8.0 or higher) for Saroglitazar and its metabolite Saroglitazar sulfoxide: 
For Single Dose (i.e. for Visit 3) 
i. Peak Plasma concentration (Cmax) 
ii. Time to reach peak Plasma concentration (Tmax) 
iii. Area under Plasma concentration vs. time curve till the last time point (AUC0-t) 
iv. Area under Plasma concentration vs. time curve extrapolated to the infinity (AUC0-∞) 
after first dose 
v. Area under plasma concentration vs. time curve in a 24 h dosing interval (AUCtau) after 
first dose 
vi. Elimination rate constant (Kel) 
vii. Elimination half-life (tHalf) 
viii. Apparent Volume of distribution (Vd/F) 
ix. Apparent Clearance (CL/F) 
Note: No value of Kel and related PK parameters will be reported for cases that do not exhibit a 
terminal log-linear phase in the concentration versus time profile. No value of Kel, AUCi, 
AUC_%Extrap_obs and tHalf will be reported for cases that do not exhibit a terminal log-linear 
phase in the concentration versus time profile.  
For Multiple Dose (i.e. for Visit 8) 
i. Peak Plasma concentration (Cmax,ss) 
i. Time to reach peak Plasma concentration (Tmax,ss) 
ii. Area under plasma concentration vs. time curve in a 24 h dosing interval (AUCtau) 
after last dose 
iii. Elimination rate constant (Kel,ss) 
iv. Elimination half-life (thalf,ss) 

 
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v. Apparent Volume of distribution (Vd/F,ss) 
vi. Apparent Clearance (CL/F,ss) 
vii. Minimal or Trough plasma concentration (Cmin) 
viii. Fluctuation index. 
ix. Accumulation index calculated as a ratio of AUCtau (last dose)/AUCtau (first dose) 
Note: No value of Kel,ss and related PK parameters will be reported for cases that do not exhibit a 
terminal log-linear phase in the concentration versus time profile. 
7.4 
ADHERENCE TO PROTOCOL 
Investigator shall strictly adhere to the protocol and Good Clinical Practice (GCP) guidelines. All 
subjects will be strictly required to follow the instructions given to them as per this protocol. For 
any deviation or violation from protocol, considered serious, the subject may be withdrawn from 
the trial at the discretion of the Sponsor or the Investigator. 
7.5 
PROTOCOL DEVIATION  
For the purposes of this study, no distinction will be made between Protocol Violations and 
Deviations. Deviations may be categorized as minor protocol deviation and a major protocol 
deviation. Minor protocol deviation includes any deviations that do not influence the outcome of 
the efficacy and safety endpoints. Minor protocol deviations do not require immediate 
notification to the IEC/IRB unless otherwise specified by IEC/IRB requirements. All minor 
protocol deviations will be noted in monitoring reports and provided to the investigator. Major 
protocol deviation includes any violation which may influence the outcome of the efficacy or 
safety endpoints. Major protocol deviations must be reported immediately to the IRB/IEC as 
specified by the IRB/IEC 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. 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 IEC/IRB and regulatory authority will be informed. The clinical study 
report will provide the list of protocol deviations/violations on separate section. Protocol 
deviation/violation will include but are not limited to the following;  
 
 Subjects that did not meet entry criteria 
 Subjects that developed withdrawal criteria but were not withdrawn  
 Subjects that received the wrong treatment or incorrect dose  
 Subjects that received an excluded medication  

 
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8 DATA MANAGEMENT AND BIOSTATISTICS 
8.1 
DATA MANAGEMENT 
8.1.1 Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the Monitor during monitoring visits. 
The Monitor will verify data recorded in the electronic data capture (EDC) system with source 
documents. All corrections or changes made to any study data must be appropriately tracked in 
an audit trail in the EDC system. An eCRF will be considered complete when all missing, 
incorrect, and/or inconsistent data has been accounted for. 
8.1.2 Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
8.1.3 Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user name and password in order to enter, review, or 
correct study data. These procedures must comply with Title 21 of the Code of Federal 
Regulations (21 CFR Part 11) and other appropriate international regulations. All passwords will 
be strictly confidential. 
8.1.4 Medical Information Coding 
For medical information, the following thesauri will be used:  
 Latest version of Medical Dictionary for Regulatory Activities (MedDRA) for adverse 
events and medical history, and  
 WHO Drug Dictionary for prior and concomitant medications. 
8.1.5 Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. The eCRFs must be 
reviewed and electronically signed by the Investigator. 

 
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8.2 
STATISTICAL DESIGN 
Statistical Analysis Plan (SAP) will be prepared and finalized prior to database lock. The SAP 
will include detailed statistical aspects of the safety and efficacy analysis. Statistical analysis will 
be performed using SAS® (version 9.4 or higher) software (SAS Institute Inc., USA). 
8.3 
NULL AND ALTERNATIVE HYPOTHESIS 
Below is the hypothesis of primary efficacy endpoint:  
Null hypothesis: H0: S ≤ P 
Alternative hypothesis H1: S > P 
Where: S = Treatment effect of Saroglitazar Magnesium 4 mg, P = Treatment effect of 
Placebo  
Rejection of the null hypothesis will lead to the conclusion that the treatment effect of 
Saroglitazar Magnesium 4 mg is statistically significantly greater than the treatment effect of 
placebo group and hence the test drug is more effective than placebo. 
8.4 
STUDY POPULATION PLANNED ANALYSIS 
8.4.1 Population 
8.4.1.1 Safety population 
Safety population will consist of all randomized patients who received at least 1 dose of study 
drug. All patients in the safety population will be analysed according to the actual treatment 
received. 
8.4.1.2 Modified Intent-to-treat population (mITT) 
The mITT population will consist of all randomized patients who received at least 1 dose of the 
study drug and have at least 1 post-baseline efficacy data. 
Last observation carried forward method will be used as an imputation method for post-baseline 
missing values for mITT analysis. 
8.4.1.3 Per-protocol population (PP) 
The PP population is a subset of mITT population. The PP population will consist of all 
randomized patients completing the treatment phase and have not deviated from or violated the 
protocol in such a way that could affect efficacy outcome (i.e., had both baseline and end-of-
treatment MRI & has taken ≥80% and ≤120% of the study drug). 

 
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8.4.1.4 Pharmacokinetic population (PK) 
Pharmacokinetic population will include all randomized patients with evaluable concentration 
profile and do not have any major protocol deviation(s) that could affect the PK profile of the 
treatment. 
8.4.2 Planned Analysis 
All efficacy analysis will be based primarily on the PP population and analysis based on mITT 
will be considered as supporting analyses for this proof of concept study. 
The PP population is a subset of mITT population. The PP population will consist of all 
randomized patients completing the treatment phase and have not deviated from or violated the 
protocol in such a way that could affect efficacy outcome (i.e., had both baseline and end-of-
treatment MRI & has taken ≥80% and ≤120% of the study drug). 
The mITT population will consist of all randomized patients who received at least 1 dose of the 
study drug and have at least 1 post-baseline efficacy data. Last observation carried forward 
method will be used as an imputation method for post-baseline missing values for mITT 
analysis. 
8.4.2.1 Primary Efficacy Analysis 
The primary analysis for the primary efficacy endpoint will be based on PP population. The 
primary efficacy endpoint in this study is the change in hepatic fat content from baseline 
following 24 weeks of treatment as measured by MRI-PDFF. The change from baseline of 
hepatic fat will be determined as (Week 24 value – Baseline value).  
The primary endpoint will be summarized and change from baseline to Week 24 will be 
evaluated using ANCOVA model with treatment as factor and baseline value as covariate. 
Statistical significance will be tested at a one-sided p-value <0.025. 
8.4.2.2 Secondary Efficacy Analysis 
Each secondary efficacy endpoint will be summarized by treatment group at each time point, as 
appropriate. 
Following secondary endpoints will be analyzed: 
1. Changes from baseline to Week 12 and Week 24 in liver enzymes/LFTs: Alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), 
Gamma-glutamyl transferase (GGT), serum protein, albumin and total bilirubin. 
2. Changes from baseline to Week 12 and Week 24 in insulin resistance as measured by 
HOMA. 

 
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3. Changes from baseline to Week 24 in markers of liver injury and fibrosis including CK-
18, hs-CRP, TNFα, and liver stiffness measured by transient elastography/FibroScan®. 
4. Changes from baseline to Week 24 in controlled attenuation parameter measured by 
transient elastography/ FibroScan®. 
5. Changes from baseline to Week 12 and Week 24 in body weight, BMI and in 
waistcircumference. 
6. Changes from baseline to Week 24 in MRI-derived measures of total liver fat index and 
total liver volume. 
7. Changes from baseline to Week 12 and Week 24 in lipid and lipoprotein levels: TG, TC, 
HDL, LDL, sdLDL, VLDL, apolipoprotein A and apolipoprotein B. 
8. Changes from baseline to Week 12 and Week 24 in SHBG level. 
9. Changes from baseline to Week 12 and Week 24 in ovarian function (Total testosterone, 
17-hydroxyprogesterone, free testosterone, luteinizing hormone, follicle-stimulating 
hormone, LH-to-FSH ratio and estradiol). 
10. Changes from baseline to Week 12 and Week 24 in free androgen index. 
11. Pharmacokinetics of Saroglitazar following first dose and last dose. 
The change from baseline will be determined as: 
Change = (Post-baseline – Baseline) 
Percent change will be calculated for all parameters except those measured in ratio or percent. 
Percent Change = ((Post-baseline – Baseline) / Baseline) * 100 
Treatment effects will be estimated using the least-square mean, standard error and 95% 
confidence interval from ANCOVA model with treatment as factor and baseline value as 
covariate. Treatment groups, Saroglitazar Magnesium 4 mg Tablets and placebo, will be 
compared using the difference in least-square means and p-values from the ANCOVA model. 
Descriptive statistics will be provided for each Pharmacokinetic parameter as detailed in Section 
7.3. 
Above analysis will also be supported by simple summaries at each visit. 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 frequencies and 
percentages. 

 
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8.4.3 Safety Analysis  
All safety analysis will be carried out on the safety population. The frequency tabulations of 
abnormal clinical laboratory values for the parameter will be presented for each treatment group 
by visit. Summary statistics for clinical laboratory parameters, ECGs, physical examination and 
vital signs will be presented for each treatment by visit. 
All AEs observed during the study period will be listed. Incidence of all AEs reported during the 
study will be summarized using the MedDRA (version 19 or higher) by treatment group, 
frequency, severity, seriousness, relationship to study drug and expectedness per System Organ 
Class and Preferred Term. 
8.4.4 Baseline Characteristics  
Demographic and baseline characteristics will be summarized by treatment and population set. 
Subject disposition and reason for withdrawal will be summarized and presented. 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 frequencies 
and percentages. 
8.4.5 Interim Analysis 
No interim analysis is planned for the study. 
8.5 
HANDLING OF MISSING DATA 
Clarifications, wherever possible, will be obtained from the respective Investigator for any 
missing data or for any illegible entry, unused or unauthenticated data and this will be recorded 
in the data handling report before the final database lock. 
Subjects who are discontinued from the study will be excluded from PP population. Any 
randomized subject who discontinued the study for any reason but have at least 1 post-baseline 
efficacy data will be included in the mITT population. Last Observation Carried Forward method 
will be used as an imputation method for the efficacy variables for mITT population. 
8.6 
DETERMINATION OF SAMPLE SIZE 
The primary efficacy endpoint of this study is the change from baseline in hepatic fat content at 
Week 24 as measured by MRI-PDFF. There is no data available on the change from baseline in 
hepatic fat content measured by MRI-PDFF. 

 
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A sample size of 74 completed subjects (37 subjects in each treatment arm) will provide 80% 
power to detect a 4% treatment difference in change from baseline in hepatic fat content at Week 
24 between Saroglitazar 4 mg and Placebo using a two-sided 5% level of significance based on a 
two-sample t-test, assuming change from baseline in hepatic fat content of 9% at Week 24 in 
Saroglitazar 4 mg treatment arm with a common standard deviation of 0.6. 
Assuming a 20% dropout rate at week 24, approximately 90 subjects will be randomized in a 1:1 
ratio to receive either Saroglitazar 4 mg (45 subjects) or placebo (45 subjects). Additional 
subjects may be enrolled if the dropout rate is more than 20%. The sample size estimation was 
performed using PASS 14 software. 
A total of 12 subjects, 6 subjects in each treatment arm will be included in the pharmacokinetic 
assessment. 
Additional patients may be enrolled into the study to ensure the pharmacokinetic assessment is 
performed on at least 6 completed patients in each treatment arm. 
8.7 
RANDOMIZATION 
Subjects will be randomly assigned in a 1:1 treatment allocation ratio to Saroglitazar Magnesium 
4 mg Tablets and placebo, respectively. The randomization schedule will be generated to ensure 
the treatment balance by using SAS® software (Version: 9.4 or higher; SAS Institute Inc., USA). 
 
 

 
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9 ADMINISTRATIVE MATTERS 
The trial will be carried out in compliance with the protocol, in accordance with the International 
Council for Harmonisation (ICH) guideline for GCP and in accordance with applicable 
regulatory requirements. 
9.1 
ETHICS 
9.1.1 Institutional/independent Committee Review and Communications  
The trial will not be initiated before the protocol and informed consent and subject information 
form have been reviewed and have received approval / favorable opinion from the IEC/IRB. 
Should a protocol amendment be made that requires IEC/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 IEC/IRB. A protocol 
amendment intended to eliminate an apparent immediate hazard to subjects may be implemented 
immediately provided that the appropriate regulatory authorities and IEC/IRB 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 IRB/IEC and the 
Regulatory Authority will be notified as soon as possible. The constitution of the IEC/IRB must 
comply with the requirements of the US Code of Federal Regulations. A list of the IEC/IRB 
members, with names and qualifications, will be requested. If such a list is unavailable, the 
Investigator must provide the name and address of the central IEC/IRB along with a statement 
from the IEC/IRB that it is organised according to GCP and the applicable laws and regulations. 
The IEC/IRB must also perform all duties outlined by the requirements of the regulatory 
agencies. 
9.1.2 Informed Consent and Subject Information 
Prior to subject participation in the trial, written informed consent will be obtained from each 
subject (or the subject’s legally authorized representative) according to the regulatory and legal 
requirements of the participating country. Each signature must be dated by each signatory and 
the informed consent and any additional subject information form retained by the Investigator as 
part of the study records. A signed copy of the IEC/IRB approved informed consent and any 
additional subject information must be given to each subject or the subject’s legally authorised 
representative. 
 
The subject must be informed that her medical records may be examined by authorised monitors 
or Clinical Quality Assurance auditors appointed by the Sponsor, by appropriate IEC/IRB 
members and by inspectors from regulatory authorities. 
 

 
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Should a protocol amendment be made, the subject consent form and subject information form 
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 received approval from the 
IEC/IRB, and to further ensure that it is signed by all subjects subsequently entered in the trial 
and those currently in the trial, if affected by the amendment. 
9.2 
RECORDS 
9.2.1 Drug Accountability 
The dispensing of study drug to the subject, and the return of the study drug from the subject, 
must be documented on drug accountability form. Subject or their legally authorized 
representative, must be instructed to return all the original containers, where empty or containing 
study drug. The subjects must return unused study drug to the site. 
 
Receipt and dispensing of study drug must be recorded by an authorized person at the study site. 
The PI will maintain an accurate record of the receipt of the study drug as shipped by the 
Sponsor, including the date received. Study drug supply management will be processed and 
maintained on drug accountability forms, which will be monitored and reconciled by the study 
monitor assigned to the site. This inventory record must be available for inspection at any time. 
Copies of this record will be provided to the Sponsor at the conclusion of the study. The PI will 
not be allowed to store study drug at any site other than those listed on Form FDA 1572 or 
Investigator’s Agreement or to dispense the study drug from sites not listed on this form. The PI 
will also agree that study drug will be dispensed by the PI or Sub-investigator named on Form 
FDA 1572 or Investigator’s Agreement, or their qualified designees. The PI, Sub-investigators 
and qualified designees also agree that study drug will be dispensed only to study patients who 
have provided written informed consent and have met all entry criteria. Study drug may not be 
used for any purpose other than that stated in the protocol. 
 
After the study has been completed, the PI must account for all study drug used, unused and 
partially used. All study drugs will be adequately destroyed at the site (per site’s SOPs) or 
returned to the Sponsor (or designee).  No study drug will be destroyed or returned until drug 
accountability has been performed by the study monitor. 
9.2.2 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 drug must be 
known by the investigator in order to provide appropriate medical treatment. If the code break 
for a subject 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. 

 
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Subjects whose treatment assignment becomes unblinded inadvertently, need not require to 
complete the scheduled evaluations and patient will be withdrawn from the trial from that visit. 
9.2.3 Case Report Forms 
All data generated by the site personnel will be captured electronically at each study center using 
eCRFs. Data from external sources (such as laboratory data) will be imported/entered into the 
database. Case reports forms must be kept current to reflect patient status at each phase during 
the course of trial. Patients are not to be identified on the case report form by name. Appropriate 
coded identification (e.g. Subject Number) and Patients initials must be used. The investigator 
must make a separate confidential record of these details (subject identification code list) to 
permit identification of all patients enrolled in a clinical trial in case follow-up is required. 
Relevant medical history will be documented at the screening visit. Thereafter during the trial 
narrative statements relative to the patient’s progress during the trial will be maintained. See also 
9.2.4. The investigator will be responsible for retaining all records pertaining to the trial as 
specified in the agreement. 
9.2.4 Source documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site. Data reported on the 
Case Report Forms that are derived from source documents must be consistent with the source 
documents or the discrepancies must be explained. The investigator may need to request 
previous medical records or transfer records, depending on the trial; also current medical records 
– not just shadow charts – must be available. The following data to be reported on the eCRF 
should be included and derived from the source documents:  
 
 Patient identification (initials, gender, data of birth/age)  
 Patient participation in the trial (drug, trial number, subject number, date informed 
consent given)  
 Dates of Patient’s visits  
 Medical history  
 Medication history  
 AE onset and end  
 SAE onset and end  
 Originals or copies of laboratory results  
 Originals or copies of ultrasound findings or MRI findings or FibroScan® findings and 
other results if applicable. 
 Conclusion of patient’s participation in the trial. 
9.2.5 Direct Access to Source Data / Documents 

 
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The Investigator/ institution will permit trial-related monitoring, audits, IRB / IEC review and 
regulatory inspection, providing direct access to all related source data / documents. Case report 
forms and all source documents, including progress notes and copies of laboratory and medical 
test results must be available at all times for review by the Sponsor’s clinical trial monitor and 
inspection by health authorities (e.g., FDA, or other applicable regulatory authorities). The on-
site monitor will review all eCRFs, and written informed consents. The accuracy of the data will 
be verified by reviewing the documents described in Section 9.2.4. 
9.2.6 Trial Monitoring 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance  
with the protocol, ICH GCP, and applicable regulatory requirements, and that valid data are  
entered into the eCRFs. To achieve this objective, the study monitor’s duties are to aid the 
Investigator and, at the same time, the Sponsor in the maintenance of complete, legible, well 
organized and easily retrievable data. Before the enrollment of any patient in this study, the 
Sponsor or their designees will review with the Investigator and site personnel the following 
documents: protocol, Investigator’s Brochure, eCRFs and procedures for their completion, 
informed consent process, and the procedure for reporting SAEs. The Investigator will permit the 
Sponsor or their designees to monitor the study as frequently as deemed necessary to determine 
that data recording and protocol adherence are satisfactory. During the monitoring visits, 
information recorded on the eCRFs will be verified against source documents and requests for 
clarification or correction may be made. After the eCRF data is entered by the site, the Monitor 
will review the data for safety information, completeness, accuracy, and logical consistency. 
Computer programs that identify data inconsistencies may be used to help monitor the clinical 
study. If necessary, requests for clarification or correction will be sent to Investigators. The 
Investigator and his/her staff will be expected to cooperate with the monitor and provide any 
missing information, whenever possible. 
9.2.7 Query Handling and Error Management 
If there are any discrepancies/errors/corrections are needed in the data entered in the eCRF then 
the responsible monitor or data manager will raise a query in the electronic data capture 
application. The designee staff at the study site will answer queries sent to the investigator. This 
process will be continued till the discrepancies/errors are adequately resolved. 
9.3 
QUALITY CONTROL AND QUALITY ASSURANCE AUDIT 
A quality assurance audit of this trial may be conducted by the sponsor or sponsor’s designee.  
The quality assurance auditor will have access to all medical records, the investigator’s trial 
related files and correspondence, and the informed consent form documentation that is relevant 
to this clinical trial. 
 

 
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9.4 
PROCEDURES 
9.4.1 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 telephone call). The Common Terminology Criteria for 
Adverse Event (Version 4.03 or higher) system will be used for reporting and grading AEs. 
9.4.1.1 Definitions 
An AE is any unfavorable or unintended sign, symptom or disease temporally associated with 
the use of study drug whether or not considered related to study drug. Adverse events may 
include:  
 Objective signs observed by the PI or study personnel 
 Subjective or objective signs/symptoms 
 Concomitant disease or accidents 
 Clinically relevant adverse changes in laboratory parameters observed in a patient in the 
course of a clinical study 
 Pre-existing conditions that worsen in severity or frequency or have new signs/symptoms 
associated with them 
Findings related to abnormal laboratory values, ECGs and vital signs, which are not considered 
clinically significant, are not to be recorded on the AE reporting page; such events should instead 
be entered in the relevant eCRF page. 
9.4.1.2 Treatment-emergent Adverse Events 
Treatment-emergent AEs are defined as any AE that started after the first dose of study drug or 
started before the first dose but increased in severity or frequency after administration of the 
initial dose of study drug. 
9.4.1.3 Collection of Adverse Events 
It is the responsibilities of the PI to collect all AEs (both serious and nonserious) derived by 
spontaneous, unsolicited reports of patients, by observation and by routine open questionings, 
e.g., "How have you felt since I last saw you?" 
9.4.1.4 Assessment of Adverse Events 
Each AE will be assessed by the PI with regard to the following categories:  
Severity 

 
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The PI will provide an assessment of the severity of each AE by recording a severity rating on 
the appropriate AE reporting page of the patient’s eCRF. Severity will be assessed according to 
the following scale:  
Mild: Event is usually transient and easily tolerated, requiring no special treatment and causing 
no disruption of the patient’s normal daily activities. 
Moderate: Event introduces a low level of inconvenience or concern to the patient and may 
interfere with daily activities, but is usually improved by simple therapeutic measures. Moderate 
experiences may cause some interference with functioning. 
Severe: Event interrupts the patient’s normal daily activities and generally requires systemic drug 
therapy or other treatment. Severe events are usually incapacitating.  
Causality  
For all AEs, the PI will provide an assessment of causal relationship to study drug. The causality 
assessment must be recorded on the appropriate AE reporting page of the patient’s eCRF. 
Causal relationship will be classified according to the following criteria:  
 Unrelated  
 Possibly related: Suggests that the association of the AE with the study drug is unknown.  
However, the AE is not reasonably supported by other conditions.  
 Probably related: Suggests that a reasonable temporal sequence of the AE with study 
drug administration exists and, based upon the PI’s clinical experience, the association of 
the AE with study drug seems likely.  
 Definitely related: Suggests that a causal relationship exists between the study drug and 
the AE, and other conditions (concomitant illness, progression or expression of the 
disease state, reaction to concomitant medication) do not appear to explain the AE.  
 Unknown 
Outcome 
Outcome of AEs will be defined according to the ICH topic E2B, ICH Guideline, as follows:  
 Recovered/Resolved  
 Recovered/Resolved with sequelae  
 Recovering/Resolving  
 Not Recovered/Not Resolved  
 Fatal  
 Unknown 
9.4.1.5 Recording Adverse Events 

 
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All AEs must be recorded on the appropriate AE eCRF for the patient. All AEs must be reported 
whether or not considered causally related to study drug. For every AE, the PI will provide an 
assessment of the severity and causal relationship to study drug, will document all actions taken 
with regard to study drug, and will document any other treatment measures for the AE. If an 
outcome for an AE is not available at the time of the initial report, follow-up will proceed until 
an outcome is known. 
9.4.1.6 Follow-up of Adverse Events 
All AEs experienced by a patient, irrespective of the suspected causality, will be monitored until 
the AE has resolved, any abnormal laboratory values have returned to baseline or stabilized at a 
level acceptable to the Investigator and Medical Monitor, until there is a satisfactory explanation 
for the changes observed, until the patient is lost to follow-up or until the patient has died. 
9.4.2 Serious Adverse Event 
An SAE is an event that:  
 
 Results in death;  
 Is life threatening;  
 Results in persistent or significant disability/incapacity;  
 Results in inpatient hospitalization or prolongs an existing inpatient  
hospitalization;  
 Is a congenital anomaly/birth defect;  
 Is another important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
Serious AEs also include events that are medically significant in the PI’s judgment, including 
medically significant laboratory abnormalities, such as those that warrant stopping study drug for 
individual patients as specified in Section 4.5 of the protocol. In general, medically significant 
events require medical/surgical intervention to prevent one of the outcomes listed above. 
9.4.2.1 Reporting Serious Adverse Events 
The PI must report any SAEs to the Sponsor/Contract Research Organization (CRO) within 24 
hours of becoming aware of the event. 
During SAE reporting, state that you are reporting an SAE and give the PI’s name, your name, 
the telephone number where you can be reached and the protocol number and title. 
The PI and the Sponsor (or Sponsor’s designated personnel) will review each SAE report and the 
Sponsor/CRO will evaluate the seriousness and the causal relationship of the event to study drug. 

 
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In addition, the Sponsor (or Sponsor’s designated personnel) will evaluate the expectedness 
according to the reference document (Investigator Brochure or Summary of Product 
Characteristics). Based on the PI and Sponsor’s assessment of the event, a decision will be made 
concerning the need for further action. All SAEs will be recorded from signing of informed 
consent until the end of the study (i.e., the safety telephone call). Information regarding serious 
adverse events will be transmitted to the sponsor using the Serious Adverse Event Form, which 
must be completed and signed by a member of the investigational staff, and transmitted to the 
sponsor within 24 hours. 
 
 
 
 
 
 
9.4.3 Expected Adverse Events 
Adverse events reported by 2% or more patients treated with Saroglitazar Magnesium during the 
double-blind, active-controlled trial with Pioglitazone as the comparator regardless of causality 
included gastritis and asthenia. In the double-blind placebo controlled study, AEs reported by 2% 
or more patients treated with Saroglitazar Magnesium included gastritis, dyspepsia, pyrexia and 
pain. The details of AE experienced during the Saroglitazar Magnesium studies are mentioned in 
an Investigator Brochure. The investigators will provide instructions and medical management to 
the patients for the symptoms of potential adverse effects such as skeletal muscle pain, weight 
gain, peripheral edema and shortness of breath. 
9.4.4 Emergency procedures 
Any serious or significant AE, whether or not considered related to the investigational product, 
and whether or not the investigational product has been administered, must be reported 
immediately to the Sponsor/CRO. Details regarding this reporting procedure will be provided in 
the safety management plan. 
9.4.5 Pregnancy 
 At screening every female subject of childbearing potential will be tested for serum 
pregnancy test. Women are advised not to become pregnant during the trial and for at 
least 4 weeks ±3 days after the end-of-treatment period. Adequate contraceptive measures 
SERIOUS ADVERSE EVENT REPORTING INSTRUCTIONS 
 
1. On discovery, all SAEs should be immediately reported (latest within 24 
hours of knowledge of the event) to Sponsor/CRO, complete the SAE report 
form and fax or email the documents to Sponsor/CRO. Details regarding the 
safety management will be specified in safety management plan. 

 
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shall be taken to prevent pregnancy. Even when contraceptive methods are used, there is 
a small risk that pregnancy might occur. 
 In case a subject becomes pregnant, then she will be withdrawn from the trial and 
adequate monitoring of the subjects will be conducted. It is the responsibility of 
Investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial or within 4 weeks ±3 days of 
completing the treatment period. 
 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 subject 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 subject. 
 
If the woman decides to terminate her pregnancy, she will be provided proper gynaecological 
care. The investigator should ensure that the subject has access to a gynaecologist for the 
termination of her pregnancy. The investigator should regularly follow up with the gynaecologist 
regarding the health status of the subject. 
9.4.5.1 Outcomes of Pregnancy 
 If the pregnancy continues to term, the outcome (health of infant) must also be reported. 
The investigator should report the pregnancy to Sponsor Clinical Safety within 24 hours 
of being notified. Sponsor Clinical Safety will then forward the Exposure in Utero form 
to the investigator for completion. 
 Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform 
mole, blighted ovum, fetal anomalies, fetal death, intrauterine death, miscarriage and 
stillbirth must be reported as serious adverse events. 
 
The following information regarding infants delivered at term will be collected and reported: 
 
 
Congenital anomalies (will be considered as a serious adverse event) (Any infant with a 
congenital anomaly should be examined by a dysmorphologist for confirmation of the 
defect) 
 Pre-term births (will be considered as a  neonatal adverse event of special interest) 
 Intrauterine growth restriction (will be considered as a neonatal adverse event of special 
interest) 
 Large for gestational age infants (will be considered as a neonatal adverse event of 
special interest) 
9.4.5.2 Follow-up of Infants: 

 
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All exposed infants will be followed up at the following time points: 
 
 At birth 
 4 weeks of age 
 Between six months and one year of age 
9.5 
RULES FOR AMENDING PROTOCOL 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB, in accordance with local legal requirements. This protocol is to be followed 
exactly. To alter the protocol, amendments must be written, receive approval from the 
appropriate personnel, and receive IEC/IRB approval before implementation (if appropriate). 
Following approval, the protocol amendment(s) will be submitted to the Investigational New 
Drug under which the study is being conducted. 
Administrative changes (not affecting the patient benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
9.6 
DISCONTINUATION OF THE TRIAL BY THE SPONSOR 
The Sponsor reserves the right to discontinue this trial at any time for failure to meet expected 
enrollment goals, for safety or any other administrative reasons. The Investigator will be 
reimbursed for reasonable expenses incurred if it is necessary to terminate the trial as per the 
agreement. 
9.7 
STATEMENT OF CONFIDENTIALITY 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions of participating 
physicians, the Sponsor’s representatives, by the IRB or IEC and the regulatory health 
authorities. Subject confidentiality will be further ensured by utilising subject identification code 
numbers to correspond to treatment data in the computer files. 
9.8 
FINAL REPORT AND PUBLICATION POLICY 
A report will be prepared under the responsibility of Investigators and according to the standards 
of the Sponsor. It will include the tabulated raw data and the biostatistical report on the data. 
By signing the clinical study protocol, the Investigator agrees with the use of results of the 
clinical study for the purposes of national and international registration, publication and 
information for medical and pharmaceutical professionals. If necessary, the competent 
authorities will be notified of the Investigator’s name, address, qualifications and extent of 
involvement. 

 
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An Investigator shall not publish any data (poster, abstract, paper, etc.) without the sponsor's 
prior written consent. 
9.9 
ARCHIVING 
Subject’s files, identification codes and other source data (including original reports of test 
results, dispensing logs, records of informed consent), IEC/IRB approval letter, correspondence 
and other documents pertaining to the conduct of the trial will be kept as per the applicable 
regulatory requirements. 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 
product. However, these documents should be retained for a longer period if required by the 
applicable legal requirements. No document pertinent to the trial shall be destroyed without prior 
written agreement between the Sponsor and the Investigator. 
 

 
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10 REFERENCES 
1. Fauser BCJM, Tarlatzis BC, Rebar RW, et al. Consensus on women’s health aspects of 
polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd 
PCOS Consensus Workshop Group. Fertil. Steril. 2012;97:28–38.e25. 
2. March WA, Moore VM, Willson KJ, Phillips DIW, Norman RJ, Davies MJ. The 
prevalence of polycystic ovary syndrome in a community sample assessed under 
contrasting diagnostic criteria. Hum. Reprod. Oxf. Engl. 2010; 25:544–551.  
3. ACOG Practice Bulletin No. 108: Polycystic ovary syndrome. Obstet. Gynecol. 2009; 
114: 936–949. 
4. Wild RA, Carmina E, Diamanti-Kandarakis E, Dokras A, Escobar-Morreale HF, 
Futterweit W. Assessment of cardiovascular risk and prevention of cardiovascular disease 
in women with the polycystic ovary syndrome: a consensus statement by the Androgen 
Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J. Clin. Endocrinol. Metab. 
2010; 95:2038–2049.  
5. Brand JS, Van der Tweel I, Grobbee DE, Emmelot-Vonk MH, Van der Schouw YT. 
Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic 
review and meta-analysis of observational studies. Int. J. Epidemiol. 2011;40:189–207.  
6. Ehrmann DA, Liljenquist DR, Kasza K, Azziz R, Legro RS, Ghazzi MN. Prevalence and 
predictors of the metabolic syndrome in women with polycystic ovary syndrome. J. Clin. 
Endocrinol. Metab. 2006; 91:48–53. 
7. Dale PO, Tanbo T, Vaaler S, Abyholm T. Body weight, hyperinsulinemia, and 
gonadotropin levels in the polycystic ovarian syndrome: evidence of two distinct 
populations. Fertil. Steril. 1992; 58:487–491.  
8. Matteoni C, Younossi Z, Gramlich T, Boparai N, Liu Y, Mccullough A. Non-alcoholic 
fatty liver disease: A spectrum of clinical and pathological severity. Gastroenterology 
1999; 116:1413–1419. 
9. Kelley CE, Brown AJ, Diehl AM, Setji TL. Review of non-alcoholic fatty liver disease in 
women with polycystic ovary syndrome. World J Gastroenterol 2014; 20(39): 14172-
14184. 
10. 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. 
11. 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. 
12. Jani RH, Kansagra K, Jain M, Patel H. Pharmacokinetics, safety, and tolerability of 
Saroglitazar (ZYH1), a predominantly PPARα agonist with moderate PPARγ agonist 
activity in healthy human subjects. Clin Drug Investig, 2013. 33(11): 809-16. 
13. 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. 11(1): 
e0146222. 
14. Corrado RL, Torres DM, Harrison SA. Review of treatment options for non-alcoholic 
fatty liver disease. Med Clin N Am. 2014 98:55–72. 
15. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural 
history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. 
Aliment Pharmacol Ther. 2011 34:274–285. 
16. J. J. Kim, D. Kim, J. Y. Yim, et al. Polycystic ovary syndrome with hyperandrogenism as 
a risk factor for non-obese non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 
2017. 45(11):1403-1412. 
17. Rocha ALL, Faria LC, Guimaraes TCM, et al. Non-alcoholic fatty liver disease in 
women with polycystic ovary syndrome: systematic review and meta-analysis. J 
Endocrinol Invest. 2017 Dec;40(12):1279-1288. 
18. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-
alcoholic fatty liver disease: practice Guideline by the American Association for the 
Study of Liver Diseases, American College of Gastroenterology, and the American 
Gastroenterological Association. Hepatology. 2012; 55(6):2005-23. 

 
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11 APPENDICES 
11.1 Appendix 1: List of Known CYP2C8 Inhibitors/Substrates 
Selected inducers, inhibitors and substrates of CYP2C8 
Substrates 
Inhibitors 
Inducers 
 
Amodiaquinea 
(antimalarial, anti-
inflammatory) 
 
Cerivastatina (statin) 
 
Enzalutamide 
(antiandrogen) 
 
Paclitaxela 
(chemotherapeutic) 
 
Repaglinidea (antidiabetic) 
 
Torsemidea (loop diuretic) 
 
Sorafeniba (tyrosine kinase 
inhibitor) 
 
Rosiglitazone 
(antidiabetic) - converted 
to active metabolitesb 
 
Buprenorphine 
(semisynthetic opioid) 
 
Polyunsaturated fatty acids 
 
Montelukast (leukotriene 
receptor antagonist) 
Strong 
 
Gemfibrozila 
(hypolipidemic) 
Moderate 
 
Trimethoprima (antibiotic) 
Unspecified potency 
 
Thiazolidinedionesa 
(antidiabetic) 
 
Montelukasta (leukotriene 
receptor antagonist) 
 
Quercetina 
(antiinflammatory) 
Unspecified potency 
 
Rifampicina 
(antibiotic) 
a Flockhart DA (2007). "Drug Interactions: Cytochrome P450 Drug Interaction Table". Indiana University School of Medicine. 
Retrieved on July 2011 
b Chapter 26 in: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. 
Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5 
11.2 Appendix 2: Declaration of Helsinki