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

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

Study Overview

• Status: Terminated
• Conditions: Nonalcoholic Fatty Liver Disease
• Intervention / Treatment: Drug: Saroglitazar Magnesium 4 mg; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-2050
      • Zydus US004
  • California
    • La Jolla, California, United States, 92037
      • Zydus US005
    • San Francisco, California, United States, 94143
      • Zydus US006
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Zydus US002
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Zydus US003
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Zydus US001
  • Texas
    • Houston, Texas, United States, 77030
      • Zydus US007
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Zydus US008

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Saroglitazar Magnesium 4 mg; Saroglitazar Magnesium 4 mg tablet orally administered once daily in the morning before breakfast without food, for the duration of treatment (24 weeks)	Drug: Saroglitazar Magnesium 4 mg; Subjects randomized to Saroglitazar Magnesium 4 mg arm will receive Saroglitazar Magnesium 4 mg treatment until the duration of treatment (24 weeks).
Placebo Comparator: Placebo Arm; Placebo tablet orally administered once daily in the morning before breakfast without food, for the duration of treatment (24 weeks).	Drug: Placebo; Subjects randomized to Placebo arm will receive Placebo treatment until the duration of treatment (24 weeks).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Evaluate the Effect of Saroglitazar Magnesium 4 mg Compared With Placebo on Changes in Hepatic Fat Content Measured by MRI Proton Density Fat Fraction (MRI PDFF)	Change from baseline in hepatic fat content	Week 24/EOT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Evaluate the Effect of Saroglitazar Magnesium 4 mg Compared With Placebo on Reduction of Hepatic Fat Content as Measured by MRI PDFF.	Proportion of participants with reduction of at least 30% in hepatic fat content from baseline	Week 24/EOT
To Evaluate the Effect of Saroglitazar Magnesium 4 mg Compared With Placebo on Changes in FibroScan®/VCTE .	Change from baseline in Liver Stiffness Measurement	Week 24/EOT
To Evaluate the Effect of Saroglitazar Magnesium 4 mg Compared With Placebo on Changes in FibroScan®/VCTE	Change from baseline in Continuous Controlled Attenuation Parameter	Week 24/EOT
To Evaluate the Effect of Saroglitazar Magnesium 4 mg Compared With Placebo on Changes in FibroScan®/Vibration-controlled Transient Elastography (VCTE).	Change from baseline in Fibroscan-aspartate aminotransferase (FAST) score	Week 24/EOT
To Evaluate the Effects of Saroglitazar Magnesium 4 mg Compared With Placebo on Changes in Non-invasive Markers of Fibrosis and Steatosis	Change from baseline in plasma pro-collagen type 3 (PRO-C3) levels	Week 24/EOT
To Evaluate the Effects of Saroglitazar Magnesium 4 mg Compared With Placebo on Changes in Non-invasive Markers of Fibrosis and Steatosis	Change from baseline in Fibrois-4 index (FIB-4) This index is based on age, platelet count, ALT level, and AST level. FIB-4 was calculated using the following formula: FIB4 = (Age (years) x AST (U/L))/(Platelet count (10^9/L) x √ALT (U/L)). A decrease in FIB-4 represents a positive outcome. A FIB-4 Index of <1.45 indicates none to moderate fibrosis and an Index of >3.25 indicates advanced fibrosis.	Week 24/EOT
To Evaluate the Effects of Saroglitazar Magnesium 4 mg Compared With Placebo on Changes in Non-invasive Markers of Fibrosis and Steatosis	Change in aspartate aminotransferase-to-platelet ratio index in Saroglitazar Magnesium groups as compared to the placebo group APRI was calculated as ([AST level/AST upper limit of normal]/ [Platelet count 1^09/L]) ×100, where AST is aspartate aminotransferase. The aspartate transaminase to platelet ratio index (APRI) is used to assess the risk of liver fibrosis. Higher APRI score represents a higher risk of liver fibrosis	Week 24/EOT
To Evaluate the Effects of Saroglitazar Magnesium 4 mg Compared With Placebo on Changes in Non-invasive Markers of Fibrosis and Steatosis	Change from baseline in Nonalcoholic fatty liver disease Fibrosis Score (NFS) The NFS is based on age, hyperglycemia, BMI, platelet count, albumin level, and AST/ALT ratio. NFS was calculated using the following formula: NAFLD fibrosis score = -1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m^2) + 1.13 × IFG/diabetes (yes = 1, no = 0) + 0.99 × AST/ALT ratio - 0.013 × platelet (×10^9/l) - 0.66 × albumin (g/dl). A decrease in NFS score represents a positive outcome. An NFS score of <-1.455 indicates no advanced fibrosis and a score of >0.676 indicates liver fibrosis.	Week 24/EOT
To Evaluate the Effect of Saroglitazar Magnesium 4 mg Compared With Placebo on Liver Enzyme	Change from baseline in liver enzyme parameters (ALT and AST)	Week 24/EOT
To Evaluate the Effect of Saroglitazar Magnesium 4 mg Compared With Placebo on Lipid Profile	Change from baseline in triglyceride [TG), high-density lipoprotein [HDL], low-density lipoprotein [LDL], very low-density lipoprotein [VLDL], total cholesterol, and non-HDL cholesterol	Week 24/EOT
To Evaluate the Effect of Saroglitazar Magnesium 4 mg Compared With Placebo on Fasting Glucose	Change from baseline in fasting plasma glucose (FPG)	Week 24/EOT
To Evaluate the Effect of Saroglitazar Magnesium 4 mg Compared With Placebo on Anthropometric Measurements.	Change from baseline in body weight	Week 24/EOT
To Evaluate the Effect of Saroglitazar Magnesium 4 mg Compared With Placebo on Anthropometric Measurements.	Change from baseline in BMI	Week 24/EOT
To Evaluate the Effect of Saroglitazar Magnesium 4 mg Compared With Placebo on Anthropometric Measurements.	Change from baseline in hip circumference and minimum waist circumference	Week 24/EOT
To Evaluate the Effect of Saroglitazar Magnesium 4 mg Compared With Placebo on Changes in Health-related Quality of Life Scores Measured by Short Form-36 (SF-36) Questionnaire.	Change from baseline in SF-36 Questionnaire mental (MCS) and physical components scores (PCS). The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of functional health and well-being scores (domains) as well as psychometrically based physical and mental health summary measures. The SF-36 taps 8 health concepts: physical functioning, bodily pain, physical role functioning, emotional role functioning, emotional well-being, social functioning, vitality, and general health perceptions. The 8 scales are further summarized to 2 distinct higher-ordered clusters: the PCS and mental composite t-score (MCS). The range for all 8 domains as well as for the composite t-scores is from 0 to 100 with 100 as best possible health status and 0 as the worst health status.	Week 24/EOT.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Adverse Events After Consuming Saroglitazar Magnesium Compared to Placebo	Number of Participants with Adverse Events. We have included data for Treatment emergent adverse events (TEAEs) only. TEAEs are those AEs that occur after administration of the study drug.	From baseline to Week 28

Collaborators and Investigators

• Sponsor: Zydus Therapeutics Inc.
• Investigators: Study Director: Deven V Parmar, Zydus Therapeutics Inc.

Study record dates

Study Major Dates

• Study Start (Actual): December 8, 2022
• Primary Completion (Actual): October 2, 2023
• Study Completion (Actual): October 2, 2023

Study Registration Dates

• First Submitted: January 24, 2022
• First Submitted That Met QC Criteria: January 24, 2022
• First Posted (Actual): January 27, 2022

Study Record Updates

• Last Update Posted (Estimated): September 2, 2025
• Last Update Submitted That Met QC Criteria: August 11, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Nonalcoholic Fatty Liver Disease; Saroglitazar Magnesium
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Substandard Drugs; Pharmaceutical Preparations; Counterfeit Drugs; saroglitazar
• Other Study ID Numbers: SARO.20.001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No