Saroglitazar Magnesium in the Treatment of Non-Alcoholic Steatohepatitis

A Phase 2, Prospective, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of Saroglitazar Magnesium 2 mg and 4 mg in Patients With Non-alcoholic Steatohepatitis (NASH)

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.

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.

Inclusion Criteria:

1. Patients able to provide written informed consent for participation in this trial.

2. Males or females, 18 to 75 years of age, both inclusive.

3. Female must be either of non-child bearing potential (surgically sterilized at least 6 months prior to screening or postmenopausal) or using one or more methods of contraception.

4. Histologic confirmation of NASH without cirrhosis (fibrosis stage 0, 1, 2, or 3) from liver biopsy performed either during the screening period or no more than 6 months prior to the first visit, with a NAS of ≥4 and a score of at least 1 in each (steatosis scored 0-3, ballooning scored 0-2, and lobular inflammation scored 0-3). If biopsy was performed within 6 months of screening, the slides, biopsy material or block should be available for baseline documentation. Such patients, whose historical biopsy report is available, should not use medications suspected of having an effect on NASH for at least 3 months prior to the screening.

5. BMI ≥25 kg/m^2.

6. For hypertensive patients, blood pressure must be controlled by a stable dose of antihypertensive medications for at least 3 months prior to screening (and the stable dose can be maintained throughout the study)

7. Patients with type 2 diabetes mellitus may be included if they fulfil the following criteria;

   1. Stable therapeutic regimen as defined by no changes in oral agents or dose for at least 3 months before screening and the stable dose can be maintained throughout the study.
   2. HbA1c ≤ 9.5%

8. Patients agree to comply with the study procedure.

Exclusion Criteria:

1. Pregnant and lactating female.

2. Positive pregnancy test.

3. Patients with history of myopathies or evidence of active muscle diseases.

4. Patients with history of alcohol consumption of >30 gm/day for men, >20 gm/day for women for consecutive previous 2 years and/or drug abuse.

5. Known allergy, sensitivity or intolerance to the study drug or formulation ingredients.

6. Participation in an interventional clinical study and/or receipt of any investigational medication within 3 months prior to screening.

7. History of malignancy in the past 5 years and/or active neoplasm with the exception of superficial, non-melanoma, skin cancer.

8. Any of the following laboratory values at screening:

   1. Direct bilirubin >1.5 mg/dL,
   2. Serum albumin <2.5 g/dL.
   3. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2.
   4. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >200 IU/L.
   5. Patient with international normalized ratio (INR) >1.5.
   6. Creatinine kinase ≥ 1.5 upper limit of normal (ULN).
   7. Lipase ≥ULN.
   8. Amylase ≥ ULN.

9. Unstable cardiovascular disease, including:

   1. unstable angina, (i.e., new or worsening symptoms of coronary heart disease within the 3 months preceding screening), acute coronary syndrome within the 6 months preceding Screening, acute myocardial infarction within the 3 months preceding screening or heart failure of New York Heart Association class (III - IV) or worsening congestive heart failure, or coronary artery intervention, within the 6 months preceding screening
   2. history of (within 3 months preceding Screening) or current unstable cardiac dysrhythmias
   3. uncontrolled hypertension (systolic blood pressure [BP] > 155 mmHg and/or diastolic BP > 95 mmHg)
   4. Stroke or transient ischemic attack within the 6 months preceding screening.

10. Previous history of bladder disease and/or hematuria.

11. Previous liver biopsy that demonstrated presence of cirrhosis or radiologic imaging consistent with cirrhosis or portal hypertension.

12. Type 1 diabetes mellitus.

13. Use of drugs that are known Cytochrome P4502C8 (CYP2C8) inhibitors/substrate.

14. Use of drugs associated with a clinical or histological picture consistent with fatty liver disease or NASH for more than 12 consecutive weeks in the 1 year prior to start of the study; (these include amiodarone, tamoxifen, methotrexate, glucocorticoids, anabolic steroids, tetracyclines, estrogens, valproate/valproic acid, chloroquine, anti-HIV drugs).

15. History of thyroid disease (hypothyroid patients who are euthyroid on thyroid hormone replacement can be included).

16. History of, or current, cardiac dysrhythmias.

17. History of bariatric surgery, or undergoing evaluation for bariatric surgery.

18. Patients with a >10% weight loss in the 3 months prior to screening.

19. 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, coronary artery disease, HIV or active gastrointestinal conditions that might interfere with drug absorption).

20. Patients on any treatment with other drugs used 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)] or any medicine in clinical trials for NASH. (However, patients who are taking stable dose of vitamin E for at least 3 months prior to screening will be enrolled in the study).

21. History of other causes of chronic liver disease [autoimmune, primary biliary cirrhosis, hepatitis B virus (HBV) and hepatitis C virus (HCV), Wilson disease, alpha-1-antitrypsin deficiency, hemochromatosis etc.