Clinical trial NCT03863574
Conditions: Non Alcoholic Steatohepatitis
Keywords: NASH
Sponsor: Zydus Therapeutics Inc.
Start date: 2019-06-12; Completion date: 2020-03-20
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled study to evaluate safety and efficacy of Saroglitazar Magnesium 2 mg and 4 mg in patients with NASH. This study will be initiated after obtaining the approvals of Institutional Ethics Committee/Institutional Review Board (IEC/IRB) and the local regulatory authority.

Detailed description:
Patients clinically suspected of NASH will be invited for a screening programme for inclusion in the study. Patients will be screened according to the inclusion and exclusion criteria. Clinical evaluation will be conducted for baseline characteristics and anthropometry measurements such as body weight and height.

After clinical evaluations, all baseline safety and efficacy parameters will be recorded as per Visit Schedule. All laboratory collections will be performed following overnight fasting (at least 8 hrs).

Following confirmation of all clinical and laboratory inclusion and exclusion criteria, patients will continue into the screening period. During the screening period liver biopsy will be performed. However, if a biopsy was performed within 6 months the slides and biopsy material, or block, must be made available for baseline documentation. Such Patients, whose historical biopsy report is available, should not use medication suspected of having an effect on NASH from the 3 months prior to the screening.

Liver biopsy will be performed to confirm the diagnosis of NASH and record a baseline Non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS). The histological evidence of NASH is defined as NAS ≥ 4 with a minimum score of 1 for all of its three components \[steatosis, hepatocyte ballooning and lobular inflammation\].

Following confirmation of inclusion/exclusion criteria and upon histological confirmation of NASH by liver biopsy, patients will be enrolled into the study.

Eligible patients will be randomly assigned to receive Saroglitazar Magnesium 2 mg or 4 mg or placebo in a 2:2:1 ratio for 24 weeks.

Upon completion of 24 weeks of treatment, liver biopsy will be performed and the NAFLD Activity Score recorded.

Arms: arm 1: Saroglitazar Magnesium 2 mg tablet orally once daily in the morning before breakfast for 24 weeks. arm 2: Saroglitazar Magnesium 4 mg tablet orally once daily in the morning before breakfast for 24 weeks. arm 3: Placebo tablet orally once daily in the morning before breakfast for 24 weeks.
Interventions: intervention 1: Saroglitazar Magnesium 2mg intervention 2: Saroglitazar Magnesium 4mg intervention 3: Placebos
Intervention descriptions: intervention 1: Patients randomly assigned to this group will receive Saroglitazar Magnesium 2 mg tablet orally once daily for 24 weeks. intervention 2: Patients randomly assigned to this group will receive Saroglitazar Magnesium 4 mg tablet orally once daily for 24 weeks. intervention 3: Patients randomly assigned to this group will receive Placebo tablet orally once daily for 24 weeks.

Protocol documents:
Prot_000.pdf: 
NCT03863574










































 
 
Zydus Discovery DMCC 
CLINICAL TRIAL PROTOCOL  
 Saroglitazar Magnesium – Phase 2 
SARO.17.004 
CONFIDENTIAL 
Page 22 of 76 
 
 
Prepared by: 
Jatin Patel 
Approved by: 
Dr. Deven V Parmar 
Protocol No.: SARO.17.004.02.PROTOCOL 
Version No.: 2.0 
 
an adaptive response in fatty liver disease, when it would be an effective pathway to enhance 
insulin sensitivity and suppress inflammatory recruitment. Thus, while pharmacologic PPARα 
activation effectively 'cured' fibrosing steatohepatitis in a murine, dietary model, the efficacy of 
such agents is less clear in humans. PPARγ is found predominantly in adipocytes. It has both 
opposite and complementary functions to PPARα. Thus, PPARγ activation leads to 
differentiation of adipocytes from pre-adipocytes in-vitro. This increases the lipid storage 
capacity of the adipose mass and in animals, also increases the number of small, insulin-sensitive 
adipocytes so as to improve insulin sensitivity. Increasingly, the importance of PPARγ is being 
recognized in the liver, despite the relatively low levels of expression normally found there. 
Steatosis is often associated with increased hepatocyte expression of PPARγ.  
 
 
 
 
 
 
 
 
 
 
 
Therefore, a prospective, randomized, double-blind, placebo-controlled phase 2 study is designed 
to evaluate the safety and efficacy safety of Saroglitazar 2 mg and 4 mg in patients with NASH. 
2.3 
DRUG PROFILE 
Saroglitazar, a dual PPAR agonist with predominantly PPARα and a moderate PPARγ agonist 
activity, 
 
  


























 
 
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 Saroglitazar Magnesium – Phase 2 
SARO.17.004 
CONFIDENTIAL 
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Approved by: 
Dr. Deven V Parmar 
Protocol No.: SARO.17.004.02.PROTOCOL 
Version No.: 2.0 
 
5.1.2 Comparator Drug Description 
 Placebo will be used as comparator, which will be formulated as tablets, and will contain above 
mentioned excipients without Saroglitazar Magnesium 
 
 
 The IP will be manufactured following current-Good Manufacturing Practice 
(cGMP) guideline. 
5.2 
DOSAGE AND TREATMENT SCHEDULE 
Subjects will receive either Saroglitazar Magnesium 2 mg or 4 mg or placebo orally once each 
morning before breakfast for a period of 24-week. 
However, on the day of the scheduled clinical visit, subjects will have the IP administered on site 
after fasting blood sample collection. If on the day of a scheduled clinic visit the subject has 
already taken the IP, all procedures except blood sample collections will be performed. The 
subject will be asked to return the next day to have the blood sample collected, and will be 
reminded not to take the IP until after the blood sample collections. If the subject again returns 


 
 
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 Saroglitazar Magnesium – Phase 2 
SARO.17.004 
CONFIDENTIAL 
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Approved by: 
Dr. Deven V Parmar 
Protocol No.: SARO.17.004.02.PROTOCOL 
Version No.: 2.0 
having taken the IP, blood samples will be collected and the subject will be asked to return for 
the next scheduled visit. 
5.3 
PACKAGING, LABELLING AND SUPPLY 
Study drugs will be packed, labelled and supplied by the Sponsor according to all local 
regulatory requirements. 
 
 
 
. The PI or designee will confirm 
the receipt of IP in writing via fax/email.  
 
 
 
 
Unused drug supplies will be returned to the Sponsor (or designee) for destruction/ destroyed at 
the site after approval for the same by the Sponsor. No study drug will be destroyed or returned 
until complete drug accountability has been performed by the study monitor. All supplies must 
be accounted for at the end of the study period.  
At the time of or in proximity to the site initiation, each Investigator will be provided sufficient 
supply of study drug. Investigational product must be dispensed to each subject in such a way 
that the subject can take the doses in accordance with the Protocol. A drug accountability log(s) 
for recording the receipt, dispensing and return of the IP must be maintained by the PI or any 
designated personnel. The drug accountability log(s) must be kept up to date and must be made 
availability to the study monitor during monitoring visits. 
A temperature log must be maintained that the drug supplies are stored at the correct temperature 
throughout the study period. 
5.4 
STORAGE CONDITIONS 
Investigational products will be stored at room temperature (20°C to 25°C or 68°F to 77°F) in a 
dry place away from light at the study site or pharmacy. If the IP temperature extends outside the 


 
 
Zydus Discovery DMCC 
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 Saroglitazar Magnesium – Phase 2 
SARO.17.004 
CONFIDENTIAL 
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Approved by: 
Dr. Deven V Parmar 
Protocol No.: SARO.17.004.02.PROTOCOL 
Version No.: 2.0 
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. Protect the IP 
from light. All IP supplies in the study will be stored in a secure location with access limited to 
the Site Pharmacist or the PI designated site staff. 
5.5 
BLINDING/UNBLINDING 
The study will be performed in a double-blind manner. All study drug will be supplied in 
identical packages and study drug kits. The study drug tablets will be similar in color, smell, 
taste and appearance, thereby maintaining double-blind conditions. 
The blinding should not be broken except in a medical emergency where knowledge of the study 
drug received would affect the treatment of the emergency. 
The blinding must only be broken following a discussion on a case-by-case basis, at the 
discretion of the Sponsor/Medical Expert. If an emergency unblinding becomes necessary, the PI 
should notify the Sponsor/Medical Expert, if possible, before unblinding. If it is determined that 
unblinding is necessary, a scratch card/blinding envelop will be decoded to reveal the treatment 
received by the patient. All cases resulting in an unblinding event will be documented and 
reported to the Medical Expert and the Sponsor. If the blind is broken, the date, time and reason 
must be recorded in the patient’s eCRF/source document and any associated AE report 
completed. 
The overall randomization code will be broken only for reporting purposes. This will occur once 
all final clinical data have been entered into the database, all data queries have been resolved, 
and the assignment of patients to the analysis sets has been completed.  
5.6 
METHOD OF ASSIGNING SUBJECT TO TREATMENT GROUP 
Patients will be randomly assigned in a 2:2:1 ratio to Saroglitazar Magnesium 2 mg or 4 mg or 
placebo. The block randomization schedule will be generated using SAS® software (Version: 9.4 
or higher; SAS Institute Inc., USA)..  


 
 
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 Saroglitazar Magnesium – Phase 2 
SARO.17.004 
CONFIDENTIAL 
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Approved by: 
Dr. Deven V Parmar 
Protocol No.: SARO.17.004.02.PROTOCOL 
Version No.: 2.0 
5.7 
SELECTION OF DOSES 
Saroglitazar Magnesium 1 mg, 2 mg and 4 mg have favorably modified the lipid profile in the 
dyslipidemic patients during its development in Phase II and III studies. Based on the safety and 
efficacy results of Saroglitazar Magnesium, it was 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”. Based on these results, Saroglitazar Magnesium 2 mg and 4 mg 
doses have been selected for this study. 
5.8 
CONCOMITANT MEDICATIONS AND OTHER RESTRICTIONS 
5.8.1 Previous and Concomitant Medications 
Any medication the subject takes other than the study drug, including herbal and other 
non-traditional remedies, is considered a concomitant medication. All concomitant medications 
and any changes in the dosage or regimen of a concomitant medication for the 30 days preceding 
Visit 1 until the end of the study (i.e., the safety follow-up) must be recorded in the CRF. 
5.8.2 Restricted Concomitant Medications 
Drugs affecting insulin resistance (Glitazones/Glitazars/GLP-1 agonists) will not be allowed 
during the study.  
Other drugs claimed for treatment of NASH (pentoxyphyllin, ursodeoxycholic acid, antioxidants 
such as vitamin E (>800 IU/day), glutathione, orlistat, betaine, incretin mimetics or non-
prescribed complementary alternative medications (including dietary supplements, megadose 
vitamins, herbal preparations and special teas) will not be allowed during the study. However, 
patients who are taking stable dose of Vitamin E for at least 3 months will be enrolled in the 
study. 
Subjects also should not take any non-allowed over-the-counter medications or complementary 
and/or alternative medications believed to have a potential impact that would affect the ability to 
evaluate the study data. 


 
 
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 Saroglitazar Magnesium – Phase 2 
SARO.17.004 
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Approved by: 
Dr. Deven V Parmar 
Protocol No.: SARO.17.004.02.PROTOCOL 
Version No.: 2.0 
 
5.8.3 Permitted Concomitant Medications 
With the exception of excluded concomitant medications, other medications that subjects have 
been taking at stable dosages for at least 3 months prior to biopsy, i.e., statins, drugs for glycemic 
control and hypertension will be permitted as concomitant medications. To the extent possible, 
subjects should continue with their current regimen of medication without any change 
throughout the study. 
Allowed over-the-counter medications include acetaminophen (maximum 1 gram/day), 
ibuprofen (maximum 800 mg/day) or naproxen (maximum 440 mg/day) or antacids such as H2 
receptor blockers or proton-pump inhibitors for shorter duration as per Investigator discretion. 
The PI should be alerted if, during the course of the study, a subject requires a new medicine or 
therapy or a change to an established dosing regimen. All medications that target NAFLD or 
NASH, or have been suggested to target the underlying causes of NAFLD or NASH, should be 
reviewed and agreed on by the PI, Medical Expert and Sponsor before being taken by the 
subject. 
5.8.4 Other Restrictions 
5.8.4.1 Alcohol 
Subjects are encouraged to stop alcohol consumption entirely during the study. They are not 
permitted to consume >1 unit of alcohol per day (>7 units per week) during the study. Alcohol 
consumption will be recorded throughout the study period. 


 
 
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 Saroglitazar Magnesium – Phase 2 
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Dr. Deven V Parmar 
Protocol No.: SARO.17.004.02.PROTOCOL 
Version No.: 2.0 
 
5.8.4.2 Diet and Exercise 
Subjects must maintain lifestyle modifications, including diet and exercise, previously 
undertaken according to AASLD guidelines for the duration of the study. Subjects should make 
no major changes in the type or amount of exercise in which they partake during the study. 
5.9 
OVER DOSE AND DRUG INTERACTION 
No incidence of overdose with Saroglitazar Magnesium has been reported. In case of overdose 
with Saroglitazar Magnesium, general supportive care of the patient is indicated, including 
monitoring of vital signs and observation of clinical status. 
 
 
 
 
 
 
 
 
 
 
 
5.10 TREATMENT COMPLIANCE 
The patients will be asked to bring their bottles of the IP to the next visit; compliance for dosing 
will be assessed by examination of the bottles and tablet count by study personnel and 
documentation on Individual drug accountability log(s). Although 100% compliance to study 
drug is desired and should be encouraged throughout the treatment phase, a compliance of ≥80% 
and ≤120% will be considered acceptable. 


 
 
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 Saroglitazar Magnesium – Phase 2 
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Dr. Deven V Parmar 
Protocol No.: SARO.17.004.02.PROTOCOL 
Version No.: 2.0 
 
6 
OBSERVATIONS 
6.1 
CRITERIA FOR SAFETY 
6.1.1 Safety Variables 
The following safety assessments are conducted to evaluate the safety: 
 Frequency and severity of adverse events 
 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. 
 Body weight 
 Vital Signs 
 Clinical laboratory testing (hematology, clinical chemistry, serology and urinalysis). 
 12-lead electrocardiogram (ECG). 
6.1.2 Medical History and Demographic Information 
The medical history comprises: 
 General medical history 
 Medication history 
 Reproductive history. 
The following demographic information will be recorded: 
 Gender  
 Age  
 Ethnic origin  
 Race  
 Height  
 Body weight  
 Body mass index.  


 
 
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 Saroglitazar Magnesium – Phase 2 
SARO.17.004 
CONFIDENTIAL 
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Approved by: 
Dr. Deven V Parmar 
Protocol No.: SARO.17.004.02.PROTOCOL 
Version No.: 2.0 
6.1.3 Clinical Laboratory Assessments 
6.1.3.1 Sample Collection 
Blood samples will be collected for clinical laboratory testing at the time points indicated in the 
Schedule of Assessments (Table 1). Safety laboratory variables are listed in Table 4. 
Table 4 Safety Laboratory Assessments 
Hematology  
Complete blood count, hemoglobin, PT, INR. 
Electrolytes (sodium, potassium, chloride and bicarbonate) 
Clinical chemistry  
 
LFT: ALT, AST, ALP, total bilirubin, GGT, total proteins and albumin. 
Amylase and lipase 
RFT: Serum creatinine, blood urea nitrogen, eGFR 
Cardiac marker: CK  
Lipid Panel and lipoprotein: TG, sdLDL, LDL, VLDL, HDL, total 
cholesterol, non HDL cholesterol, Apo A1 and Apo B 
Glycemic control: Fasting plasma glucose, HbA1c 
TSH  
Urinalysis  
Urine Chemical Examinations: pH, specific gravity, protein, glucose, 
bilirubin, urobilinogen, ketone bodies and nitrite  
Urine Microscopy: epithelial cells, RBCs, pus cells, cast and crystals 
Serology  
 
HIV type 1 and type 2  
HAV IgM 
HBsAg 
HCV 
Pregnancy test  
 
Serum pregnancy test and urine pregnancy test for females of child-
bearing potential  
AST = aminotransferase; ALT = alanine aminotransferase; ALP = alkaline phosphatase; BUN = blood urea nitrogen; CK = 
creatinine kinase; eGFR = estimated Glomerular Filtration Rate; GGT = γ-glutamyl transferase; HAV IgM= anti hepatitis A 
virus; HbA1c = Glycosylated hemoglobin; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HDL = high-
density lipoprotein; HIV = human immunodeficiency virus; INR = international normalized ratio; LDL = low-density 
lipoprotein; PT = Prothrombin time; sdLDL = Small dense low density lipoprotein; RBC = Red blood cell, sdLDL = Small 
dense low density lipoprotein; TSH = Thyroid stimulating hormone; VLDL = very low density lipoprotein. 
6.1.3.2 Urine Tests 
Urine pregnancy test (females of child-bearing potential only at Visits 2, 3, 4, 5) will be 
processed by a local laboratory. 
6.1.3.3 Vital Signs 
The following vital signs will be assessed at time points described in the Schedule of 
Assessments (Table 1): 
 Sitting blood pressure (systolic and diastolic; mmHg)  


 
 
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 Saroglitazar Magnesium – Phase 2 
SARO.17.004 
CONFIDENTIAL 
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Approved by: 
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Protocol No.: SARO.17.004.02.PROTOCOL 
Version No.: 2.0 
 
 Pulse (beats per minute) 
 Oral body temperature (°F)  
 Respiratory rate (breaths per minute).  
Vitals signs will be measured before any blood draw that occurs at the same visit and after the 
patient has been resting for at least 5 minutes. 
6.1.3.4 Twelve-lead Electrocardiograms 
Electrocardiograms will be performed locally at the study site in accordance with the Schedule of 
Assessments (Table 1). Subjects should be in resting position for 5 minutes before ECG 
recording and performed before any blood draw that occurs at the same visit.  
6.1.3.5 Physical Examinations 
Physical examinations will be performed in accordance with the Schedule of Assessments 
(Table 1). Patients’ body weight will be recorded during all physical examinations. Height will 
be recorded at Screening Visit only). 
6.2 
EFFICACY 
6.2.1 Primary Endpoint 
The primary endpoint is to assess the changes in NAFLD Activity Score (NAS) at week 24 
from baseline and with no worsening of fibrosis in NASH patients. 
6.2.2 Secondary endpoints 
From baseline to Week 24: 
1. To evaluate the percentage of responders in the treatment groups. 
Responder is defined as a decrease from baseline of at least 2 points spread across at least 
2 of the NAS components [steatosis, hepatocyte ballooning, and lobular inflammation] 
with no worsening of fibrosis. 
2. Percentage of responders, defined by the disappearance of steatohepatitis.  
3. Changes in the stage of steatosis, lobular inflammation and ballooning. 
4. Changes in the stage of fibrosis. 


 
 
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 Saroglitazar Magnesium – Phase 2 
SARO.17.004 
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Protocol No.: SARO.17.004.02.PROTOCOL 
Version No.: 2.0 
 
5. Changes in the liver function tests. 
6. Changes in the lipid profile. 
7. Changes in the glycemic control and insulin resistance. 
8. To assess the safety of Saroglitazar Magnesium 2 mg and 4 mg in patients with non-
alcoholic steatohepatitis.  
(Safety will be assessed during the study period through the reporting of AEs, by clinical 
laboratory tests, ECGs, vital sign, physical examination and body weight assessment at 
various time points during the study). 
6.2.3 Blood Samples 
Multiple venipunctures should be avoided to collect blood samples. It is recommended to 
collect blood sample for safety and efficacy measurement at a given visit. 
Samples for secondary and exploratory efficacy variables will be assessed as follows: 
 Liver function tests include ALT, AST, ALP, direct bilirubin, GGT, total proteins and 
albumin. 
 Lipid parameters and lipoproteins include LDL, sdLDL, VLDL, HDL, triglyceride, total 
cholesterol, non HDL cholesterol, and Apolipoprotein A1, Apolipoprotein B. 
 Glycemic control includes FPG, fasting insulin, adiponectin, C-peptide, HOMA IR, HOMA 
beta and HbA1c. 
6.2.4 Total Amount of Blood 
The total amount of blood drawn from each subject over the study will not exceed 500 mL. 
6.3 
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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 Saroglitazar Magnesium – Phase 2 
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Protocol No.: SARO.17.004.02.PROTOCOL 
Version No.: 2.0 
 
6.4 
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 PI considers the abnormality as of medical relevance, he/she should also record this as an 
AE. If the findings contribute to a clinical diagnosis (e.g. hepatitis in case of increased liver 
enzymes), this diagnosis should be recorded as an AE. 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE are as follows: 
1. The test result is associated with accompanying symptoms, and/or 
2. The test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
3. The test result leads to change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment or other therapy, and/or 
4. The test result leads to any of the outcomes included in the definition of an SAE, and/or 
5. The test result is considered to be an AE by the PI or designee. 
For any abnormal test result that meets one of the above conditions except for the last condition, 
the PI or designee will provide a justification in the source documentation for not reporting the 
abnormal test finding as an AE. 
Each AE shall be evaluated for the severity, seriousness, duration, resolution, action taken and its 
association with the study drug. The study participant may be withdrawn or terminated from the 
study depending on the seriousness of the adverse event(s). 


 
 
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 Saroglitazar Magnesium – Phase 2 
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7 
INVESTIGATIONAL PLAN 
7.1 
STUDY DESIGN AND PLAN 
This is a randomized, double-blind, placebo-controlled, study to evaluate safety and efficacy of 
Saroglitazar Magnesium 2 mg and 4 mg in patients with NASH. This study will be initiated after 
obtaining the approvals of Institutional Ethics Committee/Institutional Review Board (IEC/IRB) 
and the local Regulatory Authority.  
It is the responsibility of the Principal Investigator (PI) to ensure that the study is conducted in 
accordance with the protocol, International Council for Harmonisation Good Clinical Practice, 
and all applicable regulatory requirements. Informed consent will be obtained before the start of 
any study related procedures. 
As per the contemporary guidelines, the PI shall maintain Source Documents (SD), Site Master 
File (SMF), Informed Consent Forms/Documents (ICF/ICD) and other logs/forms during the 
conduct of a study. 
All laboratory reports should be reviewed by the PI and/or his/her designee and any abnormal 
findings should be addressed. All protocol deviations occurring on the study shall be documented 
and the Sponsor and IEC/IRB informed. 
Patients clinically suspected of NASH will be invited for a screening programme for inclusion in 
the study. Patients will be screened according to the inclusion and exclusion criteria. Clinical 
evaluation will be conducted for baseline characteristics and anthropometry measurements such 
as body weight and height. 
After clinical evaluations, all baseline safety and efficacy parameters will be recorded as per 
Table 1. All laboratory collections will be performed following overnight fasting (at least 8 hrs). 
Following confirmation of all clinical and laboratory inclusion and exclusion criteria, patients 
will continue into the screening period. During the screening period liver biopsy will be 
performed. However, if a biopsy was performed within 6 months the slides and biopsy material, 
or block, must be made available for baseline documentation. Such Patients, whose historical 
biopsy report is available, should not use medication suspected of having an effect on NASH 
from the 3 months prior to the screening. 




 
 
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CLINICAL TRIAL PROTOCOL  
 Saroglitazar Magnesium – Phase 2 
SARO.17.004 
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Protocol No.: SARO.17.004.02.PROTOCOL 
Version No.: 2.0 
 
7.2 
STUDY PROCEDURES AT EACH VISIT 
Visit Schedule  
 Screening Visit 1 [Week -4 (-28 days) ]  
a. All patients will be required to sign and date the IRB/IEC approved ICF after all 
study-related procedures have been explained by the PI/designee and understanding 
the contents.  
b. The informed consent process will be documented in the Source Documents, ICF and 
other relevant logs and signed and dated by the Investigator or delegated study team 
members on site. Prior to subject participation in the study, written informed consent 
will be obtained from each subject according to the regulatory and legal requirements 
of the participating country, including state-specific requirements. 
c. Patients will be screened for eligibility; those qualifying will be invited to participate 
in the study.  
d. Demographics, vitals, physical examination, medical history, prior and concomitant 
medication review will be recorded.  
e. Clinical evaluation will be done for baseline characteristics and body weight will be 
recorded. 
f. After clinical evaluations, all baseline safety and efficacy parameters will be assessed 
as per Table 1. All laboratory investigations will be performed on overnight fasting 
blood samples. Electrocardiograph (ECG) will be performed. 
g. Serum pregnancy test will be done for females of child-bearing potential. 
h. Patients are advised to maintain a stable life-style. 
i. Adverse events will be recorded.  
Liver biopsy Visit  
a. Liver biopsy will be done after the patient passes all other inclusion and exclusion 
criteria to confirm NASH diagnosis and record a baseline NAFLD Activity Score 
(Appendix 2). If biopsy is done within 6 months, the slides, biopsy material or block 
should be available for baseline documentation. Such patients, whose historical biopsy 


 
 
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 Saroglitazar Magnesium – Phase 2 
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Version No.: 2.0 
 
report is available, should not use medication suspected of having an effect on NASH 
from the 3 months prior to the Screening. 
b. Liver biopsy will be performed with a 16 gauge (1.6 mm) needle with Ultrasound 
guidance. The length of the specimen collected should be  approximately 1.5 cm. The 
specimen will be read centrally for NAFLD Activity Score by pathologist at Virginia 
Commonwealth University, Medical Center, 1250 E Marshall St Richmond, VA 
23298 United States. 
 Visit 2 Enrollment Visit [Week 0, Day 1+/- 7 Days]  
a. Patients satisfying the inclusion and exclusion criteria will be randomly assigned to 
receive Saroglitazar Magnesium 2 mg or 4 mg or placebo. 
b. Patients will undergo physical examination.  
c. Concomitant medications will be assessed.  
d. Vitals signs will be recorded. 
e. Body weight will be recorded. 
f. ECG will be performed. 
g. Adverse events will be recorded. 
h. Urine pregnancy test will be performed for females of child-bearing potential. 
i. Safety and efficacy parameters will be assessed as per Table 1. 
j. A 6-week supply of investigational product will be dispensed (42 tablets + 7 tablets 
for one week allowance). 
k. Patients are advised to maintain a stable life-style.  
 Visit 3 [Day 43 (+/- 7 Days)] 
a. Patients will undergo physical examination.  
b. Vitals signs will be measured.  
c. Body weight will be recorded. 
d. Medication compliance and concomitant medication will be assessed.  
e. A 6-week supply of investigational product will be dispensed (42 tablets + 7 tablets 
for one week allowance).  
f. Safety and efficacy parameters will be assessed as per Table 1.  
g. Adverse events will be recorded. 


 
 
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 Saroglitazar Magnesium – Phase 2 
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h. Urine pregnancy test will be performed for females of child-bearing potential. 
i. Patients will be advised to maintain a stable lifestyle.  
 Visit 4 [Day 85 (+/- 7 Days)] 
a. Patients will undergo physical examination.  
b. Vitals signs will be measured.  
c. Body weight will be recorded. 
d. Medication compliance and concomitant medication will be assessed.  
e. ECG will be performed. 
f. A 6-week supply of investigational product will be dispensed (42 tablets + 7 tablets 
for one week allowance).  
g. Safety and efficacy parameters will be assessed as per Table 1.  
h. Adverse events will be recorded. 
i. Urine pregnancy test will be performed for females of child-bearing potential. 
j. Patients will be advised to maintain a stable lifestyle.  
 Visit 5 [Day 127 (+/- 7 Days)] 
a. Patients will undergo physical examination.  
b. Vitals signs will be measured.  
c. Body weight will be recorded. 
d. Medication compliance and concomitant medication will be assessed.  
e. Safety and efficacy parameters will be assessed as per Table 1. 
f. A 6-week supply of investigational product will be dispensed (42 tablets + 7 tablets 
for one week allowance).  
g. Adverse events will be recorded. 
h. Urine pregnancy test will be performed for females of child-bearing potential. 
i. Patients will be advised to maintain a stable lifestyle.  
 Visit 6 [Day169 (+/- 7 Days)] 
a. Patients will undergo physical examination.  
b. Vitals signs will be measured.  
c. Body weight will be recorded. 
d. Medication compliance and concomitant medication will be assessed.  


 
 
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e. ECG will be performed. 
f. Liver biopsy will be performed to record final NAFLD Activity Score (Appendix 2).  
g. Safety and efficacy parameters will be assessed as per Table 1.  
h. Adverse events will be recorded.  
i. Serum pregnancy test will be performed for females of child-bearing potential. 
j. Patients will be advised to maintain a stable lifestyle. 
 Visit 7 Follow-Up Visit [Day 197 (+/- 7 Days)] 
a. Patients will undergo physical examination.  
b. Vitals signs will be measured.  
c. Body weight will be recorded. 
d. Concomitant medication will be assessed. 
e. ECG will be performed.  
f. Safety parameters will be assessed as per Table 1.  
g. Adverse events will be recorded.  
7.3 
ADHERENCE TO PROTOCOL 
The PI and the site staff shall strictly adhere to the protocol and GCP guidelines. All patients will 
be strictly required to follow the instructions given to them as per this protocol. For any 
deviation or violation from protocol, considered serious, the patient may be withdrawn from the 
study at the discretion of the Sponsor or the PI. 
7.4 
DATA MONITORING COMMITTEE 
Safety data will be reviewed regularly by a Data Monitoring Committee (DMC). The Data 
Monitoring Committee comprised of an unblinded independent statistician and hepatologist who 
will review periodic reports from the EDC. The formal structure and conduct of DMC will be 
according to a previously agreed upon remit.  
7.5 
PROTOCOL DEVIATIONS 
For the purpose of this study, no distinction will be made between Protocol Violations and 
Deviations. Deviations will be categorized as Clinical Study Report (CSR) non-reportable 
protocol deviations and as CSR reportable protocol deviations. A CSR non-reportable protocol 
deviation includes any deviations that do not necessarily influence the results/outcome of 


 
 
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primary endpoints or patient safety. A CSR non-reportable protocol deviation does not require 
immediate notification to the IRB/IEC unless otherwise specified by IRB/IEC requirements. All 
CSR non-reportable protocol deviations will be noted in monitoring reports and provided to the 
PI by monitor, if required.   
A CSR reportable protocol deviation includes any violation that may influence the 
results/outcome of primary endpoints or patient safety. CSR reportable protocol deviations must 
be reported immediately to the Regulatory, IRB/IEC, as specified by the regulatory 
requirements. All CSR reportable protocol deviations will also be reported to the Sponsor 
immediately. These deviations will also be noted in the monitoring reports and provided to the PI 
by monitor. 
Note: Persistent non-compliance of CSR non-reportable protocol deviations may rise to the level 
of being considered CSR reportable protocol deviations (i.e., persistent non-compliance with 
dosing). 
The Sponsor reserves the right to terminate the study at a given site in the event of monitoring 
and/or auditing findings of serious or persistent non-compliance with the protocol, SOPs, GCP 
and/or applicable regulatory requirement(s) by the PI/Institution. In all cases of site closure due 
to protocol deviations, the IRB/IEC and regulatory authorities will be informed. 
The clinical study report will provide the list of protocol deviations in a separate section. The 
result will be analysed for all participants with CSR reportable protocol deviations.  
Protocol deviations will include but are not limited to the following; 
 Patients who did not meet entry criteria. 
 Patients who received the wrong treatment or incorrect dose. 
 Patients who received restricted medications. 
 Failure to report within specified time lines of the planned visits. 
 IP non-compliance of 80% or >120%. 
7.6 
ADJUDICATION 
An external independent Central Adjudication Committee (CAC) will adjudicate serious adverse 
events (SAEs), including all deaths, that are known or suspected to be a Major Adverse Cardiac 
Events (MACE) or heart failure hospitalizations. The CAC members will be independent of the 


 
 
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Sponsor, the clinical study sites and Investigators. The blinded medical review of known or 
suspected MACE will primarily focus on CV death, myocardial infarction, cerebrovascular 
accident (stroke) and hospitalization for heart failure.   
A detailed CAC Charter and adjudication process will be described in a separate document. 


 
 
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8 
BIOSTATISTICS 
8.1 
STATISTICAL DESIGN 
Statistical analysis will be performed on efficacy variables.  
As this is a proof of concept (PoC) study no formal hypothesis testing will be done. All primary 
and secondary efficacy analysis will be summarised and analysed, appropriately, for modified 
Intent-To-Treat (mITT) and Per Protocol (PP) populations. The PP population will consist of all 
randomized patients completing the treatment phase (has taken ≥80% and ≤120% of the study 
drug) as per the study protocol and do not have any CSR reportable protocol deviation in such a 
way that could affect efficacy outcome. The mITT population will consist of all randomized 
patients who have taken at least one dose of the study treatment and have at least one post-
baseline efficacy data. Last observation carried forward method will be used as an imputation 
method for post-baseline missing values for mITT analysis. 
8.2 
PLANNED ANALYSIS 
8.2.1 Populations 
8.2.1.1 Safety population 
The safety population includes all enrolled patients who received at least single dose of IP. 
8.2.1.2 Modified intention-to-treat population (mITT) 
The modified intent-to-treat (mITT) population includes: 
1. All enrolled patients who received at least one dose of the IP. 
2. Appear for at least one post baseline visit. 
All primary and secondary objectives will be analyzed using mITT population with post-baseline 
LOCF method. Last observation carried forward (LOCF) method will be used as an imputation 
method for post-baseline missing values.  
8.2.1.3 Per-protocol population (PP) 
The per-protocol population (PP) includes: 
1. All enrolled patients who meet all the eligibility criteria. 


 
 
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2. Completed the study in compliance with the protocol. 
3. Do not have any CSR reportable protocol deviation that affects the evaluation of the 
efficacy endpoints. 
8.2.2 Statistical Analysis 
As this is a proof of concept (PoC) study no formal hypothesis testing will be done.  
All primary and secondary efficacy analysis will be summarised and analysed, appropriately, for 
modified Intent-To-Treat (mITT) and Per Protocol (PP) populations. 
Change and percentage change for primary and secondary efficacy endpoints (continuous data) 
will be calculated as follows: 
Change from baseline to Week 24 will be determined as (Week 24 - Baseline) and  
Percentage change from baseline will be determined as [(Week 24 - Baseline)/Baseline]*100. 
All primary and sceondary endpoints will be summarized as: n, mean, standard deviation, 
median, minimum and maximum for continuous variables; count and percentage for categorical 
variables at each visit. 
8.2.3 Safety Analysis 
All safety analysis will be carried out on the safety population. The frequency tabulations of 
abnormal clinical laboratory values for the parameter will be presented by visit. Summary 
statistics for clinical laboratory parameters, ECG, physical examination and vital signs will be 
presented by visit.  
All AEs observed during the study period will be listed. Incidence of all AEs reported during the 
study will be summarized using the Medical Dictionary for Regulatory Activities (MedDRA) 
(version 19 or higher) by body system, frequency, severity, seriousness and relationship to study 
drug and expectedness. Frequency and percentage of AEs occur during the course of study will 
be calculated and presented in the report. All AEs will be assessed for causality, severity and 
seriousness. The frequency tabulations of abnormal clinical laboratory values for the parameter 
will be presented by visit. Summary statistics for clinical laboratory findings and vital signs will 
be presented. 


 
 
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8.2.4 Demographic and Baseline Characteristics 
Demographic characteristics and baseline characteristics will be summarized. Subject disposition 
and reasons for withdrawal will be presented 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 count and percentage. 
8.2.5 Interim Analysis 
No interim analysis will be performed. 
8.2.6 Handling of Missing Data 
Clarifications, wherever possible, will be obtained from the PI or designee for any missing data 
or for any illegible entry, unused or unauthenticated data. 
Patients who are discontinued from the study will be excluded from PP analysis set. Any 
enrolled patient who are discontinued from the study for any reason and have at least one post-
baseline efficacy measurement will be included in the mITT analysis set. LOCF method will be 
used as an imputation method for post-baseline missing values in mITT population set. 
8.3 
RANDOMIZATION 
Patients will be randomly assigned in a 2:2:1 treatment allocation ratio to Saroglitazar 
Magnesium 2 mg and 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). 
8.4 
DETERMINATION OF SAMPLE SIZE 
This proof of concept study will include total 15 patients receiving from a multiple centers in a 
ratio of 2:2:1 to have 6 patients in Saroglitazar Magnesium 2 mg, 6 patients in Saroglitazar 4 mg 
and 3 patients in placebo arm for 24 weeks. 


 
 
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9 
ADMINISTRATIVE MATTERS 
The study will be carried out in compliance with the protocol, in accordance with the ICH 
Harmonised Tripartite Guideline for GCP and in accordance with applicable regulatory 
requirements. 
9.1 
ETHICS 
9.1.1 Institutional Committee Review and Communications 
The study will not be initiated before the protocol and, informed consent and patient information 
form have been reviewed and have received approval/favorable opinion from a registered 
IEC/IRB. Should a protocol amendment be written that requires central 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 patients may be 
implemented immediately providing that the appropriate regulatory authorities and IEC/IRB are 
notified as soon as possible (no longer than 5 days) 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 Authorities 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 PI or designee must provide the name and address of the IEC/IRB 
along with a statement from the IEC/IRB that it is organised according to GCP and 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 patient participation in the study, written informed consent will be obtained from each 
patient (or the patient’s legally accepted representative) according to the regulatory and legal 
requirements of the participating country and site. Each signature must be dated by each 
signatory and the informed consent and any additional patient information form retained by the 


 
 
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PI or designee as part of the study records. A signed copy of the informed consent and any 
additional patient information must be given to each patient or the patient’s legally authorised 
representative. 
The patient must be informed that his/her medical records may be examined by authorised 
monitors or Clinical Quality auditors appointed by the Sponsor, by appropriate IEC/IRB 
members and by inspectors from regulatory authorities.  
Should a protocol amendment be made, the patient informed consent form and patient 
information form may need to be revised to reflect the changes to the protocol. It is the 
responsibility of the PI to ensure that an amended consent form is reviewed and has received 
approval/favorable opinion from the IRB or IEC and that it is signed by all patients subsequently 
entered in the study and those currently in the study, if affected by the amendment. 
9.2 
DATA MANAGEMENT AND RECORD KEEPING 
9.2.1 Drug Accountability 
Drug supplies, which will be provided by the Sponsor, must be kept in a secure, controlled 
access storage area under 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 PI and/or pharmacist must maintain records of the product’s delivery to the study site, the 
inventory at the site, the dispensation to each patient and the return to the Sponsor or alternative 
disposition of unused product(s). These records will include dates, quantities, batch/serial 
numbers, expiration dates (if applicable) and the unique code numbers assigned to the IP(s) and 
study participants. The PI or designee will maintain records that document adequately that the 
patients were provided the doses specified by the protocol and reconcile all IP(s) received from 
the Sponsor. At the time of return to the Sponsor, the PI or designee must verify that all unused 
or partially used drug supplies have been returned by the study participants and that no 
remaining supplies are in the PI or site’s possession. 


 
 
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9.2.2 Data Management 
9.2.2.1 Data Handling 
Data will be recorded by the PI or designee into eCRFs and reviewed by the study monitor 
during monitoring visits. The study monitor will verify data recorded in the electronic data 
capture (EDC) system against source documents. All corrections or changes made to any study 
data must be appropriately tracked in an audit trail in the EDC system. An eCRF will be 
considered complete when all missing, incorrect and/or inconsistent data has been accounted for 
and the eCRF is signed by the PI. 
9.2.2.2 Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
9.2.2.3 Data Entry 
Data must be recorded in to the EDC system in a timely manner as the study is in progress. All 
site personnel must log into the system using their secure user name and password in order to 
enter, review, or correct study data. These procedures must comply with the appropriate 
international regulations. All passwords will be strictly confidential. 
9.2.2.4 Medical Information Coding 
For medical information, the following thesauri will be used: 
 Latest version of MedDRA for adverse events and medical history and 
 WHO Drug Dictionary for prior and concomitant medications. 
9.2.2.5 Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for reconciliation/resolution through data queries. 


 
 
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The eCRFs must be reviewed and approved/signed by the PI. 
9.2.3 Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the PI’s site. Data reported on the eCRFs 
must be consistent with the source documents or the discrepancies must be explained. 
The PI or designee may need to request previous medical records from another institution, 
depending on the study; 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 source 
documents: 
1. Subject identification (subject number, gender, date of birth/age) 
2. Subject participation in the study (subject number, date informed consent given) 
3. Dates of subject’s visits 
4. Medical history 
5. Medication history 
6. AEs (onset and end) 
7. SAEs (onset and end) 
8. 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. 
9. Conclusion of patient’s participation in the study. 
9.2.4 Direct access to Source Data/Documents 
The PI/ Institution will permit study-related monitoring, audits, IRB/IEC reviews and regulatory 
inspections by providing direct access to all related source data/documents. Case report forms 
and all source documents, including progress notes and copies of laboratory and medical test 
results must be available at all times for review by the Sponsor’s clinical trial monitor(s), 
auditor(s) and inspection by applicable regulatory authorities. The on-site monitor will review all 
eCRFs and ICFs. The accuracy of the data will be verified by reviewing the documents described 
in Section 9.2.3. 


 
 
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All ECG’s will be conducted locally. A photocopy should be made of the ECG and assessment 
of clinical significance should be conducted by site staff personnel delegated to do so. 
9.2.5 Trial Monitoring 
It is the responsibility of the PI 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 PI, and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized and easily retrievable data. 
Before the enrollment of any subject in this study, the Sponsor or their designee will review with 
the PI and site personnel the following documents: protocol, Investigator’s Brochure, eCRFs and 
procedures for their completion, informed consent process and the procedure for reporting SAEs. 
The PI will permit the Sponsor or their designee to monitor the study as frequently as deemed 
necessary to determine that data recording and protocol adherence are satisfactory. During the 
monitoring visits, information recorded on the eCRFs will be verified against source documents 
and requests for clarification or correction may be made. After the eCRF data is entered by the 
site, the monitor will review the data for safety information, completeness, accuracy and logical 
consistency. Computer programs that identify data inconsistencies may be used to help monitor 
the clinical study. If necessary, requests for clarification or correction will be sent to PIs. The PI 
and his/her staff will be expected to cooperate with the monitor and provide any missing 
information. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
9.3 
QUALITY AUDITS 
Quality audits of this study may be conducted by the Sponsor or Sponsor’s designees. The 
quality auditor must have access to all medical records, the study-related files and 
correspondence, and the informed consent documentation that is relevant to this clinical study. 


 
 
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9.4 
PROCEDURES 
9.4.1 Adverse Events 
All AEs occurring during the course of the clinical study from the signing of the informed 
consent onwards will be collected, documented and reported to the Sponsor by the PI or designee 
according to the specific definitions and instructions detailed in this section. The Common 
Terminology Criteria for Adverse Event (CTCAE) (Version 4.03 or higher) system will be used 
for reporting and grading AEs. 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. 
Any medical condition already present at screening should not be reported as an 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 PI will exercise his or her medical and scientific judgment 
in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. Clinically significant abnormal laboratory values occurring during the clinical study 
will be followed until repeat tests return to normal, stabilize, or are no longer clinically 
significant. Any abnormal test that is determined to be an error does not require reporting as an 
AE. 
9.4.2 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that: 
1. Results in death; 
2. Is life threatening; 
3. Results in persistent or significant disability/incapacity; 
4. Results in inpatient hospitalization or prolongs an existing inpatient hospitalization; 


 
 
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5. Is a congenital anomaly/birth defect; 
6. Is another important medical event that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
Serious adverse event reporting-procedures for Investigator:  
Initial Reports: 
Any SAE, or follow-up to a 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 SAE, considered by the PI or designee, who is a qualified physician to be 
related to the Sponsor’s product that is brought to the attention of the PI or designee at any time 
outside of the time period specified in the previous paragraph also must be reported immediately 
to the Sponsor.   
To report an SAE, complete the SAE form electronically in the EDC system for the study. When 
the form is completed, the CRO/Sponsor Safety personnel will be notified electronically. 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 SAE form/information 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: 


 
 
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Follow-Up Reports 
All patients with serious adverse events must be followed up for outcome. Within 24 hours of 
receipt of follow-up information, the PI or designee must update the SAE form electronically in 
the EDC system and submit any supporting documentation (e.g., subject discharge summary or 
autopsy reports) to 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 Follow-up of Adverse Events 
All AEs experienced by a subject, irrespective of the suspected causality, will be monitored until 
the AE has resolved, any abnormal laboratory values have returned to baseline or stabilized at a 
level acceptable to the PI and Medical Expert, until there is a satisfactory explanation for the 
changes observed, until the subject is lost to follow-up or until the subject has died. 
9.4.4 Evaluating Adverse Events 
Each AE will be assessed by the PI or a medically-qualified investigator with regard to the 
following categories: 
9.4.4.1 Severity  
The PI or designee will provide an assessment of the severity of each AE by recording a severity 
rating on the appropriate AE reporting page of the subject’s eCRF. The Common Terminology 
Criteria for Adverse Event (CTCAE) (Version 4.03 or higher) system will be used for reporting 
and grading AEs severity of events not classified in CTCAE will be assessed according to the 
following scale:  
Mild: Event is usually transient and easily tolerated, requiring no special treatment and causing 
no disruption of the subject’s normal daily activities.  
Moderate: Event introduces a low level of inconvenience or concern to the subject and may 
interfere with daily activities, but is usually improved by simple therapeutic measures. Moderate 
experiences may cause some interference with functioning.  
Severe: Event interrupts the subject’s normal daily activities and generally requires systemic 
drug therapy or other treatment. Severe events are usually incapacitating. 


 
 
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9.4.4.2 Causality  
For all AEs, the PI or designee will provide an assessment of causal relationship to study drug. 
The causality assessment must be recorded on the appropriate AE reporting page of the subject’s 
eCRF. 
Causal relationship will be classified according to the following criteria: 
 Unrelated 
 Possibly related: Suggests that the association of the AE with the study drug is unknown. 
However, the AE is not reasonably supported/explained by other conditions. 
 Probably related: Suggests that a reasonable temporal sequence of the AE with study 
drug administration exists and, based upon the PI’s clinical experience, the association of 
the AE with study drug seems likely. 
 Definitely related: Suggests that a causal relationship exists between the study drug and 
the AE, and other conditions (concomitant illness, progression or expression of the 
disease state, reaction to concomitant medication) do not appear to explain the AE. 
 Unknown 
9.4.4.3 Outcome 
Outcome of AEs will be defined according to the International Council for Harmonisation (ICH) 
Topic E2B, ICH Guideline, as follows: 
 Recovered/Resolved  
 Recovered/Resolved with sequelae  
 Recovering/Resolving  
 Not Recovered/Not Resolved  
 Fatal/results in death  
 Unknown 
9.4.5 Expected Adverse Events 
Adverse events reported by 2% or more subjects treated with Saroglitazar Magnesium during the 
double-blind, active-controlled study with Pioglitazone as the comparator regardless of causality 


 
 
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included gastritis and asthenia. In the double-blind placebo controlled study, AEs reported by 2% 
or more subjects treated with Saroglitazar Magnesium included gastritis, dyspepsia, pyrexia and 
pain. The details of AE(s) experienced during the Saroglitazar studies are mentioned in the IB. 
Principal Investigator(s) are advised to provide protocol education for patients and caregivers for 
potential symptoms of adverse effects that should be reported to the site/PI, such as skeletal 
muscle pain, weight gain, peripheral edema, shortness of breath, hypoglycaemia, etc. 
9.4.6 Pregnancy 
At the Screening Visit, Visit 6 and Visit 7, every female subject of child-bearing potential will be 
tested for serum pregnancy test. Urine pregnancy test will be performed at Visit 2, 3, 4 and Visit 
5. Women are advised not to become pregnant during the study and for at least 4 weeks ± 7 days 
after the end of the treatment period. Adequate contraceptive measures shall be used to prevent 
pregnancy. Even when contraceptive methods are used, there is a small risk that pregnancy might 
occur. In case a patient becomes pregnant, then she will be withdrawn from the study and 
adequate monitoring of the patients will be conducted. 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of the 
PI or their designees to report any pregnancy or lactation in a patient (spontaneously reported to 
them) that occurs during the study or within 4 weeks of completing the study. All patients who 
become pregnant must be followed to the completion/termination of the pregnancy. Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, 
fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) 
must also be reported. 
The PI or designee should report the pregnancy to Sponsor within 24 hours of being notified. 
Sponsor will then forward the completed Exposure-in-Utero form to the PI..  
9.5 
RULES FOR AMENDING PROTOCOL 
All amendments must be documented, dated and signed by all signatories (or their successors) of 
the original protocol and then will be submitted to Regulatory Authorities/IEC/IRB. 


 
 
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Modification only for logistical or administrative changes may be implemented immediately; 
however, both the IEC/IRB and the Regulatory Authority will be notified. 
9.6 
FINANCIAL DISCLOSURE 
The PI and sub-investigator are required to provide financial disclosure information to the 
Sponsor to permit the Sponsor to fulfil its obligations. In addition, the PI/sub-investigator must 
commit to promptly update this information if any relevant changes occur during the study and 
for a period of 1 year after the completion of the study. 
9.7 
DISCONTINUATION OF THE TRIAL BY THE SPONSOR 
The Sponsor reserves the right to discontinue this study at any time for failure to meet expected 
enrollment goals, for safety, or any administrative reasons. The Investigator will be reimbursed 
for reasonable expenses incurred if it is necessary to terminate the study as per the agreement. 
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, and site personnel, the Sponsor’s representatives, Monitor, Auditor, to the IRB or 
IEC and the regulatory health authorities as required under the law. Subject confidentiality will 
be further ensured by utilising subject identification code numbers to correspond to treatment 
data in the computer files. 
Such medical information may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. 
Data generated as a result of this study are to be 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 the PI and according to the standards of the 
Sponsor. It will include the tabulated data and the biostatistical report on the data. 


 
 
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Zydus Discovery DMCC is, as much as possible, dedicated to support process of free exchange 
of relevant scientific information. Any publication of the results of this study must be consistent 
with the ZYDUS publication policy. The rights of the PI and of the Sponsor with regard to 
publication of the results of this study are described in the Investigator agreement. 
9.10 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 study will be kept as per the SOPs of the 
institution. No document pertinent to the study shall be destroyed without prior written 
agreement between the Sponsor and the PI. All documents should be preserved safely after the 
completion/termination of the study for at least a period of 5 years if it is not possible to 
maintain the same permanently. 
 


 
 
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10 REFERENCES 
1. Georgescu EF; Georgescu, M. Therapeutic Options in Non-Alcoholic Steatohepatitis 
(NASH). Are all Agents Alike? Results of a Preliminary Study. J Gastrointestin Liver 
Dis. 2007:16(1);39-46. 
2. Naga Chalasani, Zobair Younossi, Joel E. Lavine, Anna Mae Diehl, Elizabeth M. Brunt, 
Kenneth Cusi, Michael Charlton, Arun J. Sanyal. The Diagnosis and Management of 
Non-Alcoholic Fatty Liver Disease: Practice Guideline by the American Association for 
the Study of Liver Diseases, American College of Gastroenterology and the American 
Gastroenterological Association. Hepatology. 2012; 55(6): 2005-2023. 
3. Kleiner et al. Design and Validation of a Histological Scoring System for Nonalcoholic 
Fatty Liver Disease. Hepatology. 2005:41(6);1313-1321. 
4. Jorge A et al. Assessment of treatment response in Non-Alcoholic steatohepatitis using 
advanced magnetic resonance imaging. Annals of Hepatology. 2014:13 (2): 166-178.  
5. Kugelmas et al. Cytokines and NASH: A Pilot Study of the Effects of Lifestyle 
Modification and Vitamin E Hepatology. 2003;38:413-419. 
6. Krauss et al., AHA Dietary Guidelines: Revision 2000: A Statement for Healthcare 
Professionals From the Nutrition Committee of the American Heart Association 
Circulation. 2000;102:2284-2299. 
7. Ibrahim et al., Nonalcoholic fatty liver disease: current and potential therapies. Life Sci. 
2013;92(2):114-8. 
8. Arun J. Sanyal, Elizabeth M. Brunt, David E. Kleiner, Kris V. Kowdley, Naga Chalasani, 
Joel E. Lavine, VladRatziu and Arthur McCullough. Endpoints and Clinical Trial Design 
for Nonalcoholic Steatohepatitis. Hepatology. 2011;54:344-353. 
9. Pai V, Paneerselvam A, Mukhopadhyay S, Bhansali A, Kamath D, Shankar V, Gambhire 
D, Jani RH, Joshi S, Patel P (2014) 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. DOI: 
10.1177/1932296813518680 
10. 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 


 
 
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saroglitazar 2 and 4 mg compared with placebo in type 2 diabetes mellitus patients 
having hypertriglyceridemia not controlled with atorvastatin therapy (PRESS VI). 
Diabetes Technology & Therapeutics. 2014;16(2): DOI: 10.1089/dia.2013.0253. 
11. Jani RH, Kansagra K, Jain M, Patel H: Pharmacokinetics, safety and tolerability of 
saroglitazar (ZYH1), a predominant PPARα agonist and moderate  agonist activity in 
healthy human subjects. Clin Drug Investig 2013;33:809-816.  
12. Claudia Filozof, Barry J. Goldstein, Richard N. Williams, Arun Sanyal. Non-Alcoholic 
Steatohepatitis: Limited Available Treatment Options but Promising Drugs in 
Development and Recent Progress Towards a Regulatory Approval Pathway. Drugs 
2015;75:1373–1392. 
13. Galgani J, Ravussin E. Energy metabolism, fuel selection and body weight regulation. Int 
J Obes. 2008;32:S109-S119.  
14. International conference on harmonisation of technical requirements for registration of 
pharmaceuticals for human use ICH harmonised guideline integrated addendum to ICH 
E6(R1): guideline for good clinical practice E6(R2) Current Step 2 version dated 11 June 
2015. 








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


 
 
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Appendix 2: NAFLD Activity Score 
 
NAFLD Activity Score 
Item 
Definition 
Score/Code 
Low- to medium-power evaluation of parenchymal involvement by steatosis 
Steatosis 
<5% 
0 
5% -33% 
1 
>33% -66% 
2 
>66% 
3 
Inflammation 
Lobular Inflammation 
No foci 
0 
<2 foci per 200 X field 
1 
2-4 foci per 200 X field 
2 
>4 foci per 200 X field 
3 
Liver cell injury 
Ballooning* 
None 
0 
Few balloon cells 
1 
Many cells/prominent 
ballooning 
2 
*Ballooning classification: few indicates rare but definite ballooned hepatocytes as well as case that are 
diagnostically borderline 
Final NAFLD Activity Score = Steatosis Score + Lobular Inflammation Score + Ballooning Score 
Fibrosis Score 
Item 
Definition 
Score/Code 
Fibrosis Stage 
None 
0 
Perisinusoidal or periportal 
1 
Mild, zone 3,perisinusoidal 
1A 
Moderate, 
zone3, 
perisinusoidal 
1B 
Portal/periportal 
1C 
Perisinusoidal and 
portal/periportal 
2 
Bridging fibrosis 
3 
Cirrhosis 
4 
Adapted from: Design and Validation of a Histological Scoring System for Non-alcoholic 
Fatty Liver Disease. (HEPATOLOGY, Vol. 41, No. 6, 2005 KLEINER ETAL.) 
 


 
 
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APPENDIX 3: Normal Laboratory Range 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: