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

A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of Saroglitazar Magnesium for the Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in People Living With Human Immunodeficiency Virus (HIV) in the US

Saroglitazar Magnesium 4 mg for NAFLD in People Living with HIV in the US

A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of Saroglitazar Magnesium for the Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in People Living with Human Immunodeficiency Virus (HIV) in the US

The four participants enrolled on version 3.0 protocol were terminated as the primary endpoint was revised from biopsy to an imaging-based approach in the subsequent protocol version 4.0. These changes were done due to recruiting challenges pertaining to biopsy. However, no participants were enrolled in the revised protocol (version 4.0) as, by then the decision to terminate the study was taken by the Sponsor considering the modifications in the internal R&D focus and a revised commercialization strategy.

The version 3.0 protocol is dated 02/Jun/2022.

Inclusion Criteria:

1. Adults (≥18 years of age) with documented HIV.
2. Documented diagnosis of NAFLD established by imaging (ultrasound, CT scan or MRI) or liver biopsy within 6 months before screening, based on American Association for the Study 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 value and one clinical care value within 6 months prior to screening and up to the randomization that meets the criteria).
6. Stable ART regimen for ≥3 months prior to screening and stable up to the randomization 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 for men, >1 drinks/day on average for women) for at least 3 consecutive months (12 consecutive weeks) within 5 year before screening (Note 1: 1 drink =12 ounces of beer, 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 to autoimmune, primary biliary cholangitis, Wilson's disease, alpha 1 antitrypsin deficiency, hemochromatosis, hepatitis B virus (HBV), and ongoing or recent (within the past 3 years) hepatitis C RNA positivity. (Exceptions: a. Participants with previously treated hepatitis C infection are eligible for consideration if their sustained virologic response was achieved more than 3 years prior to screening. The proportion of such participants in this trial will not exceed 25% of the study cohort. b. Participants with prior acute HBV infection that is resolved but currently do not have hepatitis B surface antigen (HBsAg) or detectable HBV DNA are eligible).

3. History of liver transplant.

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

5. Participants whose Visit 2 ALT, AST, or alkaline phosphatase (ALP) values exceed their Visit 1 values by more than 50%.

   Note: These participants will be required to have a third value measured at-least one week after V2, to assess for a trend. If the third value shows a continued increase ≥10% compared to the Visit 2 values, the participant is considered ineligible for randomization.

6. Ongoing use of steatogenic medications or supra-physiologic hormonal therapies (Exception: transgender women on stable (≥3 month) feminizing hormonal therapy not excluded), within 3 months prior to screening until time of randomization or anticipated use of medications that cause significant changes in weight during the study period (Refer Appendix 7 of protocol for 'List of Steatogenic Medications Or Supra-Physiologic Hormonal Therapies Or Medications That Cause Significant Weight Change').

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

8. Any of the following laboratory values at screening:

   1. ALT or AST >250 U/L
   2. Total bilirubin >1.5 mg/dL and direct bilirubin > 0.5 mg/dL (unless due to Gilbert's disease or atazanavir use per the opinion of the site investigator)
   3. Platelet count <150,000/mm3
   4. Estimated glomerular filtration rate (e-GFR) <60 mL/min/1.73m2 using the chronic kidney disease-epidemiology collaboration (CKD-EPI) equation (Refer Appendix 6 of protocol for 'CKD-EPI Calculator')
   5. International normalized ratio (INR) >1.3.
   6. Albumin < 3.6 g/dL

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

10. Unstable cardiovascular disease, including:

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

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

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

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

14. Use of thiazolidinediones or Telmisartan within 3 months prior to screening or until time of randomization.

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

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

17. Known allergy, sensitivity or intolerance to the study medication or formulation ingredients.

18. History of any known bleeding disorder or coagulopathy.

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

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

21. 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 of randomization.

22. Participant with weight change >5% within 6 months prior to screening until time of randomization.

23. History of bariatric surgery or currently undergoing evaluation for bariatric surgery.

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

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

26. Pregnancy-related exclusions, include:

    1. Pregnant/lactating female (including positive pregnancy test at screening)
    2. Pregnancy should be avoided by male and female participants either by complete abstinence or the use of acceptable effective contraceptive measures for the duration of the study and for at least 1 month after the end of the study treatment. Refer Appendix 3 Contraceptive Guidance 27. Participants having an absolute contraindication to MRI (eg., any implants, magnetic metals, cardiac pacemakers, neurostimulator) as per investigators' discretion