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CTRI Number  CTRI/2019/12/022339 [Registered on: 12/12/2019] Trial Registered Prospectively
Last Modified On: 04/12/2019
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug
Behavioral 
Study Design  Randomized, Parallel Group, Multiple Arm Trial 
Public Title of Study   Treatment of nonalcoholic fatty liver using different types of medicines and lifestyle changes  
Scientific Title of Study   An Investigator initiated prospective, four arms randomized comparative study of efficacy and safety of Saroglitazar, Vitamin E and Life style modification in patients with Non alcoholic fatty liver disease (NAFLD)/ Non-alcoholic Steatohepatitis (NASH). 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
ECR/346/Inst/AP/2013/RR-16  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Mithun Sharma 
Designation  Consultant Hepatologist 
Affiliation  Asian Institute of Gastroenterology 
Address  Cluster M, Department of Hepatology, Room no. 6

Hyderabad
TELANGANA
500032
India 
Phone  08790622655  
Fax  91-40-23324255  
Email  drmithunsharma@gmail.com  
 
Details of Contact Person
Scientific Query  
Name  Mithun Sharma 
Designation  Consultant Hepatologist 
Affiliation  Asian Institute of Gastroenterology 
Address  Cluster M, Department of Hepatology, Room no. 6

Hyderabad
TELANGANA
500032
India 
Phone  08790622655  
Fax  91-40-23324255  
Email  drmithunsharma@gmail.com  
 
Details of Contact Person
Public Query  
Name  Mithun Sharma 
Designation  Consultant Hepatologist 
Affiliation  Asian Institute of Gastroenterology 
Address  Cluster M, Department of Hepatology, Room no. 6

Hyderabad
TELANGANA
500032
India 
Phone  08790622655  
Fax  91-40-23324255  
Email  drmithunsharma@gmail.com  
 
Source of Monetary or Material Support  
Asian Institute of Gastroenterology. Plot No 2/3/4/5, Survey No 136/1, Mindspace Road, Gachibowli, Hyderabad, Telangana 500032 
 
Primary Sponsor  
Name  Asian Institute of Gastroenterology 
Address  Plot No 2/3/4/5, Survey No 136/1, Mindspace Road, Gachibowli, Hyderabad 
Type of Sponsor  Research institution and hospital 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 1  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Mithun Sharma  Asian Institute of Gastroenterology  Cluster M, Department of Hepatology, Room no. 6
Hyderabad
TELANGANA 		 08790622655
91-40-23324255
drmithunsharma@gmail.com 
 
Details of Ethics Committee  
No of Ethics Committees= 1  
Name of Committee  Approval Status 
IEC of Asian Institute of Gastroenterology  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: K760||Fatty (change of) liver, not elsewhere classified,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Comparator Agent  Lifestyle modification   It will include low calorie diet based on current body weight of the patient which would be given by dietician and exercise quantify by 45 min of aerobic exercise in the form of walking, jogging, running, swimming and cycling.  
Intervention  Saroglitazar and Vitamin E  Patients randomly assigned to this group will receive both Saroglitazar 4 mg once daily and Vitamin E twice daily for 24 weeks. 
Intervention  Saroglitazar Magnesium  Patients randomly assigned to this group will receive Saroglitazar Magnesium 4 mg tablet orally once daily for 24 weeks. 
Intervention  Vitamin E  Patients randomly assigned to this group will receive Vitamin E orally twice daily for 24 weeks. 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  60.00 Year(s)
Gender  Both 
Details  1. Adults (age 18 to 60)
2. Confirmed Diagnosis of NAFLD established either by imaging (ultrasound, CT scan or MRI) or liver biopsy showing simple steatosis, within 6 months of the Screening Phase for this study. The diagnosis of NAFLD is made according to the American Association for the Study of Liver Diseases (AASLD) criteria (Chalasaniet al.2017).
(a) There is hepatic steatosis by imaging or histology,
(b) There is no significant alcohol consumption,
(c) There are no competing etiologies for hepatic steatosis
(d) There are no co-existing causes for chronic liver disease.
3. Patient’s demonstration of understanding of study requirements and treatment procedures, willingness to comply with all protocol-required evaluations.
4. Either take biopsy proven NAFLD or imaging based NAFLD with ALT more than 1.5 times the upper limit of normal. (being considered as 32)
5. Liver biopsy would be done in selected cases where the cause of transaminitis was uncertain of possible biopsy would be done on case to case basis.  
 
ExclusionCriteria 
Details  1. Absence of regular or excessive use of alcohol within 2 years prior to initial screening.
2. Presence of alternative causes of fatty liver.
 Weight loss >10% in the 6 months before the Screening Visit
 Total parenteral nutrition, starvation or protein-calorie malnutrition
 Use of drugs associated with NAFLD for more than 12 consecutive weeks in the 1 year before start of the study, including amiodarone, tamoxifen, methotrexate, systemic glucocorticoids, anabolic steroids, tetracycline, estrogens in doses higher than used in oral contraceptives, vitamin A, L asparaginase, valproate, chloroquine, or antiretroviral drugs.
3. History of bowel surgery, gastrointestinal (bariatric) surgery or undergoing evaluation for bariatric surgery for obesity, extensive small-bowel resection, or orthotopic liver transplants (OLT) or listed for OLT.
4. History of other chronic liver disease (Viral hepatitis B or C, autoimmune hepatitis, cholestatic and metabolic liver diseases) and hemochromatosis.
5. Patient has known cirrhosis (compensated /decompensated) either based on clinical criteria or liver histology or Imaging techniques.
6. Patients with Hypothyroidism.
7. Patients with 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 dysarrhythmias
 uncontrolled hypertension (systolic BP>180 mmHg and/or diastolic BP >110 mmHg on two consecutive occasions)
 stroke or transient ischemic attack within the prior 6 months
8. History of myopathies or evidence of active muscle disease.
9. History of malignancy in the past 5 years and/or active neoplasm with the exception of resolved superficial non-melanoma skin cancer.
10. Participation in any other therapeutic clinical study in the past 3 months, including participation in any other NAFLD clinical trials.
11. History of bladder disease and/or hematuria or has current hematuria except due to a urinary tract infection.
12. Illicit substance abuse within the past 12 months.
13. Pregnant/lactating female (including positive pregnancy test at the Screening Visit)
14. 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).
15. Patients who will not comply with diet and lifestyle changes can be excluded from the final analysis. 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Not Applicable 
Blinding/Masking   Not Applicable 
Primary Outcome  
Outcome  TimePoints 
1. Change in NAFLD fibrosis score at 8week, 16week and 24week.
2. Compare the overall efficacy of patients with NAFLD/ NASH treated with Saroglitazar magnesium, vitamin E and Saroglitazar magnesium with Vitamin E and Life style modifications alone.
3. Determine the safety profile of these regimens in those patients. 		 2 month, 4 month, 6 month 
 
Secondary Outcome  
Outcome  TimePoints 
1. Serum alanine aminotransferase (ALT) & aspartate aminotransferase (AST) level.
2. Serum triglycerides (TG) level, high-density lipoprotein (HDL), low density lipoprotein (LDL) & fasting plasma glucose (FPG)/glycosylated haemoglobin (HbA1c).
3. Liver Biopsy at 24week in selected patients. 		 2 month, 4 month, 6 month 
 
Target Sample Size   Total Sample Size="200"
Sample Size from India="200" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 3/ Phase 4 
Date of First Enrollment (India)   16/12/2019 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="0"
Months="6"
Days="0" 
Recruitment Status of Trial (Global)   Not Applicable 
Recruitment Status of Trial (India)  Not Yet Recruiting 
Publication Details   Georgescu1, E F; 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. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2017; 142:1592-609. 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Brief Summary  

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease. The severity of NAFLD ranges from relatively benign simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which is characterized by hepatocellular injury, inflammation and risk of progression to cirrhosis with complications of portal hypertension, liver failure and hepatocellular carcinoma. Nonalcoholic steatohepatitis is considered a hepatic manifestation of the metabolic syndrome. In many patients, insulin resistance underlies the development of the metabolic syndrome; consequently, NASH is highly prevalent among patients with type 2 diabetes mellitus (T2DM). Currently, obesity and associated T2DM have reached epidemic proportions and are considered burgeoning public health problems.

Saroglitazar, [benzenepropanoic acid, α-ethoxy-4-[2-[2-methyl-5-[4-(methylthio) phenyl]-1Hpyrrol- 1yl]ethoxy]- , magnesium salt (2:1), (αS)], is a novel peroxisome proliferator activated receptor (PPAR) agonist with dual PPAR agonistic properties – it is a potent and predominant PPARα agonist with moderate PPARγ agonistic activity. Saroglitazar has been the first glitazar granted marketing authorization in India and is indicated for treatment of diabetic Dyslipidemia. The drug was developed with an expectation to achieve optimum anti-dyslipidemia and ant hyperglycemic 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.

Saroglitazar is known to safely and effectively improve Dyslipidemia by reducing triglyceride(TG), low density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL)cholesterol, non-high-density lipoprotein (non-HDL) cholesterol and increasing high density lipoprotein (HDL) cholesterol. In addition, Saroglitazar can improve glycemic indices in diabetic patients by reducing fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c).

Vitamin E consists of two families of compounds, the tocopherols and tocotrienols, characterised by a 6-chromanol ring and an isoprenoid side chain. The members of each family are designated alpha((α)-, beta(β)-, gamma(γ)-, or delta(δ)- according to the position of methyl groups attached to the chroman nucleus. Vitamin E’s major function appears to be as a non-specific chain-breaking antioxidant that prevents the propagation of free-radical reactions. The vitamin is a peroxyl radical scavenger and especially protects polyunsaturated fatty acids (PUFAs) within membrane phospholipids and in plasma lipoproteins.

Considering the association between insulin resistance, Dyslipidemia and the development of NAFLD/NASH, Saroglitazar could potentially benefit patients with NAFLD including those with borderline NASH. Therefore, the purpose of the present study is to examine the efficacy of Saroglitazar and vitamin E with or without combination in improving NAFLD Fibrosis Score and liver biochemistry in patients with NAFLD/NASH.

In this study we aim to evaluate the hospital based clinic-pathological profile, diagnosis, treatment regimen and follow up of Indian patients with NAFLD/ NASH.

 
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