A Phase 2, Prospective, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate Safety, Tolerability and Efficacy of Saroglitazar Magnesium in Patients With Primary Biliary Cholangitis (EPICS )
Phase: PHASE2
Conditions: Primary Biliary Cirrhosis
Sponsor: Zydus Therapeutics Inc.

Zydus Discovery DMCC 
CLINICAL TRIAL PROTOCOL 
Saroglitazar Magnesium – Phase II 
SARO.16.004 
CONFIDENTIAL 
Page 1 of 82 
Approved by: 
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Protocol No. SARO.16.004 
Version No.: 6.0 
CLINICAL TRIAL PROTOCOL 
Protocol No. 
SARO.16.004 
Version No. and 
Date 
6.0, dated 21 August 2019 
Superseded Protocol 
No 
SARO.16.004 
Version No. and 
Date 
5.0, dated 24 October 2018 
Investigational 
Product(s) 
Saroglitazar Magnesium (
 
) 
Title: 
A Phase 2, Prospective, Multicenter, Randomized, Double-blind, Placebo-
controlled Study to Evaluate Safety, Tolerability and Efficacy of 
Saroglitazar Magnesium in Patients with Primary Biliary Cholangitis 
(EPICS) 
Clinical Phase 
Phase 2 
Sponsor 
Zydus Discovery DMCC 
Unit No 909, Armada 2 
Plot No: JLT-PH2-P2A,  
Jumeriah Lakes Towers 
Dubai UAE 
P.O Box 113536
Study Director: 
(Sponsor’s 
Representative) 
Dr. Deven V Parmar, MD  
 
 
 
 
 
Sponsor’s Medical 
Expert and Monitor 
  
 
 
 
 
 
NCT03112681

 
Zydus Discovery DMCC 
CLINICAL TRIAL PROTOCOL 
Saroglitazar Magnesium – Phase II 
 
SARO.16.004 
CONFIDENTIAL 
 
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Approved by: 
Dr. Deven Parmar 
Protocol No. SARO.16.004 
Version No.: 6.0 
 
 
Clinical Laboratory 
 
 
 
Bio analytical 
Laboratory for 
Pharmacokinetic 
Assessment 
 
 
 
 
 
 
Data Management 
and Biostatistics 
 
 
  
 
 
Planned Date of 
Trial 
 December 2018 
Confidential 
 
 
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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CLINICAL TRIAL PROTOCOL  
Saroglitazar Magnesium – Phase II 
SARO.16.004 
 
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Protocol No. SARO.16.004 
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STUDY PROTOCOL SUMMARY 
Name of Sponsor 
Zydus Discovery DMCC 
Unit No 909, Armada 2 
Plot No: JLT-PH2-P2A,  
Jumeriah Lakes Towers 
Dubai UAE 
P.O Box 113536 
Name of the Test Product 
Saroglitazar Tablet 
 
 
Name of Active Ingredient of Test Product 
Saroglitazar Magnesium 2 mg and 4 mg  
Name of the Reference Drug 
Placebo tablet 
Name of Active Ingredient of Reference Product 
Placebo 
Potential Indication 
Primary Biliary Cholangitis 
Study Subjects 
Patients with Primary Biliary Cholangitis 
Clinical Phase 
Phase 2 
Trial Number 
SARO.16.004 
Treatment Duration 
16 weeks double-blind treatment  
Planned Study Period 
20 weeks 
Study Title: A Phase 2, Prospective, Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate Safety, Tolerability and Efficacy of Saroglitazar Magnesium in Patients with 
Primary Biliary Cholangitis 
Background: 
Primary Biliary Cholangitis (PBC; previously referred to as “Primary Biliary Cirrhosis”) is a 
chronic progressive, autoimmune cholestatic disease that mainly affects middle-aged women. It is 
characterized by progressive inflammatory destruction of the intrahepatic small and medium-size 
bile ducts and resulting in bile duct destruction, ductopenia and portal fibrosis that progresses 
slowly to biliary cirrhosis and subsequent liver failure. Fatigue (65% to 85% of patients) and 
pruritus (25 – 70% of patients) are the two common symptoms and have a major impact on quality 
of life (QoL) in patients with PBC. Additionally hyperlipidemia occurs in up to 85% of patients, and 
could even be the initial serum abnormality in PBC. 
 
The etiology and exact pathogenesis of PBC are still not clear, and proposed to be related to a 
combination of genetic factors, viral and bacterial infections, autoantibodies to mitochondrial 
antigens, and/ or environmental factors. At present ursodeoxycholic acid (UDCA) is the first line 
therapeautic agent and obeticholic acid (OCA) is the second line agent for UDCA intolerant or 
unresponsive. However, OCA is associated with dose-related worsening in pruritus. In the POISE 
trial, pruritus occurred more frequently in the OCA-treated groups relative to placebo, with 38%, 
56%, and 68% of patients experiencing pruritus in the placebo, 5-10 mg, and 10 mg groups, 
respectively. Adverse changes in lipid levels, mostly due to reductions in high-density lipoprotein 
(HDL), were also common in all OCA-treated patients.  
 
It has been reported that patients treated with UDCA monotherapy also have a suboptimal response 
in endpoints (alkaline phosphatase [ALP], alanine aminotransferase [ALT], or immunoglobulin 

 
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[Ig]M), and some of patients will subsequently die or require liver transplantation, thus indicating a 
clear need for additional therapies. 
 
Ligand-activated peroxisome proliferator-activated receptor alpha (PPARα) contributes to a range of 
actions including cholesterol and bile acid homeostasis. PPARα primarily downregulates BA 
synthesis through inhibition of the BA-synthesizing enzymes, cytochrome P450 cholesterol 7A1-
hydroxylase (CYP7A1). PPARα is the molecular target of fibrates and improvements in liver 
enzymes and lipid profiles have been reported with their use. Fenofibrate has been evaluated for 
cholestatic liver diseases. A recent study reported significantly higher decompensation-free and 
transplant-free survival in patients treated with fenofibrate and UDCA when compared to UDCA 
alone. 
Saroglitazar, 
 
 
 
 
 it is a potent and predominant PPARα agonist with moderate PPARγ agonistic 
activity. Saroglitazar magnesium is the first glitazar granted marketing authorization in India and is 
indicated for treatment of diabetic dyslipidemia and hypertriglyceridemia with type 2 diabetes 
mellitus not controlled by statin therapy. 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. 
There is strong mechanistic rationale for studying Saroglitazar magnesium in PBC due to its α/γ 
agonist activity. Moreover, Saroglitazar magnesium also improved liver function biomarkers, i.e., 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and 
gamma-glutamyl transferase (GGT) in patients with nonalcoholic steatohepatitis (NASH). 
Therefore, this study is designed to evaluate safety, tolerability and efficacy of Saroglitazar 
magnesium 2 mg and 4 mg  in patients with PBC.  
Objectives - The purpose of this study is to evaluate the safety, tolerability, and efficacy of 
Saroglitazar magnesium in patients with PBC. 
Primary Objective: 
1. To investigate the effect of a 16-week treatment regimen of Saroglitazar magnesium 2 mg 
and 4 mg on ALP levels in patients with PBC. 
Secondary Objectives: 
1. To compare the effect of Saroglitazar magnesium (2 mg and 4 mg) and placebo on below 
mentioned parameters following a 16-week treatment: 
i. 
Alkaline Phosphatase 
ii. 
Lipids profile: TG, TC, HDL, LDL, and VLDL  

 
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iii. 
Liver biochemistries: GGT, ALT, AST, bilirubin and albumin. 
iv. 
Serum total bile acids 
v. 
7α-hydroxy-4-cholesten-3-one (C4) and  
vi. 
Fibroblast growth factor 19 (FGF19)  
2. Proportion of patients with ALP improvement. 
3. Quality of life (QoL) by using PBC-40. 
4. Safety and tolerability of Saroglitazar magnesium 2 mg and 4 mg. 
5. Pharmacokinetics of Saroglitazar. 
Criteria for Inclusion/Exclusion  
Inclusion criteria: 
1. Males or females, between 18 and 75 years of age, inclusive. 
2. a) Patients on therapeutic doses of Ursodeoxycholic acid (UDCA) for ≥12 months and 
stable therapy for ≥3 months prior to enrolment  
OR 
b) Patients who are unable to tolerate UDCA, and did not receive UDCA for at least 3 
months from the date of screening. 
3. History of confirmed Primary Biliary Cholangitis Diagnosis, based on American 
Association for the Study of Liver Disease [AASLD] and European Association for Study 
of the Liver [EASL] Practice Guidelines [Lindor 2009; EASL 2009], as demonstrated by 
the presence of at least ≥2 of the following 3 diagnostic factors: 
 
History of elevated ALP levels for at least 6 months at Screening Visit 1 
 
Positive antimitochondrial antibodies (AMA) titer or if AMA negative or in low 
titer (<1:80) PBC specific antibodies (anti-GP210 and/or anti-SP100 and/or 
antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid 
dehydrogenase complex]) 
 
Liver biopsy consistent with PBC. 
4. ALP ≥1.67x upper limit of normal (ULN) at Visit 1 and Visit 2 and with < 30% variance 
between the levels from Visit 1 to Visit 2. 

 
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5. Contraception: Female patients must be postmenopausal, surgically sterile, or if 
premenopausal, agree to use ≥ 1 effective method of contraception during the trial. 
Effective methods of contraception are considered to be hormonal (e.g., contraceptive pill, 
patch, intramuscular implant or injection); or double barrier method, i.e., (a) condom 
(male or female) or (b) diaphragm, with spermicide; or Intrauterine device (IUD); or 
Vasectomy (partner). 
6. Must provide written informed consent and agree to comply with the trial protocol. 
Exclusion criteria:  
1. Consumption of >3 units of alcohol per day (>21 units per week) if male and >2 units of 
alcohol per day (>14 units per week) if female for at least 3 consecutive months in the last 5 
years (Note: 1 unit = 12 ounces of beer, 4 ounces of wine or 1 ounce of spirits/hard liquor). 
2. History or presence of other concomitant liver diseases including: 
 
Hepatitis B or C virus (HCV, HBV) infection 
 
Primary sclerosing cholangitis (PSC) 
 
Alcoholic liver disease 
 
Definite autoimmune hepatitis (AIH) or overlap syndrome of AIH with PBC 
 
Non-alcoholic steatohepatitis (NASH). 
3. Cirrhosis with complications, including history or presence of: spontaneous bacterial 
peritonitis, hepatocellular carcinoma, bilirubin > 2x ULN, ascites, encephalopathy or 
variceal bleed, known esophageal varices or history of variceal bleeding and active or 
history of hepatorenal syndrome. 
4. History of any venous thromboembolism, TIA, intracranial hemorrhage, neoplasm, 
arteriovenous malformation, vasculitis, bleeding disorder, coagulation disorders or 
screening blood tests that indicate altered coagulability (e.g. platelet count, aPTT, PTT or 
TT tests). 
5. Patients with INR > ULN at visit 1. 
6.  Patients with total bilirubin > ULN at visit 1 that is not due to Gilbert’s syndrome. 
7. Patients with >30% increase in ALT, total bilirubin, or INR between visit 1 to visit 2, unless 
both results (visit 1 and visit 2) are within the reference range. 
8. Patients with serum creatinine >ULN according to the gender at Visit 1. 
9. Patients with abnormal total creatine kinase (CK) OR lipase OR amylase at Visit 1. 
10. Unstable cardiovascular disease, including: 
 
unstable angina, (i.e., new or worsening symptoms of coronary heart disease within 
the past 3 months), acute coronary syndrome within the past 6 months, acute 

 
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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 
 
history of (within prior 3 months) or current unstable cardiac dysrhythmias 
 
uncontrolled hypertension (systolic blood pressure [BP]>160 mmHg and/or 
diastolic BP >100 mmHg) 
 
stroke or transient ischemic attack within the prior 6 months 
11. History of malignancy in the past 5 years and/or active neoplasm with the exception of 
resolved superficial nonmelanoma skin cancer. 
12. Contraindications to Saroglitazar magnesium or has any conditions affecting the ability to 
evaluate the effects of Saroglitazar magnesium. 
13. Known allergy, sensitivity or intolerance to the study drug, comparator or formulation 
ingredients. 
14. Participation in any other clinical study within the previous 3 months of screening.,  
15. Illicit substance abuse within the past 6 months. 
16. History or other evidence of severe illness or any other conditions that would make the 
patient, in the opinion of the investigator, unsuitable for the study (such as poorly controlled 
psychiatric disease, HIV, coronary artery disease or active gastrointestinal conditions that 
might interfere with drug absorption). 
Methodology: 
This is a Phase 2 prospective, multicenter, randomized, double-blind, placebo-controlled study 
planned to enroll a total of 36 patients from  ~10-12 sites with a diagnosis of PBC who meet the 
study’s inclusion/exlcusion criteria. The study will be conducted over a period of up to 26 weeks 
and will include a 6-week Screening Phase, a 16-week double-blind Treatment Phase and a safety 
follow-up visit after 4 weeks. Six patients in each group are planned for pharmacokinetic 
assessment therefore a total of 18 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. 
 
Screening Phase 
 
Visit 1 (Day -42): Patient eligibility for participation in the study will be assessed. Medical 
history will be obtained and physical examination, electrocardiogram (ECG) and laboratory 
evaluations (including serology, [anti-nuclear antibody, smooth muscle antibody and serum 
immunoglobulin level G], clinical chemistry, hematology, liver biochemistries, and urinalysis) 
will be performed. In patients with ANA or SMA antibody positive titers, a liver biopsy must 
have been performed to rule out autoimmune hepatitis or overlap syndrome. Female patients 
will undergo a pregnancy test. Serum ALP must be ≥1.67 upper limit of normal (ULN) to 

 
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Protocol No. SARO.16.004 
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proceed further in the study. 
 
Visit 2 (Day -14 to -7): Liver biochemistries (ALT, ALP, total bilirubin (TB) and INR will be 
re-measured approximately 4 weeks from Day -42 to determine eligibility.  
Elevated ALP must be ≥1.67 ULN on 2 occasions in the Screening Phase and is necessary for 
study entry. If there is an increase of more than 30% in the levels of ALT, total bilirubin or 
INR at Day (-14) to Day (-7) [Visit 2] as compared to the values on Day (-42) [Visit 1], then 
such patients will not be eligible for study entry. 
The average of two assessments (Visit 1 and Visit 2) of liver biochemistries and INR will be 
considered as baseline values for these parameters. 
Randomization & Treatment Phase  
 
Visit 3: The Randomization & Treatment Phase will include 6 outpatient visits over a period 
of 16 weeks, including the randomization visit. Patients will be randomly assigned to receive 
either Saroglitazar magnesium ( 2 mg or 4 mg) or placebo orally once daily in addition to their 
ongoing treatment with UDCA (Patients unable to tolerate UDCA will receive only the 
investigational medicinal products), starting on Day 1 and contuining for 16 weeks. Efficacy 
and safety parameters will be assessed during each study visit as per the Schedule Visit Table. 
 
Visit 3.1: Patient will visit study site at 2 weeks after randomization visit for LFTs. The LFTs 
will be performed at local laboratory. 
 
Visits 4, 5 and 6: Patients will visit the study site at Week 4 (Visit 4), Week 8 (Visit 5) and 
Week 12 (Visit 6) for clinical assessment, dispensation and reconciliation of study drug, and 
measurements of efficacy endpoints.  
 
End-of-treatment Visit (Visit 7): An End-of-double-blind treatment will occur at Week 16 
and considered as End of Treatment visit. The clinical assessment, reconciliation of study 
drug, and measurements of efficacy and safety endpoints will be performed as per the study 
schedule. 
 
Safety Follow-up Visit (Visit 8): A final post-treatment visit will occur 4 weeks (±3 days) 
after the End-of-treatment Visit for safety monitoring. A clinical examination and safety lab 
assessment will be performed during this visit. 
Patient withdrawal 
In the event a patient is withdrawn from the study prematurely for any reason, the End of 
Treatment Visit procedures should be followed.   
The Investigator may withdraw a subject from the study for any of the following reasons: 
1. Subject who reports AE and if considered in Investigator’s/Medical Expert’s opinion 

 
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that it is not in the subject’s best interest to continue. 
2. Any subject found to have entered the study in violation of this protocol.  
3. Subject’s lack of compliance to the study protocol.  
4. Any subject who wishes to withdraw his / her consent for participation in the study.  
5. In case a subject becomes pregnant, then she will be withdrawn from the trial. 
6. Any subject who requires the use of unacceptable concomitant medications as 
mentioned in exclusion criteria and restrictions. 
7. Termination of study by sponsor, IRB/IEC, or the regulatory authority. 
Discontinuation of Subject Investigational Product (IP) 
Patients with worsening liver function will not be enrolled in the study. Evidence of worsening liver 
function will be assessed based on the 2 initial laboratory values used to establish the baseline.  
Elevations in ALT and/or AST, occurring after the initiation of study drug, that meet the definition 
of a potential Case of Drug-Induced Liver Injury per below; 
1. If patients with abnormal baseline liver indices develop elevations of AST or ALT 
greater than 2x baseline or total bilirubin greater than 1.5x baseline values while on 
study, testing shall be repeated within 48 -72 hours.  
2. If there are persistent elevations in ALT or AST greater than 2x baseline or TBL greater 
than 1.5x baseline values, then close observation (testing and physical examination 2-3 
times per week) shall be initiated or study drug will be discontinued 
 
A decision to discontinue or temporarily interrupt the study drug will 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. Study drug will be discontinued or 
temporarily interrupted:  
a. When the baseline values were < 2x ULN, discontinue if ALT or AST 
increases to > 5x baseline, 
b. When the baseline values were ≥ 2x ULN but < 5x ULN, discontinue if ALT 
or AST increases to >3x baseline, 
c. When the baseline values were ≥ 5x ULN, discontinue if ALT or AST 
increases to > 2x baseline, 
d. Discontinue if ALT or AST increase > 2x baseline AND the increase is 

 
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accompanied by a concomitant TBL increase to >2x baseline OR the INR 
concomitantly increases by >0.2, 
e. In any patients with signs and symptoms of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
 
If a patient lives in a remote area, laboratory testing can be performed locally and 
the results shall be promptly communicated to the investigator site promptly. 
 
If patient develops an adverse event of grade 3 that is probably or possibly related 
to study drug and any patient regardless of attribution to drug who develops a grade 
4 or higher Common Terminology Criteria for Adverse Event (CTCAE version 
4.03). 
 
Parameters of renal function: IP is to be discontinued if the estimated glomerular 
filtration rate (eGFR) falls to <60 mL/min/1.73m2 (calculated using Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) equation) and where the value is 
reconfirmed after 24 hrs repeat. Additionally, any subject who requires renal 
replacement therapy will also have IP discontinued. 
 
Patient will be immediately discontinued from study drug and followed until 
resolution of adverse event and laboratory values have returned to baseline, if any 
of the following ceriteria occur.  
a. TB ≥3.0 mg/dL in individuals with normal baseline TB. In individuals with 
elevated baseline TB due to known Gilbert’s syndrome, doubling of direct 
bilirubin will prompt immediate discontinuation of the study drug. 
b. Total CK > 5x ULN 
c. Amylase and lipase > ULN 
d. Hemoglobin < 100 g/L or HCT <30% 
e. Platelets < 100000/µL 
f. WBC <3.5 X 109/L 
g. if more than 3 patients develop a CTCAE grade 3 or higher in the same 
category, or if 3 or more patients meet the above individual criteria (a to f) 
the trial may be stopped and/ or unblinded safety data will be evaluated  
Excluded concomitant medications: Patients are not permitted to take thiazolidinedione 
(pioglitazone, rosiglitazone), chemotherapy, or other investigational medications during the study. 
Patients should not take any over-the-counter medications or complementary and/or alternative 
medications without prior consultation of the Investigator. 

 
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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 before study 
entry. Statins are permitted as concomitant medications; however, patients will be monitored for 
statin related toxicity when it is co-administered. Glycemic control medications will be permitted as 
concomitant medications, including antidiabetic drugs such as metformin, sulfonylureas, dipeptidyl 
peptidase 4 (DPP-4) inhibitors and insulin. Patients must continue with their current drug regimen 
without any change in dosage. 
Treatment for common illness during the study may be allowed.  
Total Enrolment: 
A total of 36 patients will be enrolled in a 1:1:1 ratio (12 patients in 
each arm i.e. Saroglitazar magnesium 2 mg, Saroglitazar 
magnesium 4 mg and placebo). 
Six patients in each group are planned for pharmacokinetic 
assessment therefore a total of 18 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. Additional patients will be enrolled 
if the dropout rate is more than 20%. 
Test Product: 
Dose: 
Mode of Administration: 
Saroglitazar magnesium 
2 mg and 4 mg 
Oral (once daily) 
Reference Therapy: 
Dose: 
Mode of Administration: 
Placebo (provided by sponsor) 
Matching placebo 
Oral (once daily) 
Duration of Treatment:  
16-week double-blind placebo-controlled treatment period 
Criteria for Efficacy 
Primary Efficacy Endpoint 
1. Improvement in ALP levels after 16 weeks of Saroglitazar magnesium 2 mg and 4 mg 
treatment. 
Secondary Efficacy Endpoints 
1. To compare the effect of Saroglitazar magnesium (2 mg and 4 mg) and placebo on below 
mentioned parameters following a 16-week treatment: 
i. 
Change from baseline in ALP at Week 4, Week 8, Week 12 and Week 16 in 
Saroglitazar magnesium as compared to Placebo. 
ii. 
Change from baseline in lipid profile (TG, TC, HDL, LDL, and VLDL) at Week 4, 
Week 8, Week 12 and Week 16 in Saroglitazar magnesium as compared to Placebo. 
iii. 
Change from baseline in liver biochemistries (GGT, ALT, AST, Bilirubin and 

 
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albumin) at Week 4, Week 8, Week 12 and Week 16 in Saroglitazar magnesium as 
compared to Placebo. 
iv. 
Change from baseline in serum total bile acids at Week 4, Week 8, Week 12 and 
Week 16 in Saroglitazar as compared to Placebo. 
v. 
Change from baseline in 7α-hydroxy-4-cholesten-3-one (C4) at Week 16 in 
Saroglitazar as compared to Placebo. 
vi. 
Change from baseline in fibroblast growth factor 19 (FGF 19) at Week 16 in 
Saroglitazar as compared to Placebo. 
2. Proportion of patients with ALP improvement, i.e. 15%, 20%, 30%, 40% and normalization 
at Week 8 and Week 16. 
3. Change in QoL at Week 16 by using PBC-40. 
4. Change from baseline in ALP in patients who are unable to tolerate UDCA at week 16 in 
Saroglitazar 2 mg and 4 mg as compared to Placebo. 
5. Safety and tolerability of Saroglitazar magnesium 2 mg and 4 mg.  
6. Pharmacokinetics of Saroglitazar. 
Pharmacokinetics of Saroglitazar will be performed in patients with PBC. The samples will be 
collected at Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0 and 24 hours post-dose on Visit 3 
and Visit 7. In addition, pre-dose sample will be collected at Visits 4, 5, and 6. 
The following pharmacokinetic parameters will be evaluated: 
i. 
Peak Plasma concentration (Cmax) 
ii. 
Time to reach peak Plasma concentration (Tmax) 
iii. 
Area under Plasma concentration vs. time curve till the last time point (AUC0-t) 
iv. 
Area under Plasma concentration vs. time curve extrapolated to the infinity (AUC0-∞) after 
first dose 
v. 
Area under plasma concentration vs. time curve in a 24 h dosing interval (AUCtau) 
vi. 
Elimination rate constant (λz) 
vii. 
Elimination half-life (t1/2) 
viii. 
Apparent Volume of distribution (Vd/F) 
ix. 
Apparent Clearance (CL/F) 
x. 
Minimal or Trough plasma concentration (Cmin) -for last dose only  
xi. 
Accumulation index calculated as a ratio of AUCtau (last dose)/AUCtau (first dose) 

 
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xii. 
Fluctuation index. 
Criteria for Safety 
 
Frequency and severity of adverse events  
 
Clinical laboratory testing (hematology, clinical chemistry and urinalysis) 
 
Twelve-lead electrocardiogram (ECG) 
 
Vital signs 
 
Body weight and height (at screening) 
 
Physical examination 
Statistical Methods: 
Statistical Analysis Plan (SAP) will be prepared and finalized prior to database lock. The SAP will 
include detailed statistical aspects of the efficacy and safety analysis. Statistical analysis will be 
performed using SAS® software (version 9.4 or higher) (SAS Institute Inc., USA).  
Demographic characteristics and Baseline Characteristics will be summarized by treatment, subject 
disposition, reasons for withdrawal or by any other variables as appropriate. Unless otherwise 
stated, all the continuous variables will be represented by n, mean, standard deviation, minimum, 
median and maximum. All the categorical variables will be presented as counts and percentages. 
Efficacy Analysis:  
Modified intent-to-treat (MITT) and Per Protocol (PP) analysis will be carried out for the study trial. 
All efficacy analyses will be based primarily on the MITT, and analyses based on the Per Protocol 
(PP) analysis will be secondary to this.  
The MITT population will consist of all patients who have been randomized, taken at least 1 dose of 
the study treatment and have provided efficacy data for at least 1 post baseline evaluation. Missing 
values will be imputed by carrying forward the last observation value after baseline. 
The PP analysis population will consist of all patients who have completed the treatment phase and 
have not deviated from or violated the protocol in such a way that could affect efficacy outcome. 
Primary Efficacy Analysis:  
 
The primary analysis for the primary efficacy endpoint will be based on the MITT. The primary 
efficacy endpoint in this study is improvement in ALP levels after 16 weeks of Saroglitazar 
magnesium treatment.  
The primary endpoint will be summarized and improvement from baseline to week 16 will be 

 
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evaluated using Paired t-Test. Statistical significance will be defined as a p-value <0.05. 
Secondary Efficacy Analysis:  
Each secondary efficacy endpoint will be summarized by treatment group at each visit, as 
appropriate. 
Endpoints such as change from baseline in ALP at Week 4, Week 8, Week 12 and Week 16 in 
Saroglitazar magnesium groups as compared to placebo; change from baseline in lipid profile (TG, 
TC, HDL, LDL, and VLDL) at Week 4, Week 8, Week 12 and Week 16 in Saroglitazar magnesium 
as compared to placebo; change from baseline in liver biochemistries (GGT, ALT, AST, Bilirubin 
and albumin) at Week 4, Week 8, Week 12 and Week 16 change from baseline in serum total bile 
acids at Week 4, Week 8, Week 12 and Week 16 in Saroglitazar magnesium as compared to 
placebo; change from baseline in C4 and FGF 19 at week 16; and change in QoL (PBC40) at Week 
16 will be analyzed using ANCOVA model. Treatment effects will be estimated using the least-
square mean, standard error and 95% confidence intervals from ANCOVA model with baseline 
value as covariate. Comparison will be performed for Saroglitazar magnesium groups (i.e., 2 mg 
and 4 mg) and placebo using the difference in least-square means from the ANCOVA model. 
Proportion of patients with ALP improvement, i.e. 15%, 20%, 30%, 40% and normalization at 
Week 8 and Week 16 will be presented as counts and percentages. 
Descriptive statistics will be provided for each pharmacokinetic parameter. 
These analyses will also be supported by simple summaries (n, mean, standard deviation, median, 
minimum and maximum) at each visit. 
Safety Analysis:  
Safety analyses will be based on the Safety population which will consist of all patients who are 
known to have received at least 1 dose of study treatment, with patients grouped according to the 
actual treatment received.  
All safety endpoints (AEs, clinical laboratory testing, ECG, 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, and patient 
counts and percentages for categorical variables. 
 

 
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ABBREVIATIONS 
Abbreviation 
Definition 
AASLD 
American Association for the Study of Liver Disease 
ADRs 
Adverse drug reactions 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AMA 
Antimitochondrial antibodies 
ANA 
Anti-nuclear antibody 
ANCOVA 
Analysis of Co-variance 
API 
Active pharmaceutical ingredient 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase  
BMI 
Body mass index 
BP 
Blood pressure 
C4 
7α-hydroxy-4-cholesten-3-one 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CAP 
College of American Pathologist 
CFR 
Code of Federal Regulation 
CRA 
Clinical research associate 
CRF 
Case report form 
CRO 
Contract research organisation 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum serum concentration 
CSR 
Clinical Study Report 
CYP 
Cytochrome  
DPP-4 
Dipeptidyl peptidase 4 
EASL 
European Association for study of the Liver 
ECG 
Electrocardiogram 
ECI 
Events of clinical interest 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EDC 
Electronic data capture 
EPICS 
Evaluation in primary biliary cholangitis with Saroglitazar magnesium 
FGF 19 
Fibroblast growth factor 19 
FPG 
Fasting plasma glucose 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyltransferase 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 

 
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Abbreviation 
Definition 
HDL 
High density lipoprotein 
HIV 
Human Immunodeficiency Virus 
ICH 
International Council for Harmonisation 
ICF 
Informed consent form 
IEC 
Independent Ethics Committee 
[Ig]M 
Immunoglobulin M 
IP 
Investigational product  
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
LDL 
Low density lipoprotein 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent-to-treat 
NASH 
Non-alcoholic steatohepatitis 
PBC 
Primary Biliary Cholangitis 
PP 
Per-protocol 
PPAR 
Peroxisome proliferator-activated receptors 
PSC 
Primary sclerosing cholangitis 
QID 
Quater in die  
QoL 
Quality of life 
SAE 
Serious adverse event 
SAS 
Statistical Analysis System 
SDs 
Source documents 
SMA 
Smooth muscle antibody 
SOPs 
Standard operating procedures 
T2DM 
Type 2 diabetes mellitus 
TBL 
Total bilirubin 
TG-C 
Triglyceride-cholesterol 
TIA 
Transient ischemic attack 
TT 
Thrombin time 
TZD 
Thiazolidinedione 
UDCA 
Ursodeoxycholic acid 
USFDA 
United State of Food and Drug Administration 
ULN 
Upper limit of normal 
VLDL 
Very low density lipoprotein 
WHO 
World Health Organisation 
ZYDUS 
Zydus Discovery DMCC 
 
 
 
 
 

 
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TABLE OF CONTENTS 
Contents 
STUDY PROTOCOL SUMMARY ........................................................................................ 3 
ABBREVIATIONS ................................................................................................................. 15 
TABLE OF CONTENTS ....................................................................................................... 17 
1 
STUDY FLOW CHART .............................................................................................. 20 
2 
INTRODUCTION ......................................................................................................... 25 
2.1 
MEDICAL BACKGROUND ........................................................................... 25 
2.2 
RATIONALE FOR CONDUCTING THE TRIAL ....................................... 25 
2.3 
DRUG PROFILE .............................................................................................. 28 
2.4 
RISK AND BENEFIT ....................................................................................... 29 
3 
STUDY OBJECTIVES ................................................................................................. 30 
3.1 
PRIMARY OBJECTIVES ............................................................................... 30 
3.2 
SECONDARY OBJECTIVES ......................................................................... 30 
3.3 
SAFETY ASSESSMENT ................................................................................. 30 
4 
STUDY POPULATION ............................................................................................... 32 
4.1 
NUMBER OF SUBJECTS PLANNED ........................................................... 32 
4.2 
INCLUSION CRITERIA ................................................................................. 32 
4.3 
EXCLUSION CRITERIA ................................................................................ 33 
4.4 
WITHDRAWAL CRITERIA .......................................................................... 35 
4.4.1 
Discontinuation of Subject Investigational Product (IP) ................ 35 
4.5 
HANDLING OF PATIENT WITHDRAWAL ............................................... 37 
5 
STUDY TREATMENTS / IP MANAGEMENT ........................................................ 38 
5.1 
TREATMENTS TO BE COMPARED ........................................................... 38 
5.1.1 
Investigational Product Description ................................................. 38 
5.1.2 
Comparator Drug Description .......................................................... 39 
5.2 
DOSAGE AND TREATMENT SCHEDULE ................................................ 39 
5.3 
PACKAGING, LABELLING AND RE-SUPPLY ......................................... 40 
5.4 
STORAGE CONDITIONS .............................................................................. 41 
5.5 
BLINDING / UNBLINDING ........................................................................... 41 
5.6 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ......... 42 
5.7 
SELECTION OF DOSES ................................................................................. 42 
5.8 
CONCOMITANT THERAPY ......................................................................... 43 
5.9 
RESCUE MEDICATION AND ADDITIONAL TREATMENT(S) ............ 43 
5.10 
RESTRICTIONS .............................................................................................. 44 
5.11 
OVER DOSE AND DRUG INTERACTION ................................................. 44 

 
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5.12 
TREATMENT COMPLIANCE ...................................................................... 45 
6 
OBSERVATIONS ......................................................................................................... 46 
6.1 
EFFICACY ........................................................................................................ 46 
6.1.1 
Primary Endpoint ............................................................................... 46 
6.1.2 
Secondary Endpoints .......................................................................... 46 
6.2 
SAFETY ............................................................................................................. 47 
6.2.1 
Appropriateness of Measurement ..................................................... 48 
6.2.2 
Abnormal Laboratory Findings ........................................................ 49 
7 
INVESTIGATIONAL PLAN ....................................................................................... 50 
7.1 
STUDY DESIGN AND PLAN ......................................................................... 50 
7.2 
STUDY PROCEDURES AT EACH VISIT .................................................... 51 
7.3 
PHARMACOKINETIC ASESSMENT .......................................................... 54 
7.4 
ADHERENCE TO PROTOCOL .................................................................... 54 
7.5 
PROTOCOL DEVIATIONS ........................................................................... 54 
7.6 
DATA MONITORING COMMITTEE .......................................................... 55 
8 
BIOSTATISTICS .......................................................................................................... 56 
8.1 
STATISTICAL DESIGN ................................................................................. 56 
8.2 
NULL AND ALTERNATIVE HYPOTHESIS ............................................... 56 
8.3 
STUDY POPULATION AND PLANNED ANALYSIS ................................ 56 
8.3.1 
Populations .......................................................................................... 56 
8.3.2 
Planned Analysis ................................................................................. 57 
8.3.3 
Safety Analysis .................................................................................... 59 
8.3.4 
Baseline Characteristics ..................................................................... 60 
8.3.5 
Interim Analysis .................................................................................. 60 
8.3.6 
Handling of Missing Data .................................................................. 60 
8.4 
RANDOMIZATION ......................................................................................... 60 
8.5 
DETERMINATION OF SAMPLE SIZE ....................................................... 61 
9 
ADMINISTRATIVE MATTERS ................................................................................ 62 
9.1 
ETHICS .............................................................................................................. 62 
9.1.1 
Institutional Committee Review and Communications .................. 62 
9.1.2 
Informed Consent and Subject Information .................................... 62 
9.2 
DATA MANAGEMENT AND RECORDKEEPING .................................... 63 
9.2.1 
Drug Accountability ........................................................................... 63 
9.2.2 
Patient Card ........................................................................................ 64 
9.2.3 
Data Management ............................................................................... 64 
9.2.4 
Source documents ............................................................................... 65 
9.2.5 
Direct access to source data / documents .......................................... 66 
9.2.6 
Trial Monitoring ................................................................................. 66 
9.3 
QUALITY ASSURANCE AUDIT ................................................................... 67 
9.4 
PROCEDURES ................................................................................................. 67 

 
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9.4.1 
Adverse Events .................................................................................... 67 
9.4.2 
Serious Adverse Event ........................................................................ 68 
9.4.3 
Evaluating Adverse Events ................................................................ 69 
9.4.4 
Events of Clinical Interest .................................................................. 72 
9.4.5 
Expected Adverse Events ................................................................... 72 
9.4.6 
Pregnancy ............................................................................................ 72 
9.5 
RULES FOR AMENDING PROTOCOL ...................................................... 73 
9.6 
FINANCIAL DISCLOSURE ........................................................................... 73 
9.7 
DISCONTINUATION OF THE TRIAL BY THE SPONSOR .................... 73 
9.8 
STATEMENT OF CONFIDENTIALITY ...................................................... 74 
9.9 
FINAL REPORT AND PUBLICATION POLICY ....................................... 74 
9.10 
ARCHIVING ..................................................................................................... 74 
10 
REFERENCES .............................................................................................................. 76 
11 
APPENDICES ............................................................................................................... 79 
12 
SIGNATURE PAGE(S) ................................................................................................ 80 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1 STUDY FLOW CHART 
 
 
 
 
 
 
 
 

 
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2 INTRODUCTION 
2.1 
MEDICAL BACKGROUND 
Primary biliary Cholangitis (PBC) previously referred as “Primary biliary cirrhosis (PBC)” 
is a chronic progressive inflammatory autoimmune mediated cholestatic disease that mainly 
affects middle age women and is characterized by progressive inflammatory destruction of 
the interlobular bile duct, and the subsequent development of liver fibrosis and cirrhosis, 
eventually leading to liver failure (Ulrich et al., 2015; Keith et al., 2009; EASL 2009). 
Fatigue (65% to 85% of patients) and pruritus (25 – 70% of patients) are the most prevalent 
symptoms and have a major impact on quality of life (QoL). Additionally Hyperlipidaemia 
arises in up to 85% of patients, and could be the initial serum abnormality in PBC (Jayant 
and Keith, 2003). 
The etiology and exact pathogenesis of PBC are still not clear, and proposed to be related 
with genetic factors, viral and bacterial infections, autoimmune status, and environmental 
factors. At present ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are approved 
therapeutic options for the treatment of PBC. But, up to 40% of UDCA-treated patients have 
an inadequate biochemical response, depending on the criteria used, and such patients have 
significantly worse transplant-free survival rates than UDCA-responsive patients (Gideon et 
al., 2015). Recently, OCA has been approved for use in PBC patients who are UDCA 
unresponsive or intolerant. However, OCA is associated with an increase in pruritus and its 
tolerability may be sub-optimal in the real world. In the POISE trial, pruritus occurred more 
frequently in the OCA-treated groups relative to placebo, with 38%, 56%, and 68% of 
patients experiencing pruritus in the placebo, 5-10 mg, and 10 mg groups, respectively. 
Adverse changes in lipid levels, mostly due to reductions in high-density lipoprotein (HDL), 
were also common in all OCA-treated patients. Although, it is unclear if these changes by 
themselves are of any clinical significance (Nevens etal., 2014), the presence of additional 
risk factors such as smoking and family history of cardiovascular disease is of concern. 
2.2 
RATIONALE FOR CONDUCTING THE TRIAL 
A growing body of literature supports the notion that nuclear receptors are critically involved 
in the regulation of hepatic bile salt secretion and bile formation. In particular, PPARα which 

 
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is highly expressed in liver, muscle, kidney and heart regulates the transcription of several 
genes involved in lipid metabolism, cholesterol and bile acid homeostasis through inhibition 
of cytochrome P450 cholesterol 7A1-hydroxylase (CYP7A1), the rate limiting step in bile 
acid synthesis. 
PPARα is the molecular target for the fibrate hypolipidemic agents, including fenofibrate, 
gemfibrozil and clofibrate, which are FDA-approved for the treatment of dylipidemia, 
though each fibrate differs in its specificity for the different PPAR subtypes, α, β/δand γ. 
Fibrates were first noted to reduce hepatic alkaline phosphatase (ALP) isoenzyme levels 
during their development as cholesterol-lowering agents in the 1970s (Zumoff 1977). Since 
then, case reports and pilot studies demonstrated the efficacy of bezafibrate and fenofibrate 
in reducing the biomarkers of cholestatis and liver test abnormalities (Ghonem et al., 2015). 
A recent study reported significantly higher decompensation-free and transplant-free 
survival in patients treated with fenofibrate and UDCA when compared to UDCA alone 
(Cheung et al., 2016). 
Saroglitazar magnesium 
), a dual PPAR agonist with predominantly PPARα and a 
moderate PPARγ agonist, is approved in India at the doses of 2 mg and 4 mg QD for the 
treatment of “diabetic dyslipidemia” and “hypertriglyceridemia with type 2 diabetes mellitus 
(T2DM) not controlled by statin therapy”. Saroglitazar magnesium Phase 2 and 3 studies in 
patients with dyslipidemia with and without diabetes, and in patients with NASH 
demonstrated potential of favorably modulating the predicting markers of PBC (alkaline 
phosphate and Gamma-glutamyl transferase) in addition to its anti-hypertriglyceridemia 
activity. 
There is a strong mechanistic rationale for studying PPARα/γ agonist in PBC, therefore, this 
proof of concept placebo-controlled Phase 2 study is designed to evaluate the Safety, 
Tolerability and Efficacy of Saroglitazar magnesium (2 mg and 4 mg) in Patients with PBC. 
Pre-clinical Experience 
 
 
 

 
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Clinical Experience 
Maximum Tolerated Dose in Phase 1 was 16 mg/day for 10 days was found to be well 
tolerated. In Phase I trials in healthy human volunteers, Saroglitazar magnesium was found 
to be well tolerated in single[Jani et al., 2013] and multiple dose studies without any safety 
concern. Several Phase 2 study were conducted to evaluate the safety and efficacy of 
Saroglitazar magnesium in dyslipidemic subjects without diabetes, diabetes and subjects 
with impaired glucose tolerance test.  

 
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In dyslipidemic subjects with and without 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 TG-C, total cholesterol and FPG levels. 
Saroglitazar magnesium has been tested in Phase 2 for NASH at 4 mg dosage form and 
demonstrated statistically significant reduction of ALT levels compared to placebo which 
was measured as the primary endpoint. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3 
DRUG PROFILE 
 
 
 
 
 
 

 
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2.4 
RISK AND BENEFIT 
The safety and tolerability of Saroglitazar magnesium is well-established on the basis of 
pre-clinical and clinical studies (Phase 1 to Phase 3).This study will evaluate the safety and 
efficacy of Saroglitazar magnesium in Primary Biliary Cholangitis patients. The commonly 
reported adverse events (AEs) during clinical studies were gastritis, asthenia and pyrexia.  
Saroglitazar magnesium is approved in India at doses of 2 mg and 4 mg QD for the treatment 
of “diabetic dyslipidemia” and “hypertriglyceridemia with T2DM not controlled by statin 
therapy”.  
 

 
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3 STUDY OBJECTIVES 
The purpose of this study is to evaluate the safety, tolerability and efficacy of Saroglitazar 
magnesium in patients with Primary Biliary Cholangitis. 
3.1 
PRIMARY OBJECTIVES 
1. To investigate the effect of a 16-week treatment regimen of Saroglitazar 
magnesium 2 mg and 4 mg on ALP levels in patients with Primary Biliary 
Cholangitis. 
3.2 
SECONDARY OBJECTIVES 
1. To compare the effect of Saroglitazar magnesium (2 mg and 4 mg) and placebo 
on below mentioned parameters following a 16-week treatment: 
i. 
Alkaline Phosphatase 
ii. 
Lipids profile: TG, TC, HDL, LDL, and VLDL  
iii. 
Liver biochemistries: GGT, ALT, AST, bilirubin and albumin. 
iv. 
Serum total bile acids 
v. 
7α-hydroxy-4-cholesten-3-one (C4)  
vi. 
Fibroblast growth factor 19 (FGF19) 
2. Proportion of patients with ALP improvement. 
3. Quality of life by using (PBC40; Jacoby et al., 2005). 
4. Safety and tolerability of Saroglitazar magnesium 2 mg and 4 mg. 
5.  Pharmacokinetics of Saroglitazar. 
3.3 
SAFETY ASSESSMENT 
To assess the safety of Saroglitazar magnesium in the study population over the duration of 
study. 
 
Frequency and severity of adverse events  
 
Clinical laboratory testing (hematology, clinical chemistry and urinalysis) 
 
Twelve-lead electrocardiogram (ECG) 
 
Vital signs 

 
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 
Body weight and height (at screening) 
 
The physical examination will consist of an evaluation of the head, neck, eyes, ears, 
nose, throat, chest, heart, lungs, abdomen, skin, extremities, and the neurological 
and musculoskeletal systems. 

 
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4 STUDY POPULATION 
4.1 
NUMBER OF SUBJECTS PLANNED 
A total 36 subjects (including 20% dropout), will be enrolled on competitive basis at ~10-12 
sites in a ratio of 1:1:1 to have 12 subjects in each arm i.e., Saroglitazar magnesium 2 mg, 
Saroglitazar magnesium 4 mg and placebo. Six patients in each group are planned for 
pharmacokinetic assessment therefore a total of 18 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. Additional patients will be 
enrolled if the dropout rate is more than 20%.  
4.2 
INCLUSION CRITERIA 
1. Males or females, between 18 and 75 years of age, inclusive. 
2. a) Patients on therapeutic doses of Ursodeoxycholic acid (UDCA) for ≥12 months 
and stable therapy for ≥3 months prior to enrolment. 
OR 
b) Patients who are unable to tolerate UDCA, and did not receive UDCA for at 
least 3 months from the date of screening. 
3. History of confirmed Primary Biliary Cholangitis Diagnosis, based on American 
Association for the Study of Liver Disease [AASLD] and European Association 
for Study of the Liver [EASL] Practice Guidelines; [Lindor 2009; EASL 2009], 
as demonstrated by the presence of at least≥2 of the following 3 diagnostic 
factors: 
 History of elevated Alkaline Phosphatase levels for at least 6 months prior to 
Screening Visit 1 
 Positive antimitochondrial antibodies (AMA) titer or if AMA negative or in 
low titer (<1:80) PBC specific antibodies (anti-GP210 and/or anti-SP100 
and/or antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric 
acid dehydrogenase complex]) 
 Liver biopsy consistent with PBC. 

 
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4. ALP ≥1.67x upper limit of normal (ULN) at Visit 1 and Visit 2 and with < 30% 
variance between the levels from Visit 1 to Visit 2. 
5. Contraception: Female patients must be postmenopausal, surgically sterile, or if 
premenopausal, agree to use ≥ 1 effective method of contraception during the 
trial. Effective methods of contraception are considered to be Hormonal (e.g., 
contraceptive pill, patch, intramuscular implant or injection); or Double barrier 
method, i.e., (a) condom (male or female) or (b) diaphragm, with spermicide; or 
Intrauterine device (IUD); or Vasectomy (partner). 
6. Must provide written informed consent and agree to comply with the trial 
protocol. 
4.3 
EXCLUSION CRITERIA 
1. Consumption of >3 units of alcohol per day (>21 units per week) if male and 
>2 units of alcohol per day (>14 units per week) if female for at least 
3 consecutive months in the last 5 years (Note: 1 unit = 12 ounces of beer, 
4 ounces of wine or 1 ounce of spirits/hard liquor). 
2. History or presence of other concomitant liver diseases including: 
 Hepatitis B or C virus (HCV, HBV) infection 
 Primary sclerosing cholangitis (PSC) 
 Alcoholic liver disease 
 Definite autoimmune liver disease or overlap syndrome  
 Non-alcoholic steatohepatitis (NASH) 
3. Cirrhosis with complications, including history or presence of: spontaneous 
bacterial peritonitis, hepatocellular carcinoma, bilirubin > 2x ULN, ascites, 
encephalopathy, known esophageal varices or history of variceal bleeding and 
active or history of hepatorenal syndrome. 
4. History of any venous thromboembolism, TIA, intracranial hemorrhage, 
neoplasm, arteriovenous malformation, vasculitis, bleeding disorder, coagulation 
disorders or screening blood tests that indicate altered coagulability (e.g. platelet 
count, aPTT, PTT or TT tests). 
5.  Patients with INR > ULN at visit 1. 

 
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6.  Patients with total bilirubin > ULN at visit 1 that is not due to Gilbert’s 
syndrome. 
7. Patients with >30% increase in ALT, total bilirubin, or INR between Visit 1 to 
Visit 2, unless both results (visit 1 and visit 2) are within the reference range. 
8. Patients with serum creatinine >ULN according to the gender at Visit 1. 
9. Patients with abnormal total creatine kinase (CK) OR lipase OR amylase at Visit 
1. 
10. Unstable cardiovascular disease, including: 
 unstable angina, (i.e., new or worsening symptoms of coronary heart disease 
within the past 3 months), acute coronary syndrome within the past 6 months, 
acute myocardial infarction in the past 3 months or heart failure of New York 
Heart Association class (III – IV) or worsening congestive heart failure, or 
coronary artery intervention, within the past 6 months 
 history of (within prior 3 months) or current unstable cardiac dysrhythmias  
 uncontrolled hypertension (systolic blood pressure [BP] >160 mmHg and/or 
diastolic BP >100 mmHg) 
 stroke or transient ischemic attack within the prior 6 months 
11. History of malignancy in the past 5 years and/or active neoplasm with the 
exception of resolved superficial nonmelanoma skin cancer. 
12. Contraindications to Saroglitazar magnesium or has any conditions affecting the 
ability to evaluate the effects of Saroglitazar magnesium.  
13. Known allergy, sensitivity or intolerance to the study drug, comparator or 
formulation ingredients. 
14. Participation in any other clinical study within the previous 3 months of 
screening. 
15. Illicit substance abuse within the past 6 months. 
16. History or other evidence of severe illness or any other conditions that would 
make the patient, in the opinion of the investigator, unsuitable for the study (such 
as poorly controlled psychiatric disease, human immunodeficiency virus (HIV), 
coronary artery disease or active gastrointestinal conditions that might interfere 
with drug absorption). 

 
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4.4 
WITHDRAWAL CRITERIA 
The Investigator may withdraw a subject from the study for any of the following: 
1. Subject who reports AE and if considered in Investigator’s/Medical Expert’s 
opinion that it is not in the subject’s best interest to continue. 
2. Any subject found to have entered the study in violation of this protocol.  
3. Subject’s lack of compliance to the study protocol.  
4. Any subject who wishes to withdraw his / her consent for participation in the 
study.  
5. In case a subject becomes pregnant, then she will be withdrawn from the trial. 
6. Any subject who requires the use of unacceptable concomitant medications as 
mentioned in exclusion criteria (Section 4.3) and restrictions (Section 5.10). 
7. Termination of study by sponsor, IRB/IEC, or the regulatory authority. 
4.4.1 Discontinuation of Subject Investigational Product (IP) 
Patients with worsening liver function will not be enrolled in the study. Evidence of 
worsening liver function will be assessed based on the 2 initial laboratory values used to 
establish the baseline.  
Elevations in ALT and/or AST, occurring after the initiation of study drug, that meet the 
definition of a potential Case of Drug-Induced Liver Injury per below; 
1. If patients with abnormal baseline liver indices develop elevations of AST or 
ALT greater than 2x baseline or total bilirubin greater than 1.5x baseline values 
while on study, testing shall be repeated within 48 -72 hours.  
2. If there are persistent elevations in ALT or AST greater than 2x baseline or TBL 
greater than 1.5x baseline values, then close observation (testing and physical 
examination 2-3 times per week) shall be initiated or study drug will be 
discontinued 
 A decision to discontinue or temporarily interrupt the study drug will 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 

 
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whether there is concomitant elevation of bilirubin or INR. Study drug will be 
discontinued or temporarily interrupted:  
a. When the baseline values were < 2x ULN, discontinue if ALT or AST 
increases to > 5x baseline, 
b. When the baseline values were ≥ 2x ULN but < 5x ULN, discontinue if 
ALT or AST increases to >3x baseline, 
c. When the baseline values were ≥ 5x ULN, discontinue if ALT or AST 
increases to > 2x baseline, 
d. Discontinue if ALT or AST increase > 2x baseline AND the increase is 
accompanied by a concomitant TBL increase to >2x baseline OR the INR 
concomitantly increases by >0.2, 
e. In any patients with signs and symptoms of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 
5%). 
 If a patient lives in a remote area, laboratory testing can be performed locally and 
the results shall be promptly communicated to the investigator site promptly. 
 If patient develops an adverse event of grade 3 that is probably or possibly related 
to study drug and any patient regardless of attribution to drug who develops a 
grade 4 or higher Common Terminology Criteria for Adverse Event (CTCAE 
version 4.03). 
 Parameters of renal function: IP is to be discontinued if the estimated glomerular 
filtration rate (eGFR) falls to <60 mL/min/1.73m2 (calculated using Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation) and where the 
value is reconfirmed after 24 hrs repeat. Additionally, any subject who requires 
renal replacement therapy will also have IP discontinued. 
 Patient will be immediately discontinued from study drug and followed until 
resolution of adverse event and laboratory values have returned to baseline, if any 
of the following criteria occur.  

 
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a. TB ≥3.0 mg/dL in individuals with normal baseline TB. In individuals 
with elevated baseline TB due to known Gilbert’s syndrome, doubling of 
direct bilirubin will prompt immediate discontinuation of the study drug. 
b. Total CK > 5x ULN 
c. Amylase and lipase > ULN 
d. Hemoglobin < 100 g/L or HCT <30% 
e. Platelets < 100000/µL 
f. WBC <3.5 X 109/L 
g. If more than 3 patients develop a CTCAE grade 3 or higher in the same 
category, or if 3 or more patients meet the above individual criteria (a to f) 
the trial may be stopped and/or unblended safety data will be evaluated.  
4.5 
HANDLING OF PATIENT WITHDRAWAL 
In case of withdrawal of consent, and unless otherwise stated by the patient in the informed 
consent form, Investigators will be encouraged to get information from the medical care 
provider, in order to follow the medical status of the patients (especially in cases where the 
patients have withdrawn their consent after having experienced an adverse event). 
Investigators will also be expected to try as much as possible to re-contact those patients at 
the end of the trial, in order to obtain status.  
If subject discontinues from the study for any reason, before the End of Treatment Visit, the 
investigator will make all attempts to carry out all End of treatment Visit procedures. 
 
 

 
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5 STUDY TREATMENTS / IP MANAGEMENT 
Saroglitazar magnesium 2 mg or Saroglitazar magnesium 4 mg or placebo tablet will be 
administered in patients with Primary Biliary Cholangitis once daily in the morning before 
breakfast without food, for a period of 16 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. 
Table 2 Identity of Study Drugs 
 
Study Drug 
Formulation 
Strength 
Route 
Manufacturer 
Saroglitazar 
Magnesium 
Tablet 
2 mg 
Oral 
 
Saroglitazar 
Magnesium 
Tablet 
4 mg 
Oral 
 
Placebo 
Tablet 
Matching 
placebo 
Oral 
 
Data source: Investigator’s Brochure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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scheduled visits patients will have the IP administered on site after the blood sample 
collection. 
5.3 
PACKAGING, LABELLING AND RE-SUPPLY 
Tablets of Saroglitazar magnesium (2 mg and 4 mg) and placebo will be packed, labeled and 
supplied by the Sponsor according to all local legal requirements. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
All drug supplies must be stored in a temperature-controlled environment for ambient 
temperature 20-250C.   
All Investigators will be provided with a sufficient number of units of the IP for the conduct 
of the study. Investigational product would then be dispensed to each subject in such a way 
that the subject can take the doses in accordance with the protocol. A drug accountability log 
for recording the receipt, storage, dispensing and return of the IP will be maintained by the 
Investigator or any designated personnel.  
Site will contact the sponsor/designee for re-supply of the Investigational product.  
After the study has been completed, the PI must account for all study drug used, unused and 
partially used. All study drugs will be destroyed at the site (per site’s SOPs) or returned to 
the Sponsor (or designee). Unused drug supplies will be destroyed at the site after approval 

 
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for the same by the Sponsor. No study drug will be destroyed or returned until drug 
accountability has been performed by the study monitor. 
5.4 
STORAGE CONDITIONS 
Investigational product will be stored at room temperature (20°C to 25°C) 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 the study-specific temperature log, and sent to the 
Sponsor. If the excursion is within 15-30°C, quarantine is not required, and the IP is 
acceptable for use. If the excursion is outside of the 15-30°C range, the IP must be 
quarantined until a decision on the stability of the IP is made by the Sponsor. If the 
excursion goes beyond the range of 15-300 C it will be considered as a protocol deviation. 
All IP supplies in the study will be stored in a secure place with access limited to the Site 
Pharmacist or the Investigator designated site staff.  
5.5 
BLINDING / UNBLINDING 
The study is a double blind study, hence study participants and investigator will not be made 
aware which preparation (Saroglitazar magnesium 2 mg or Saroglitazar magnesium 4 mg or 
placebo), is to be administered. The randmization code will be available to the Investigator, 
for emergency purposes only. The randomization code will be available on each kit which is 
concealed in the form of scratchcard. In an emergency, when knowledge of the patient’s 
treatment assignment is essential for the clinical management or welfare of the patient, the 
investigator should make every effort to first contact the Sponsor/ designee. 
The formulation of Saroglitazar magnesium (2 mg and 4 mg) and placebo IPs will be similar 
in appearance to make any difference in treatment unobvious to the patients and to maintain 
adequate blinding of evaluators. Neither the Investigator nor the patient should be able to 
identify the received treatment.  
In an emergency, when knowledge of the patient’s treatment assignment is essential for the 
clinical management or welfare of the patient, the investigator should make every effort to 
first contact the Sponsor/ designee.  
Prior to unblinding the patient’s treatment assignment, the investigator should assess the 
relationship of an adverse event to the administration of the study drug (Yes or No). If the 

 
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blind is broken for any reason, the investigator must record the date and reason for breaking 
the blind on the appropriate electronic Case Report Form (eCRF) and source documents. 
5.6 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Patients will be randomly assigned in 1:1:1 ratio to Saroglitazar magnesium 2 mg, 
Saroglitazar magnesium 4 mg and placebo. The block randomization schedule will be 
generated using SAS® software (Version: 9.4 or higher; SAS Institute Inc., USA). Each 
block will contain investigational medicinal products; Saroglitazar magnesium 2 mg, 
Saroglitazar magnesium 4 mg and placebo. Each block will contain at least 3 kits of IMP for 
3 patients i.e., 1 kit of Saroglitazar magnesium 2 mg, 1 kit of Saroglitazar magnesium 4 mg 
and 1 kits of placebo. 
The subject identification number will be established at the site based on the randomization 
number/kit number/patient number and will be used to identify the subject throughout the 
study and will be entered on all documentation. The same subject number will not be 
assigned to more than 1 subject. If a subject is not eligible to receive treatment, or if a 
subject discontinues from the study, the same subject number cannot be assigned to another 
subject. 
The subjects will first be screened into the study. Once patients are determined to be eligible, 
they will be randomized. The subject will also be assigned a study drug in accordance to 
their assigned treatment group upon completion of the randomization. 
Patients will be considered randomized as soon as the first allocation of treatment number is 
assigned. The first study drug intake should take place as soon as possible after 
randomization (on the same day), under medical supervision. 
5.7 
SELECTION OF DOSES 
Saroglitazar magnesium 2 mg and 4 mg have favorably modified the lipid profile in the 
dyslipidemic patients during its development in Phase 2 and 3 studies. Based on the efficacy, 
safety and tolerability results of Saroglitazar magnesium, it is approved in India at the doses 
of 2 mg and 4 mg QD for the treatment of “Diabetic Dyslipidemia” and 
“Hypertriglyceridemia with T2DM not controlled by statin therapy”. Saroglitazar 

 
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magnesium 2 mg and 4 mg also demonstrated the favorable effects on ALP and GGT. Hence 
Saroglitazar magnesium 2 mg and 4 mg doses have 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 
electronic case report form (eCRF). The site may rely on subject report 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. 
i. 
Statins are permitted as concomitant medications; however, patients will be 
monitored for statin related toxicity when it is co-administered. 
ii. 
Glycemic control medications will be permitted as concomitant medications, 
including antidiabetic drugs such as metformin, sulfonylureas, dipeptidyl 
peptidase 4 (DPP-4) inhibitors and insulin. 
iii. 
Treatment for common illness during the study may be allowed.  
iv. 
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. 
5.9 
RESCUE MEDICATION AND ADDITIONAL TREATMENT(S) 
The Investigator at his/her discretion will be allowed to offer a rescue medication for 
clinically significant conditions correlated with the laboratory findings, if required, however, 
such interventions shall be recorded in the eCRF with description of type of intervention, 
dose and duration. If medication given is in violation to the protocol, then such subjects will 
be withdrawn from the trial. 

 
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Subjects on antidiabetic drug shall also be assessed on scheduled visits for 
hyperglycemia/hypoglecemia and rescue medication will also be allowed if required. 
Treatment for such conditions should be initiated as soon as the need for treatment is 
identified, 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 
should be recorded on the appropriate case report form (CRF). 
Investigator’s shall advise subjects to report at the site for any inconvenience during the 
course of trial. 
5.10 RESTRICTIONS 
Patients are not permitted to take thiazolidinedione (pioglitazone, rosiglitazone), 
chemotherapy, or other investigational medications during the study duration.  
Patients also should not take any over-the-counter medications or complementary and/or 
alternative medications without prior consultation of the Investigator. 
The PI should be alerted if, during the course of the study, a patient requires a new 
medicine or therapy or a changes to an established dosing regimen. 
5.11 OVER DOSE AND DRUG INTERACTION 
 
 
 
 
 
 
 
 
 
 
 
  

 
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. 
5.12 TREATMENT COMPLIANCE 
The subjects will be asked to bring the container of the study medication on the next 
follow-up visit; compliance for dosing will be assessed by examination of the container and 
tablet count by study personnel and documentation on individual drug accountability logs. 

 
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6 OBSERVATIONS 
6.1 
EFFICACY 
6.1.1 Primary Endpoint 
1. Improvement in ALP levels after 16 weeks of Saroglitazar magnesium 2 mg and 4 
mg treatment. 
6.1.2 Secondary Endpoints 
1. To compare the effect of Saroglitazar magnesium (2 mg and 4 mg) and placebo on 
below mentioned parameters following a 16-week treatment: 
i. 
Change from baseline in ALP at Week 4, Week 8, Week 12 and Week 16 in 
Saroglitazar magnesium as compared to placebo. 
ii. 
Change from baseline in lipid profile (TG, TC, HDL, LDL, and VLDL) at 
Week 4, Week 8, Week 12 and Week 16 in Saroglitazar magnesium as 
compared to placebo. 
iii. 
Change from baseline in liver biochemistries (GGT, ALT, AST, Bilirubin and 
albumin) at Week 4, Week 8, Week 12 and Week 16 in Saroglitazar 
magnesium as compared to placebo. 
iv. 
Change from baseline in serum total bile acids, at Week 4, Week 8, Week 12 
and Week 16 in saroglitazar as compared to Placebo. 
v. 
Change from baseline in 7α-hydroxy-4-cholesten-3-one (C4) at Week 16 in 
saroglitazar as compared to Placebo. 
vi. 
Change from baseline in fibroblast growth factor 19 (FGF 19) at Week 16 in 
saroglitazar as compared to Placebo. 
2. Proportion of patients with ALP improvement, i.e. 15%, 20%, 30%, 40% and 
normalization at Week 8 and Week 16. 
3. Change in QoL at Week 16 by using PBC40. 
4. Change from baseline in ALP in patients who are unable to tolerate UDCA at week 
16 in Saroglitazar 2 mg and 4 mg as compared to Placebo. 
5. Safety and tolerability of Saroglitazar magnesium 2 mg and 4 mg. 
6. Pharmacokinetics of Saroglitazar. 

 
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Pharmacokinetics of Saroglitazar Magnesium will be performed in patients with PBC. The 
samples will be collected at Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0 and 24 hours 
post-dose on Visit 3 and Visit 7. In addition, pre-dose sample will be collected at Visits 4, 5, 
and 6.  
The following pharmacokinetic parameters will be evaluated: 
i. 
Peak Plasma concentration (Cmax) 
ii. 
Time to reach peak Plasma concentration (Tmax) 
iii. 
Area under Plasma concentration vs. time curve till the last time point (AUC0-t) 
iv. 
Area under Plasma concentration vs. time curve extrapolated to the infinity (AUC0-
∞) after first dose 
v. 
Area under plasma concentration vs. time curve in a 24 h dosing interval (AUCtau) 
vi. 
Elimination rate constant (λz) 
vii. 
Elimination half-life (t1/2) 
viii. 
Apparent Volume of distribution (Vd/F) 
ix. 
Apparent Clearance (CL/F) 
x. 
Minimal or Trough plasma concentration (Cmin) -for last dose only  
xi. 
Accumulation index calculated as a ratio of AUCtau (last dose)/AUCtau (first dose) 
xii. 
Fluctuation index.  
6.2 
SAFETY 
To assess the safety of Saroglitazar magnesium in the study population over the duration of 
study. 
 
Adverse event(s): frequency and severity of AE / SAEs, drop-out 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:  
o Causality  
o Severity 
o Seriousness 
o Expectedness 
 
Clinical laboratory testing (hematology, clinical chemistry and urinalysis) 

 
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 
Twelve-lead electrocardiogram (ECG) 
 
Vital signs 
 
Body weight and height (at screening) 
 
The physical examination will consist of an evaluation of the head, neck, eyes, ears, 
nose, throat, chest, heart, lungs, abdomen, skin, extremities, and the neurological 
and musculoskeletal systems. 
All AEs will be captured and notification sent to the Sponsor. All AEs will be captured in 
eCRF. At a minimum, SAEs will be reported in the CRFs as per the timelines defined in the 
Protocol in adverse event section. However, each research institution’s IRB/IEC reporting 
requirements may contain shorter timelines. 
Serious adverse events reporting must comply with the United State of Food and Drug 
Administration (USFDA) reporting requirements and IRB/IEC reporting requirements. 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the Investigator that may make it unfeasible to 
perform the test. In these cases, the Investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol required test cannot be performed the 
Investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible. 
The trial team will be informed of these incidents in a timely fashion. 
All biological samples will be assayed by a Sponsor-identified CAP and/or CLIA-certified 
laboratory, using analytical methods in compliance with standard and validated 
methodologies, with adherence to written standard operating procedures (SOPs).  
Details regarding the sample processing, handling, storage, and shipment will be offered 
separately in the study-specific central laboratory manual prior to the initiation of the trial. 
6.2.1 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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6.2.2 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 ECG, 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. 

 
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7 INVESTIGATIONAL PLAN 
7.1 
STUDY DESIGN AND PLAN 
This is a Phase 2 prospective, multicentre, randomized, double-blind, placebo-controlled 
study includes a total 36 patients with a diagnosis of Primary Biliary Cholangitis. The study 
will be conducted over a period of up to 26 weeks and will include a 6-week Screening 
Phase, a 16-week Treatment Phase and a safety follow-up visit after 4 weeks. 
Screening Phase: 
 Visit 1 (Day -42): Patient eligibility for participation in the study will be assessed. 
Medical history will be obtained and physical examination, electrocardiogram (ECG) 
and laboratory evaluations (including serology, [anti-nuclear antibody, smooth muscle 
antibody and serum immunoglobulin level G], clinical chemistry, hematology, liver 
biochemistries, and urinalysis) will be performed. In patients with ANA or SMA 
antibody positive titers, a liver biopsy must have been performed to rule out 
autoimmune hepatitis or overlap syndrome. Female patients will undergo a pregnancy 
test. Serum ALP must be ≥1.67 upper limit of normal (ULN) to proceed further in the 
study. 
 Visit 2 (Day -14 to -7): Liver biochemistries (ALT, ALP, total bilirubin (TB) and INR 
will be re-measured approximately 4 weeks from Day -42 to determine eligibility.  
Elevated ALP must be ≥1.67 ULN on 2 occasions in the Screening Phase and is 
necessary for study entry. If there is an increase of more than 30% in the levels of ALT, 
total bilirubin or INR at Day (-14) to Day (-7) [Visit 2] as compared to the values on 
Day (-42) [Visit 1], then such patients will not be eligible for study entry. 
The average of two assessments (Visit 1 and Visit 2) of liver biochemistries and INR 
will be considered as baseline values for these parameters. 
Randomization & Treatment Phase:  
 Visit 3: The Randomization & Treatment Phase will include 6 outpatient visits over a 
period of 16 weeks, including the randomization visit. Patients will be randomly 
assigned to receive either Saroglitazar magnesium (2 mg or 4 mg) or placebo orally 

 
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once daily in addition to their ongoing treatment with UDCA (Patients unable to 
tolerate UDCA will receive only the investigational medicinal products), starting on 
Day 1 and continuing for 16 weeks. Efficacy and safety parameters will be assessed 
during each study visit as per the Schedule Visit Table 1.  
 Visit 3.1: Patient will visit study site at 2 weeks after randomization visit for LFTs. The 
LFTs will be performed at local laboratory. 
 Visits 4, 5 and 6: Patients will visit the study site at Week 4 (Visit 4), Week 8 (Visit 5) 
and Week 12 (Visit 6) for clinical assessment, dispensation and/or reconciliation of 
study drug, and measurements of efficacy endpoints.  
 End-of-Treatment Visit (Visit 7): An End-of-double-blind treatment will occur at Week 
16. The clinical assessment, reconciliation of study drug, and measurements of efficacy 
and safety endpoints will be performed as per the schedule. 
Safety follow-up visit (Visit 8) will occur 4 weeks (± 3 days) after the End-of-treatment Visit 
for safety monitoring. Clinical examination and safety lab assessment will be performed 
during this visit. 
7.2 
STUDY PROCEDURES AT EACH VISIT 
Study schedule for the trial is given in Table 1. 
 Screening Visit (Week -6) 
All subjects will be required to sign the informed consent forms (ICF) after understanding 
the ICF before any trial related procedure is initiated as per the applicable regulatory 
guideline.  
Informed consent process will be documented in source document, ICF and other relevant 
logs, and signed with dated by the Investigator or designee. Prior to subject participation in 
the trial, written informed consent will be obtained from each subject (or the subject’s 
legally accepted representative) according to the regulatory and legal requirements of the 
participating state and country. 

 
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Subjects with the history of PBC will be screened for eligibility to participate in the study. 
Demographic detail, medical history will be recorded. ECG will be performed. Pregnancy 
test will be performed for women of childbearing potential. 
Vital signs, height and weight measurements, and physical and laboratory examinations 
listed in Table 1 will be carried out in subjects suffering from PBC; those satisfying the 
inclusion-exclusion criteria will be invited to participate in this study. (The physical 
examination will consist of an evaluation of the head, neck, eyes, ears, nose, throat, chest, 
heart, lungs, abdomen, skin, extremities, and the neurological and musculoskeletal 
systems). Concomitant medications will be recorded. Serum ALP must be ≥1.67 upper 
limit of normal (ULN) to proceed further in the study. 
Visit 2 (Week -2 to -1): Liver biochemistries (ALT, ALP, total bilirubin (TB) and INR will 
be re-measured approximately 4 weeks from Day -42 to determine eligibility. Physical 
examination, vital signs and lab investigation will be performed as per Table 1. 
Elevated ALP must be ≥1.67 ULN on 2 occasions in the Screening Phase and is necessary 
for study entry. If there is an increase of more than 30% in the levels of ALT, Total 
bilirubin or INR at Day(-14) to Day(-7)[Visit 2] as compared to the values on Day 
(-42)[Visit 1], then such patients will not be eligible for study entry. 
The average of two assessments (Visit 1 and Visit 2) of liver biochemistries and INR will 
be considered as baseline values for these parameters. 
 Visit 3: Randomization Visit (Week 0±3 days) 
After screening, the eligible patients will be randomly assigned to one of the following 
treatment groups in addition to their ongoing treatment with UDCA (Patients unable to 
tolerate UDCA will receive only the investigational medicinal products) i.e., Saroglitazar 
magnesium 2 mg, Saroglitazar magnesium 4 mg, or placebo. Vital signs measurements, 
weight measurements, physical examination, and laboratory examination will be performed 
as mentioned in Table 1. Concomitant medications will be recorded. AEs will be noted, if 
any. Urine pregnancy test will be performed for women of childbearing potential. Subjects 
will undergo cardiac evaluation (ECG). A 4-week supply of study medication (one bottle) 
will be dispensed. Baseline quality of life assessment will be performed. 

 
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 Visit 3.1 (Week 2±3 Days) 
Patient will visit study site at 2 weeks after randomization visit for LFTs. The LFTs will be 
performed at local laboratory. 
 Visit 4 (Week 4±3 Days), Visit 5 (Week 8±3 Days) and Visit 6 (Week 12±3 
Days) 
Subjects will be undergo a physical examination and laboratory parameters (safety and 
efficacy) will be assessed as per Table 1. Vitals signs, body weight will be recorded.  
AEs, if any, will be noted. Urine pregnancy test will be performed for women of 
childbearing potential. Concomitant medications will be recorded. Medication compliance 
will be checked. Medication will be dispensed on each visit for next 4 weeks. 
 End-of-treatment Visit 7 (Week 16±3 Days) 
Subjects undergo physical examination and laboratory parameters (safety andefficacy) will 
be assessed as per Table 1. Vitals signs and weight will be recorded. AEs will be noted, if 
any. Subjects will undergo cardiac (ECG) evaluation. Pregnancy test will be performed for 
all women of childbearing potential. Concomitant medications will be recorded. 
Medication compliance will be checked.  
 Safety follow-up Visit 8 End of Study (Week 20±3 Days) 
A safety follow-up visit will be performed 4 weeks after End-of-treatment Visit. Patients 
clinical examination and safety lab assessment will be performed as per Table 1. 
Unscheduled visits- will be allowed any time during the study for assessment and 
management of AEs and any concurrent clinical conditions. Unscheduled visits shall be 
captured in the CRF. 
 If further investigations are required in case of any AE, Investigator will assess the 
AE and take necessary action, if required.  

 
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 During this 16-week program, if it is necessary to follow-up on any AE, a 
designated person from the center will interview the subject for his/her general 
health, telephonically.  
If subject discontinues the study, due to any reason, before End of Treatment Visit, all 
procedures of End of Treatment Visit should be carried out. 
7.3 
PHARMACOKINETIC ASESSMENT 
Eighteen subjects will participate in a pharmacokinetic sub-study. 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. 
On Study Visit 3, and Study Visit 7 subjects will be asked to remain at the clinic for 10 
hours. On these dates, additional blood samples will be collected at the following time-
points: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, and 10.0. 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 and Visit 7. In addition to these collections, pre dose 
blood samples will be collected at Study Visits 4, 5, and 6.  
The pharmacokinetic blood samples will be sent to a central laboratory as assigned by the 
sponsor. The total amount of blood drawn for Pharmacokinetic study from each patient over 
the study will be less than ~120 mL/25tablespoons. A detail pharmacokinetic study plan will 
be prepared separately.  
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 DEVIATIONS 
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 necessarily influence 

 
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the results/outcome of primary endpoints or subject safety. 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 results/outcome of 
primary endpoints or subject safety. 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, 
SOPs, 
GCP, 
and/or 
applicable 
regulatory 
requirement(s) 
by 
an 
investigator/institution. In all case 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 deviation/violation on separate 
section. The result will be analysed for all participants with major protocol deviations.  
Protocol deviation/violation will include but are not limited to the following; 
o Subjects that did not meet entry criteria 
o Subjects that developed withdrawal criteria but were not withdrawn 
o Subjects that received the wrong treatment or incorrect dose 
o Subjects that received an excluded medication 
7.6 
DATA MONITORING COMMITTEE 
Safety data including adverse events and liver-related events (i.e., clinically meaningful 
elevations in liver biochemistries ALT, AST, and bilirubin) will be reviewed regularly by a 
Data Monitoring Committee. The Data Monitoring Committee will have a formal structure 
and will operate according to a previously agreed upon remit.  
 

 
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8 BIOSTATISTICS 
8.1 
STATISTICAL DESIGN 
Statistical Analysis Plan (SAP) will be prepared and finalized prior to database lock. The 
SAP will include detailed statistical aspects of the safety and efficacy analysis. Statistical 
analysis will be performed using SAS® (version 9.4 or higher) software (SAS Institute Inc., 
USA). 
8.2 
NULL AND ALTERNATIVE HYPOTHESIS 
Below is the hypothesis of primary efficacy endpoint:  
Null hypothesis: H0: μs = 0 
Alternative hypothesis H1: -μs > 0 
Where: μs = change from baseline in ALP levels of the Saroglitazar magnesium (2 
mg and 4 mg).  
Rejection of the null hypothesis will lead to conclude that the change from baseline in 
Saroglitazar magnesium 2 mg and 4 mg is statistically significant and hence the test drug is 
effective. 
8.3 
STUDY POPULATION AND PLANNED ANALYSIS 
8.3.1 Populations 
8.3.1.1 Safety population 
The safety population includes the subjects who satisfy all inclusion/exclusion criteria, are 
randomized and received at least single dose of study medication. 
8.3.1.2 Modified intent-to-treat population 
The modified intent-to-treat (MITT) population includes: all randomized subjects who 
received any study drug and have at least one post-randomized efficacy measurement. 
All primary and secondary objectives will be analysed using MITT population with LOCF 
method. Last observation carried forward (LOCF) method will be used as an imputation 
method for the efficacy variables for MITT analysis. 
 

 
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8.3.1.3 Per-protocol population (PP) 
The per-protocol population (PP) includes all randomized patients who meet all the 
inclusions/exclusion criteria, completed the treatment phase and have not deviated from or 
violated the protocol in such a way that could affect efficacy outcome. 
8.3.2 Planned Analysis 
Modified intent-to-treat (MITT) and Per Protocol (PP) analysis will be carried out for the 
efficacy analysis. 
All efficacy analyses will be based primarily on the MITT, and analyses based on the Per 
Protocol (PP) analysis set will be secondary to this.  
The MITT will consist of all patients who have been randomized, taken at least 1 dose of the 
study treatment and have provided at least a post-randomized efficacy data. Missing values 
will be imputed by carrying forward the last observation value after baseline. 
8.3.2.1 Primary Efficacy Analysis 
The primary analysis for the primary efficacy endpoint will be based on the MITT. The 
primary efficacy endpoint in this study is improvement in ALP levels after 16 weeks in 
Saroglitazar magnesium treatment.  
The primary endpoint will be summarized and improvement from baseline to week 16 will 
be evaluated using Paired t-Test. Statistical significance will be defined as a p-value <0.05. 
8.3.2.2 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: 
 Change from baseline in ALP at Week 4, Week 8, Week 12 and Week 16 in 
Saroglitazar magnesium as compared to placebo.  

 
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 Change from baseline in lipid profile (TG, TC, HDL, LDL, and VLDL) at 
Week 4, Week 8, Week 12 and Week 16 in Saroglitazar magnesium as 
compared to placebo.  
 Change from baseline in liver biochemistries (GGT, ALT, AST, bilirubin and 
albumin) at Week 4, Week 8, Week 12 and Week 16 in Saroglitazar 
magnesium as compared to placebo. 
 Change from baseline in serum total bile acids at Week 4, Week 8, Week 12 
and Week 16 in Saroglitazar magnesium as compared to placebo. 
 Change from baseline in 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast 
growth factor 19 (FGF 19) at Week 16 in Saroglitazar magnesium as 
compared to placebo. 
 Proportion of patients with ALP improvement, i.e. 15%, 20%, 30%, 40% and 
normalization at Week 8 and Week 16. 
 Change in QoL at Week 16 by using PBC40.  
o This instrument consists of 6 domain and 40 questions: symptoms, 
itch, cognition, emotion and social. 
 Change from baseline in ALP in patients who are unable to tolerate UDCA at 
week 16 in Saroglitazar 2 mg and 4 mg as compared to Placebo. 
 Pharmacokinetics of Saroglitazar. 
The change from baseline will be determined as: 
Change = (Post-baseline – Baseline) 
Percent Change = (Post-baseline – Baseline) / Baseline * 100 
Treatment effects will be estimated using the least-square mean, standard error and 95% 
confidence intervals from ANCOVA model with baseline value as covariate. Comparison 
will be done for Saroglitazar magnesium (2 mg and 4 mg) and placebo using the difference 
in least-square means from the ANCOVA model. Proportion of patients with ALP 

 
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improvement, i.e., 15%, 20%, 30%, 40% and normalization at Week 8 and Week 16 will be 
presented as counts and percentages. 
Descriptive statistics will be provided for each pharmacokinetic parameter. 
The following pharmacokinetic parameters will be evaluated: 
i. 
Peak Plasma concentration (Cmax) 
ii. 
Time to reach peak Plasma concentration (Tmax) 
iii. 
Area under Plasma concentration vs. time curve till the last time point (AUC0-t) 
iv. 
Area under Plasma concentration vs. time curve extrapolated to the infinity (AUC0-
∞) after first dose 
v. 
Area under plasma concentration vs. time curve in a 24 h dosing interval (AUCtau) 
vi. 
Elimination rate constant (λz) 
vii. 
Elimination half-life (t1/2) 
viii. 
Apparent Volume of distribution (Vd/F) 
ix. 
Apparent Clearance (CL/F) 
x. 
Minimal or Trough plasma concentration (Cmin) -for last dose only  
xi. 
Accumulation index calculated as a ratio of AUCtau (last dose)/AUCtau (first dose) 
xii. 
Fluctuation index.  
Above analyses will also be supported by simple summaries (n, mean, standard deviation, 
median, minimum and maximum) at each visit.  
8.3.3 Safety Analysis 
All safety analysis will be carried out on 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, ECG, physical 
examination and vital signs will be presented for each treatment by visit.  
All AEs seen during the study period will be listed. Incidence of all AEs reported during the 
study will be summarized using the Medical Dictionary for Regulatory Activities 
(MedDRA) (version 19 or higher) by treatment group, body system, frequency, severity, 
seriousness, and relationship to study drug and expectedness. 

 
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8.3.4 Baseline Characteristics 
Demographic characteristics and Baseline Characteristics will be summarized by treatment, 
subject disposition, reasons for withdrawal or by any other variables as appropriate. Unless 
otherwise stated, all the continuous variables will be represented by n, mean, standard 
deviation, minimum, median and maximum. All the categorical variables will be presented 
as counts and percentages. 
8.3.5 Interim Analysis 
8.3.6 An interim analysis will be conducted when approximately 24th active 
randomized subject completes the study, that is Week 20 visit assessment.  The 
purpose of this interim analysis is to assess the effect of Saroglitazar Magnesium 
in PBC patients and to choose the optimal dose for planning the phase III study. 
The interim analysis will be performed with unmasking of specified individuals 
from the Sponsor who are not involved in the direct conduct of the trial. The 
study will continue until all planned subjects complete the study. Treatment 
masking of individual subjects will remain intact for all subjects, Investigators, 
and staff from the Sponsor who have contact with subjects or Investigators or 
those who are involved in the direct conduct of the study until all planned 
randomized subjects complete the study and the final database lock has 
occurred.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 should be excluded from PP analysis set. Any 
randomized subjects who are discontinued from the study for any reason and have at least a 
post-baseline efficacy data should be included in the MITT analysis set using Last 
observation carried forward (LOCF) method. LOCF method will be used as an imputation 
method for the efficacy variables for MITT analysis. 
8.4 
RANDOMIZATION 
Subjects will be randomly assigned in 1:1:1 treatment allocation ratio to Saroglitazar 
magnesium 2 mg, Saroglitazar magnesium 4 mg 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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8.5 
DETERMINATION OF SAMPLE SIZE 
This proof of concept study will include a total 36 subjects. Subject will be enrolled in 1:1:1 
ratio to have 12 subjects in each arm i.e., Saroglitazar magnesium 2 mg, Saroglitazar 
magnesium 4 mg and placebo. Six patients in each group are planned for pharmacokinetic 
assessment therefore a total of 18 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. Additional patients will be enrolled if the dropout 
rate is more than 20%.  
 
 

 
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9 ADMINISTRATIVE MATTERS 
The trial will be carried out in compliance with the protocol, in accordance with the ICH 
Harmonised Tripartite Guideline for GCP and in accordance with applicable regulatory 
requirements. 
9.1 
ETHICS 
9.1.1 Institutional Committee Review and Communications 
The 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 USFDA-registered IEC/IRB. Should a protocol amendment be written 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 providing 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 accepted 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 

 
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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 his / her medical records may be examined by authorised 
monitors or Clinical Quality Assurance auditors appointed by the Sponsor, by appropriate 
IEC / IRB members and by inspectors from regulatory authorities.   
Should a protocol amendment be made, the 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 
 
DATA MANAGEMENT AND RECORDKEEPING 
9.2.1 Drug Accountability 
Drug supplies, which will be provided by the Sponsor, must be kept in a secure, limited 
access storage area under the storage conditions defined by the Sponsor. A temperature log 
must be maintained to make certain that the drug supplies are stored at the correct 
temperature. 
The Investigator and/or pharmacist must maintain records of the product’s delivery to the 
trial site, the inventory at the site, the use by each subject, and the return to the Sponsor or 
alternative disposition of unused product(s). These records will include dates, quantities, 
batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned 
to the IP(s) and trial subjects. Investigators will maintain records that document adequately 
that the subjects were provided the doses specified by the protocol and reconcile all IP(s) 
received from the Sponsor.  
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). Unused drug supplies will be destroyed at the site 

 
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after approval for the same by the Sponsor. No study drug will be destroyed or returned until 
drug accountability has been performed by the study monitor. 
9.2.2 Patient Card 
Upon enrolment in the study, patients will receive a patient card to be carried at all times. 
The patient card will state that the patient is participating in a clinical research study, type of 
treatment, number of treatment packs received, and contact details in case of an SAE. 
9.2.3 Data Management 
9.2.3.1 Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the clinical research associate 
(CRA) during monitoring visits. The CRAs 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. 
9.2.3.2 Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
9.2.3.3 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. 
9.2.3.4 Medical Information Coding 
For medical information, the following thesauri will be used: 
o Latest version of MedDRA for adverse events and medical history, and 

 
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o WHO Drug Dictionary for prior and concomitant medications. 
9.2.3.5 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. 
9.2.4 Source documents 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. Data 
reported on the eCRFs that are derived from source documents (SDs) must be consistent 
with the SDs 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: 
 Subject identification (subject number, gender, date of birth/age) 
 Subject participation in the trial (substance, trial number, patient number, date 
informed consent given) 
 Dates of subject’s visits 
 Medical history 
 Medication history 
 AEs (onset and end) 
 SAEs (onset and end) 
 Originals or copies of laboratory results: All laboratory reports must be 
reviewed by the Investigator and/or his/her designee; any abnormal findings 
should be addressed. 

 
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 Conclusion of subject’s participation in the trial. 
9.2.5 Direct access to source data / documents 
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 SDs, 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 enrolment of any patient in this study, the Sponsor or their 
designee 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 designee to monitor the study as frequently 
as deemed necessary to determine that data recording and protocol adherence are 
satisfactory. During the monitoring visits, information recorded on the eCRFs will be 
verified against source documents and requests for clarification or correction may be made. 
After the eCRF data is entered by the site, the CRA 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. 

 
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9.3 
QUALITY ASSURANCE AUDIT 
A quality assurance audit of this trial may be conducted by the Sponsor or Sponsor’s 
designees. The quality assurance auditor will have access to all medical records, the 
Investigator’s trial related files and correspondence, and the informed consent 
documentation that is relevant to this clinical trial. 
9.4 
PROCEDURES 
9.4.1 Adverse Events 
All AEs occurring during the course of the clinical trial (i.e., from signing the informed 
consent onwards) will be collected, documented and reported to the Sponsor by the 
Investigator according to the specific definitions and instructions detailed in this section. 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
Any medical condition already present at screening should not be reported as an adverse 
event unless the medical condition or signs or symptoms present at baseline changes in 
severity or seriousness at any time during the study. In this case, it should be reported as an 
adverse event. 
Clinically significant abnormal laboratory or other examination (e.g. electrocardiogram) 
findings that are detected during the study or are present at screening and significantly 
worsen during the study should be reported as AEs. The investigator will exercise his or her 
medical and scientific judgment in deciding whether an abnormal laboratory finding or other 
abnormal assessment is clinically significant. Clinically significant abnormal laboratory 
values occurring during the clinical study will be followed until repeat tests return to normal, 
stabilize, or are no longer clinically significant. Any abnormal test that is determined to be 
an error does not require reporting as an AE. 

 
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9.4.2 Serious Adverse Event 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that: 
 Results in death; 
 Is life threatening; 
 Results in persistent or significant disability/incapacity; 
 Results in inpatient hospitalization or prolongs an existing inpatient 
hospitalization; 
 Is a congenital anomaly/birth defect; 
 Is another important medical event that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
Serious Adverse Event Reporting-Procedures for Investigators:  
Initial Reports: 
Any serious adverse event, or follow-up to a serious adverse event, including death due to 
any cause that occurs to any subject from the time the consent is signed through 7 days 
following cessation of treatment, whether or not related to the Sponsor's product, must be 
reported to the Sponsor within 24 hours of the knowledge of the occurrence to 
investigational site. 
Additionally, any serious adverse event, considered by an Investigator who is a qualified 
physician to be related to the Sponsor’s product that is brought to the attention of the 
Investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.   
To report the SAE, complete the SAE form electronically in the electronic data capture 
(EDC) system for the study. When the form is completed, CRO/Sponsor Safety personnel 

 
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will be notified electronically and will retrieve the form. If the event meets serious criteria 
and it is not possible to access the EDC system, send an email to CRO/Sponsor or call the 
CRO/Sponsor SAE hotline (phone number listed below), and email the completed paper 
SAE form to CRO/Sponsor (email listed below) within 24 hours of awareness. When the 
EDC system becomes available, the SAE information must be entered within 24 hours of the 
system becoming available. 
Safety Contact Information: 
 
Dr. Deven V Parmar, MD  
 
 
 
 
 
 
 
 
 
Follow-Up Reports 
All subjects with serious adverse events must be followed up for outcome. Within 24 hours 
of receipt of follow-up information, the investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(e.g., subject discharge summary or autopsy reports) to CRO/Sponsor Clinical Safety via fax 
or e-mail. If it is not possible to access the EDC system, refer to the procedures outlined 
above for initial reporting of SAEs. 
9.4.3 Evaluating Adverse Events 
An Investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 4. The Investigator’s assessment of causality is required for 
each adverse event. Refer to Table 4 for instructions in evaluating adverse events. 

 
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Table 4. Evaluating Adverse Events 
Maximum 
Mild 
awareness of sign or symptom, but easily tolerated  
Intensity 
Moderate 
discomfort enough to cause interference with usual activity (for pediatric trials, definitely 
acting like something is wrong) 
 
Severe 
incapacitating with inability to work or do usual activity (for pediatric trials, extremely 
distressed or unable to do usual activities) 
Seriousness 
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's 
product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the Investigator, at immediate risk of death from 
the event as it occurred [Note: This does not include an adverse event that, had it occurred in a more severe 
form, might have caused death.]; or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to 
conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient 
admission, regardless of length of stay, even if the hospitalization is a precautionary measure for continued 
observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a pre-existing 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to 
diagnosis); or 
 
Is a cancer; or 
 
Is associated with an overdose (whether accidental or intentional). Any adverse event associated with an 
overdose is considered a serious adverse event. An overdose that is not associated with an adverse event is 
considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require 
hospitalization may be considered a serious adverse event when, based upon appropriate medical judgment, 
the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of 
time and units 
Action 
taken  
Did the adverse event cause the Sponsor's product to be discontinued? 
Relationship 
to Sponsor's 
Product 
Did the Sponsor's product cause the adverse event? The determination of the likelihood that the Sponsor's 
product caused the adverse event will be provided by an Investigator who is a qualified physician. The 
Investigator’s signed/dated initials on the source document or worksheet that supports the causality noted 
on the AE form, ensures that a medically qualified assessment of causality was done. This initialled 
document must be retained for the required regulatory time frame. The criteria below are intended as 
reference guidelines to assist the Investigator in assessing the likelihood of a relationship between the test 
drug and the adverse event based upon the available information.   
The following components are to be used to assess the relationship between the Sponsor's product 
and the AE; the greater the correlation with the components and their respective elements (in number 
and/or intensity), the more likely the Sponsor's product caused the adverse event: 
 
Exposure 
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  
reliable history, acceptable compliance assessment (pill count, diary, etc.), expected 
pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time 
Course 
Did the AE follow in a reasonable temporal sequence from administration of the Sponsor's 
product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with 
investigational medicinal product)? 
 
Likely 
Cause 
Is the AE not reasonably explained by another aetiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors 
Relationship 
to Sponsor's 
Product 
(continued)  
The following components are to be used to assess the relationship between the Sponsor’s product 
and the AE: (continued) 
Dechallenge 
Was the Sponsor's product discontinued or dose/exposure/frequency reduced? 
      If yes, did the AE resolve or improve? 
           If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 

 
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All AEs, serious and non-serious, will be fully documented on the appropriate eCRF(s). For 
each AE, the Investigator will provide the onset, duration, intensity, treatment required, 
outcome and action taken with the IP. The Investigator will determine the relationship of the 
IP to all AEs. 
Fatal or life-threatening, unexpected adverse drug reactions (ADRs) occurring in clinical 
investigations qualify for expedited reporting. Regulatory agencies shall be notified (e.g., by 
telephone, facsimile transmission, or in writing) as soon as possible but no later than 7 
calendar days after first knowledge by the sponsor that a case qualifies, followed by as 
complete a report as possible within 8 additional calendar days. 
Serious, unexpected ADRs that are not fatal or life-threatening must be filed with the 
regulatory agency as soon as possible but no later than 15 calendar days after first 
knowledge by the sponsor that the case meets the minimum criteria for expedited reporting. 
disability; (2) the AE resolved/improved despite continuation of the Sponsor's product; (3) 
the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Sponsor's product in this trial? 
      If yes, did the AE recur or worsen? 
          If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the trial is a single-dose drug trial); or (3) Sponsor's product(s) is/are used 
only one time.) 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH 
WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S 
PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT THEN THE 
RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge 
regarding the Sponsor's product or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an Investigator who is a qualified 
physician according to his/her best clinical judgment, including consideration of the above elements. 
Record one of the 
following: 
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor's product relationship). 
Yes, there is a reasonable 
possibility of Sponsor's 
product relationship. 
There is evidence of exposure to the Sponsor's product. The temporal sequence of the AE 
onset relative to the administration of the Sponsor's product is reasonable. The AE is more 
likely explained by the Sponsor's product than by another cause.  
No, there is not a 
reasonable possibility of 
Sponsor's product 
relationship 
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset 
relative to administration of the Sponsor's product is not reasonable OR there is another 
obvious cause of the AE. (Also entered for a subject with overdose without an associated 
AE.) 

 
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9.4.4 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hrs to CRO/Sponsor Clinical Safety following the 
same procedures as outlined in Section 9.4.2. Sponsor Contact information can be found in 
the Investigator Trial File Binder (or equivalent). 
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology.     
9.4.5 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 IB. 
9.4.6 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 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. 

 
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Although pregnancy and lactation are not considered adverse events, 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. All subjects who become pregnant must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
The investigator should report the pregnancy to CRO/Sponsor Clinical Safety within 24 
hours of being notified. CRO/Sponsor Clinical Safety will then forward the Exposure In 
Utero form to the investigator for completion.  
9.5 
RULES FOR AMENDING PROTOCOL 
All amendments must be documented, dated and signed by all signatories (or their 
successors) of the original protocol. Protocol amendments only for logistical or 
administrative changes may be implemented immediately; however, both the IEC/IRB and 
USFDA will be notified immediately. 
9.6 
FINANCIAL DISCLOSURE 
Investigators are required to provide financial disclosure information to the Sponsor to 
permit the Sponsor to fulfil its obligations under 21 CFR §54. In addition, Investigators must 
commit to promptly updating this information if any relevant changes occur during the study 
and for a period of 1 year after the completion of the study. Details of insurance coverage 
will be covered in separate document/CTA/agreement. 
9.7 
DISCONTINUATION OF THE TRIAL BY THE SPONSOR 
The Sponsor reserves the right to discontinue this trial at any time for failure to meet 
expected enrolment 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. 

 
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9.8 
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. 
Such medical information may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. 
Data generated as a result of this trial are to be available for inspection on request by the 
participating physicians, the Sponsor’s representatives, by the IRB or IEC and the regulatory 
health authorities. 
9.9 
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. 
Zydus Discovery DMCC (ZYDUS) is as much as possible dedicated to support process of 
free exchange of relevant scientific information. Any publication of the results of this trial 
must be consistent with the ZYDUS publication policy. The rights of the Investigator and of 
the Sponsor with regard to publication of the results of this trial are described in the 
Investigator agreement. 
9.10 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 

 
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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. Ahmad HA, Thomas JB, Keith DL. Orphan drugs in development for primary biliary 
cirrhosis: challenges and progress. Orphan Drugs: Research and Reviews. 2015;5: 
83–97. 
2. American Diabetes Association Inc. Dyslipidemia Management in Adults with 
Diabetes, Diabetes Care. 2004; 27: S68-S71.  
3. American Diabetes Association. Standard of medical care in diabetes-2013. Diabetes 
Care. 2013; 36: S11-S66. 
4. Anderson F, Thomson SR, Clarke DL, Buccimazza I. Dyslipidaemic pancreatitis 
clinical assessment and analysis of disease severity and outcomes. Pancreatology. 
2009; 9:252–257. 
5. Cheung AC, Lapointe-Shaw L, Kowgier M, et al. Combined ursodeoxycholic acid 
(UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete 
UDCA response may improve outcomes. Aliment PharmacolTher. 2016;43(2):283-
93. 
6. Deng LH, Xue P, Xia Q, Yang XN, Wan MH. Effect of admission 
hypertriglyceidemia on the episodes of severe acute pancreatitis. World J 
Gastroenterol. 2008; 14:4558–4561. 
7. Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new measure of 
pruritus. Br J Dermatol. 2010;162(3): 587–593. 
8. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: 
Management of cholestatic liver diseases. Journal of Hepatology. 2009; 51: 237–267. 
9. Ghonem NS, Assis DN, Boyer JL. On Fibrates and Cholestasis: A review. 
Hepatology. 2015; 62(2): 635–643. 
10. Gideon MH, Andrew M, Velimir L, et al. Efficacy of Obeticholic Acid in Patients 
With Primary Biliary Cirrhosis and Inadequate Response to Ursodeoxycholic Acid. 
Gastroenterology 2015;148:751–761. 

 
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11. Gui-Qi Z, Ke-Qing S, Sha Huang, et al. Network Meta-Analysis of Randomized 
Controlled Trials: Efficacy and Safety of UDCA-Based Therapies in Primary Biliary 
Cirrhosis. Medicine. 2015; 94(11): 1-9. 
12. Lloret Linares C, Pelletier AL, Czernichow S, Vergnaud AC, Bonnefont-Rousselot 
D, Levy P, Ruszniewski P, Bruckert E. Acute pancreatitis in a cohort of 129 patients 
referred for severe hypertriglyceridemia. Pancreas. 2008; 37:13–22. 
13. Jacoby A, Rannard A, Buck D, et al. Development, validation, and evaluation of the 
PBC-40, a disease specific health related quality of life measure for primary biliary 
cirrhosis. Gut 2005;54:1622–1629. 
14. Jani RH, Kansagra K, Jain M, Patel H: Pharmacokinetics, safety, and tolerability of 
Saroglitazar (ZYH1), a predominant PPAR agonist and moderate c agonist activity 
in healthy human subjects. Clin Drug Investig 2013 September 24 [Epub ahead of 
print]. doi: 10.1007/s40261-013-0128-3. 
15. Jani RH, Pai V, Jha P, Jariwala G, Mukhopadhyay S, Bhansali A, Joshi S. A 
multicenter, prospective, randomized, double-blind study to evaluate the safety and 
efficacy of Saroglitazar 2 and 4mg compared with placebo in type 2 diabetes mellitus 
patients having hypertriglyceridemia not controlled with atorvastatin therapy (PRESS 
VI). Diabetes Technology and Therapeutics. 2014;16(2):63–71. 
16. Jayant AT, Keith DL. Primary biliary cirrhosis. Lancet 2003; 362: 53–61. 
17. Keith DL, M Eric G, Raoul P, Marshall K, Nora VB, E Jenny H. Primary Biliary 
Cirrhosis. Hepatology. 2009; 50(1): 291-308. 
18. Marschall HU, Wagner M, Zollner G, et al. Complementary stimulation of 
hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic 
acid in humans. Gastroenterology. 2005;129(2):476–485. 
19. Nevens F, Andreone P, Mazzella G, et al. An international phase 3 study of the FXR 
agonist obeticholic acid in PBC patients: Effects on markers of cholestasis associated 
with clinical outcomes and hepatocellular damage. Hepatology (Baltimore, Md.). 
2014;60(8). 

 
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20. Pai V, Paneerselvam A, Mukhopadhyay S, Bhansali A, Kamath D, Shankar V, 
Gambhire D, Jani RH, Joshi S, Patel P. 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):132-141. 
21. Parés A, Caballería L, Rodés J. Excellent long-term survival in patients with primary 
biliary 
cirrhosis 
and 
biochemical 
response 
to 
ursodeoxycholic 
acid. 
Gastroenterology. 2006;130(3):715–720.  
22. Ulrich B, M Eric G, Robert G G, et al. Changing nomenclature for PBC: From 
‘cirrhosis’ to ‘cholangitis’. Digestive and Liver Disease 47 (2015) 924–926. 
23. Zumoff B. Effect of clofibrate on plasma levels of alkaline phosphatase. N Engl J 
Med 1977; 297: 669. 
 

 
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11 APPENDICES 
 
1. PBC-40 Questionnaire 
Jacoby A, Rannard A, Buck D, et al. Development, validation, and evaluation of the 
PBC-40, a disease specific health related quality of life measure for primary biliary 
cirrhosis. Gut 2005;54:1622–1629. 
 
2. Normal Reference Range of Laboratory Parameters 
 
 

 
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DECLARATION OF PRINCIPAL INVESTIGATOR 
 
 
STUDY TITLE: A Phase 2, Prospective, Multicenter, Randomized, Double-blind, Placebo-
controlled Study to Evaluate Safety, Tolerability and Efficacy of Saroglitazar Magnesium in 
Patients with Primary Biliary Cholangitis (EPICS). 
 
 
 
I, the undersigned, have read and understood this protocol and hereby agree to conduct the study 
in accordance with this protocol and to comply with all requirements regarding the obligations of 
Principal Investigator(s) and all other pertinent requirements of the ICH E6 ‘Guidelines on Good 
Clinical Practice’, Declaration of Helsinki (Fortaleza, 2013) and applicable regulatory authorities. 
 
All documentation for this study that is supplied to me, and that has not been previously published, will be 
kept in the strictest confidence. This documentation includes this study protocol, Investigator's Brochure, 
Case Report Forms, and other scientific data. Copying, disclosing and publishing without written consent 
of Sponsor is prohibited. 
 
The study will not be commenced without the prior written approval of Regulatory Authorities and a 
properly constituted Institutional Review Board (IRB) or Institutional Ethics Committee (IEC). No 
changes will be made to the study protocol without the prior written approval of the Sponsor and the IRB 
or IEC, except where necessary to eliminate an immediate hazard to the patients. 
 
I further agree to ensure that all associates assisting in the conduct of this study are well informed 
regarding their obligations and confirm to conduct this study under my direction at the following address: 
 
Name of the Principal Investigator: 
 
Name and Address of the site: 
 
 
Contact Details: 
 
 
______________________________________ _____/_____/__________ 
Signature                                                                          Date 
 
 
Note: Please retain original page of the investigator’s declaration at the site and send a copy of this page 
to the Sponsor.