Saroglitazar Magnesium 4 mg for Nonalcoholic Fatty Liver Disease (NAFLD) in People Living With HIV in the US

Inclusion Criteria:

1. Adults (≥18 years of age) with documented HIV.

2. Documented diagnosis of NAFLD established by imaging (ultrasound, CT scan or MRI) orliver biopsy within 6 months before screening, based on American Association for theStudy of Liver Disease [AASLD] criteria

3. Hepatic fat fraction ≥8% by MRI-PDFF

4. ALT level ≥31 U/L in men and ≥19 U/L in women at Visit 1 and 2

5. HIV-1 RNA <200 copies/mL for ≥6 months on ART (must have screening HIV-1 RNA valueand one clinical care value within 6 months prior to screening and up to therandomization that meets the criteria).

6. Stable ART regimen for ≥3 months prior to screening and stable up to therandomization and no active plans to change ART while on study.

7. Willingness to participate in the study.

Exclusion Criteria:

1. History of significant alcohol consumption (defined as >2 drinks/day on average formen, >1 drinks/day on average for women) for at least 3 consecutive months (12consecutive weeks) within 5 year before screening (Note 1: 1 drink =12 ounces ofbeer, 8-9 ounces of malt liquor, 4 ounces of wine or 1 ounce of spirits/hard liquor.Note 2: Use sex assigned at birth for alcohol consumption limits).

2. History of other acute or chronic liver disease, including, but not limited toautoimmune, primary biliary cholangitis, Wilson's disease, alpha 1 antitrypsindeficiency, hemochromatosis, hepatitis B virus (HBV), and ongoing or recent (withinthe past 3 years) hepatitis C RNA positivity. (Exceptions: a. Participants withpreviously treated hepatitis C infection are eligible for consideration if theirsustained virologic response was achieved more than 3 years prior to screening. Theproportion of such participants in this trial will not exceed 25% of the studycohort. b. Participants with prior acute HBV infection that is resolved butcurrently do not have hepatitis B surface antigen (HBsAg) or detectable HBV DNA areeligible).

3. History of liver transplant.

4. Liver biopsy or radiologic imaging consistent with the clinical presence ofcirrhosis or portal hypertension at screening.

5. Participants whose Visit 2 ALT, AST, or alkaline phosphatase (ALP) values exceedtheir Visit 1 values by more than 50%. Note: These participants will be required to have a third value measured at-leastone week after V2, to assess for a trend. If the third value shows a continuedincrease ≥10% compared to the Visit 2 values, the participant is consideredineligible for randomization.

6. Ongoing use of steatogenic medications or supra-physiologic hormonal therapies (Exception: transgender women on stable (≥3 month) feminizing hormonal therapy notexcluded), within 3 months prior to screening until time of randomization oranticipated use of medications that cause significant changes in weight during thestudy period (Refer Appendix 7 for 'List of Steatogenic Medications OrSupra-Physiologic Hormonal Therapies Or Medications That Cause Significant WeightChange').

7. Uncontrolled T2DM, defined as HbA1c >9.5% at screening.

8. Any of the following laboratory values at screening:

9. ALT or AST >250 U/L

10. Total bilirubin >1.5 mg/dL and direct bilirubin > 0.5 mg/dL (unless due toGilbert's disease or atazanavir use per the opinion of the site investigator)

11. Platelet count <150,000/mm3

12. Estimated glomerular filtration rate (e-GFR) <60 mL/min/1.73m2 using thechronic kidney disease-epidemiology collaboration (CKD-EPI) equation (ReferAppendix 6 for 'CKD-EPI Calculator')

13. International normalized ratio (INR) >1.3.

14. Albumin < 3.6 g/dL

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

16. Unstable cardiovascular disease, including:

17. Unstable angina, (i.e., new or worsening symptoms of coronary heart disease)and/or acute myocardial infarction within the 3 months preceding screening

18. Acute coronary syndrome or coronary artery intervention within the 3 monthspreceding screening,

19. Heart failure of New York Heart Association (NYHA) class (III-IV) or worseningcongestive heart failure within the 6 months preceding screening.

20. History of (within 3 months preceding screening) or current unstable cardiacdysrhythmias.

21. Uncontrolled hypertension (systolic blood pressure [SBP] >155 mmHg and/ordiastolic blood pressure [DBP] >95 mmHg) at screening.

22. Stroke or transient ischemic attack within the 6 months preceding screening.

23. Unstable pulmonary disease (based upon site investigator's evaluation) at screening.

24. Use of drugs that are known CYP2C8 inhibitors/substrates (Refer Appendix 2 for the 'List of Known CYP2C8 Inhibitors/Substrates') in the last 28 days prior toscreening.

25. History of severe illness or any other conditions that require systematictreatment/or hospitalization, until participant either completes therapy or isclinically stable on therapy as per the opinion of the investigator, for at least 7days prior to screening (such as poorly controlled psychiatric disease, activegastrointestinal conditions that might interfere with drug absorption, etc.).

26. Use of thiazolidinediones or Telmisartan within 3 months prior to screening or untiltime of randomization.

27. Use of unstable doses of SGLT2 inhibitors (e.g. canagliflozin, empagliflozin,dapagliflozin, etc.), glucose-dependent insulinotropic polypeptide (GIP) and/orGLP-1 agonists (e.g. semaglutide, exenatide, liraglutide, lixisenatide, tirzepatideetc.) within 6 months prior to screening until time of randomization.

28. Use of pentoxifylline, ursodeoxycholic acid, antioxidants such as vitamin E (>200IU/day), glutathione, orlistat, betaine, or non-prescribed complementary alternativemedications within 6 months prior to screening until time of randomization.

29. Known allergy, sensitivity or intolerance to the study medication or formulationingredients.

30. History of any known bleeding disorder or coagulopathy.

31. Any condition that in the opinion of the site investigator, would compromise theparticipant's ability to participate in the study.

32. Unstable doses of anti-diabetic agents including sulfonylureas, biguanides or DPP-4inhibitors in the last 3 months prior to screening until time of randomization.

33. Unstable doses of lipid lowering agents such as statins (e.g. simvastatin,pravastatin, atorvastatin, fluvastatin, lovastatin, rosuvastatin, etc.) or fibrates (clofibrate, Fenofibrate) in the last 3 months prior to screening until time ofrandomization.

34. Participant with weight change >5% within 6 months prior to screening until time ofrandomization.

35. History of bariatric surgery or currently undergoing evaluation for bariatricsurgery.

36. Participation in another interventional clinical study and/or receipt of any otherinvestigational medication within 3 months prior to screening.

37. History of COVID-19 infection in the last 30 days prior to screening.

38. Pregnancy-related exclusions, include:

39. Pregnant/lactating female (including positive pregnancy test at screening)

40. Pregnancy should be avoided by male and female participants either by completeabstinence or the use of acceptable effective contraceptive measures for theduration of the study and for at least 1 month after the end of the studytreatment. Refer Appendix 3 Contraceptive Guidance 27. Participants having anabsolute contraindication to MRI (eg., any implants, magnetic metals, cardiacpacemakers, neurostimulator) as per investigators' discretion