An Investigator Initiated Prospective, Four Arms Randomized Comparative Study of Efficacy and Safety of Saroglitazar, Vitamin E and Life Style Modification in Patients With Nonalcoholic Fatty Liver Disease (NAFLD)/ Non-alcoholic Steatohepatitis (NASH)

• ClinicalTrials.gov Identifier: NCT04193982
• Recruitment Status: Unknown
• First Posted: December 11, 2019
• Last Update Posted: January 26, 2021
• Sponsor: Asian Institute of Gastroenterology, India
• Information provided by (Responsible Party): Asian Institute of Gastroenterology, India

Study Description

Brief Summary:

Saroglitazar and Vitamin E are both being extensively used in India for non alcoholic fatty liver disease, though none of these drugs are FDA approved for this indication.However they are backed up by number of studies which shows improvement in liver function , reduction in NAS score. However, there is no head to head trial , nor is there any study with a paired biopsy comparing two arms for a head to head study. We therefore designed this study to see the effect of Vitamin E vs Vitamin E plus saroglitazar vs Saroglitazar alone when compared to standard dietary and weight loss treatment for NAFLD with raised ALT levels.

Condition or disease	Intervention/treatment	Phase
NAFLD	Drug: Saroglitazar; Drug: Vitamin E; Drug: Combination drug; Behavioral: Lifestyle Changes	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 250 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: An Investigator Initiated Prospective, Four Arms Randomized Comparative Study of Efficacy and Safety of Saroglitazar, Vitamin E and Life Style Modification in Patients With Nonalcoholic Fatty Liver Disease (NAFLD)/ Non-alcoholic Steatohepatitis (NASH)
• Estimated Study Start Date: January 31, 2021
• Estimated Primary Completion Date: September 30, 2021
• Estimated Study Completion Date: October 31, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Saraglitazar; Patients will receive Saraglitazar 4 mg once daily for 6 months	Drug: Saroglitazar; Patient receives Saraglitazar 4mg once daily
Experimental: Vitamin E; Patients will receive Vitamin E 400mg twice daily for 6 months	Drug: Vitamin E; Patient receive Vitamin E 400mg twice daily after food for 6 months
Experimental: Combination; Patients will receive combination of Saraglitazar 4 mg once daily and Vitamin E 400mg twice daily for 6 months	Drug: Combination drug; Patient receives Vitamine E 400mg twice daily and Saraglitazar 4 mg once daily for 6 months
Active Comparator: Lifestyle; Patients will follow instruction from dietician and life style changes advise as per protocol including targeting 7 to 10percent weight loss in 6 months	Behavioral: Lifestyle Changes; Patients receives dietary advise and does exercise in form of aerobic and targets 7 to 10 percent weight loss in 6 months

Outcome Measures

Primary Outcome Measures :

1. Change in Non alcoholic fatty liver fibrosis score at 8week, 16week and 24week. [ Time Frame: 6 months ]

   Non alcoholic fatty liver fibrosis score would be assessed . This is a non invasive test calculated by the formula : -1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × IFG/diabetes (yes = 1, no = 0) + 0.99 × AST/ALT ratio - 0.013 × platelet (×109/l) - 0.66 × albumin (g/dl)

   Results are interpreted as :

   NAFLD Score < -1.455 = F0-F2 NAFLD Score -1.455 - 0.675 = indeterminate score NAFLD Score > 0.675 = F3-F4

   Change in the NAFLD fibrosis score from the initiation of treatment and at end of 6 months would be assessed.

Secondary Outcome Measures :

1. Serum Alanine aminotransferase (ALT) changes at 6 months. [ Time Frame: 6 months ]
   Changes in Alanine aminotransferase at 6 months would be assessed.
2. Serum triglycerides (TG) level. [ Time Frame: 6 months ]
   Improvement as evidenced by decrease in triglyceride at 6 months.
3. Change in fibrosis on Liver Biopsy at 6 months. [ Time Frame: 6 months ]

   The study involves a paired liver biopsy and patients who undergo the second biopsy will be assessed for regression or decrease in fibrosis and steatosis score on biopsy.

   Score interpretation:

   Steatosis: < 5%- 0, 5-33%- 1, >33-66%- 2, >66%- 3. Fibrosis: F0- No fibrosis, F1- Mild fibrosis, F2- Moderate fibrosis, F3- Severe fibrosis

4. Serum Aspartate aminotransferase (AST) level at 6 months. [ Time Frame: 6 months ]
   Changes in Aspartate aminotransferase at 6 months would be assessed.
5. Non alcoholic steatosis (NAS) score on liver biopsy at 6 months. [ Time Frame: 6 months ]

   Change in Non alcoholic Steatosis (NAS) score at 6 months. NAS score interpretation: Range- 0 to 8

   ≥5- Non-alcoholic steatohepatitis (NASH)

6. Glycosylated Hemoglobin (HbA1C) Level at 6 months. [ Time Frame: 6 months ]
   Change in glycosylated hemoglobin level (amount of glucose attached to hemoglobin) from baseline and at 6 months.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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).

  1. There is hepatic steatosis by imaging or histology,
  2. There is no significant alcohol consumption,
  3. There are no competing etiologies for hepatic steatosis

  4. 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.

     Exclusion Criteria:

     1. Absence of regular or excessive use of alcohol within 2 years prior to initial screening. History of alcohol will be taken from the patient and one or more family member and patient will be defined as non-alcoholic if he/she is a total abstainer or takes >20g (males) or 10g (females) of alcohol per day or greater than 14 drinks per week in males or greater than 7 drinks per week in females. Approximately 10 g of alcohol equals one 'drink' unit. One unit equals 30 ml of distilled spirits, 355 ml beer, or 120 ml glass of wine.

     2. Presence of alternative causes of fatty liver, including:

        • 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. 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.

Contacts and Locations

Contacts

Contact: Mithun Sharma, MD; 8790622655; drmithunsharma@gmail.com

Locations

India

Asian Institute of Gastroenterology Hospitals; Recruiting

Hyderabad, Telangana, India, 500089

Contact: Mithun Sharma, MD 8790622655 drmithunsharma@gmail.com

Sub-Investigator: Padaki N Rao, MD DM

Sub-Investigator: Anand Kulkarni, MD DM

Sub-Investigator: Pramod DA, MD DM

Sub-Investigator: Nitin Jagtap, MD DNB

Sub-Investigator: Duvurr Nageshwar Reddy, MD DM

Sub-Investigator: Syeda Fatima Sultana, Pharm D

Sponsors and Collaborators

Asian Institute of Gastroenterology, India

More Information

Publications:

Duseja A, Singh SP, Saraswat VA, Acharya SK, Chawla YK, Chowdhury S, Dhiman RK, Jayakumar RV, Madan K, Misra SP, Mishra H, Modi SK, Muruganathan A, Saboo B, Sahay R, Upadhyay R. Non-alcoholic Fatty Liver Disease and Metabolic Syndrome-Position Paper of the Indian National Association for the Study of the Liver, Endocrine Society of India, Indian College of Cardiology and Indian Society of Gastroenterology. J Clin Exp Hepatol. 2015 Mar;5(1):51-68. doi: 10.1016/j.jceh.2015.02.006. Epub 2015 Mar 6.

Dhiman RK, Duseja A, Chawla Y. Asians need different criteria for defining overweight and obesity. Arch Intern Med. 2005 May 9;165(9):1069-70. doi: 10.1001/archinte.165.9.1069-b. No abstract available.

Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ; American Gastroenterological Association; American Association for the Study of Liver Diseases; American College of Gastroenterologyh. 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. 2012 Jun;142(7):1592-609. doi: 10.1053/j.gastro.2012.04.001. Epub 2012 May 15. No abstract available. Erratum In: Gastroenterology. 2012 Aug;143(2):503.

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 Mar;16(1):39-46.

Sanyal AJ, Brunt EM, Kleiner DE, Kowdley KV, Chalasani N, Lavine JE, Ratziu V, McCullough A. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology. 2011 Jul;54(1):344-53. doi: 10.1002/hep.24376.

• Responsible Party: Asian Institute of Gastroenterology, India
• ClinicalTrials.gov Identifier: NCT04193982
• Other Study ID Numbers: ECR/346/Inst/AP/2013/RR-16
• First Posted: December 11, 2019
• Last Update Posted: January 26, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Asian Institute of Gastroenterology, India:

Saraglitazar; Vitamin E

Additional relevant MeSH terms:

Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Digestive System Diseases; Vitamin E; Vitamins; Micronutrients; Physiological Effects of Drugs; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents