Saroglitazar Magnesium 4 mg for NASH in People Living With HIV in the US

Study Overview
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Brief Summary
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Saroglitazar Magnesium 4 mg for NASH in People Living with HIV in the US

Detailed Description
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A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of Saroglitazar Magnesium for the Treatment of Nonalcoholic Steatohepatitis (NASH) in People Living with Human Immunodeficiency Virus (HIV) in the US

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of Saroglitazar Magnesium for the Treatment of Nonalcoholic Steatohepatitis (NASH) in People Living With Human Immunodeficiency Virus (HIV) in the US

Conditions
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Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Saroglitazar Magnesium 4 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (≥18 years of age) with documented HIV. Histologic confirmation of NASH from liver biopsy within 6 months prior to screening or planned clinical biopsy in patients with suspected NASH pending confirmation of liver biopsy criteria including a NAS ≥4 (with at least one-point each for steatosis, lobular inflammation, and ballooning). HIV-1 RNA <50 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). 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. Willingness to participate in the study and undergo an EOT liver biopsy Exclusion Criteria: 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). 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 Deoxyribonucleic acid (HBV DNA) are eligible). History of liver transplant. Liver biopsy or radiologic imaging consistent with the clinical presence of cirrhosis or portal hypertension at screening. 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 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. Ongoing use of steatogenic medications or supra-physiologic hormonal therapies (exception: transgender women on stable dose [for ≥3 months] of feminizing hormonal therapy), within 3 months prior to screening or historical liver biopsy until time of randomization or anticipated use of medications that cause significant changes in weight during the study period; (Refer Appendix 7 for 'List of Medications'). Uncontrolled type 2 diabetes mellitus, defined as HbA1c >9.5% at screening. Any of the following laboratory values at screening: ALT or AST >250 U/L. 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). Platelet count <150,000/mm3. Estimated glomerular filtration rate (e-GFR) <60 mL/min/1.73m2 using the chronic kidney disease-epidemiology collaboration (CKD-EPI) equation (Refer Appendix 6 for 'CKD-EPI Calculator'). International normalized ratio (INR) >1.3. Albumin < 3.6 g/dL History of malignancy in the past 5 years and/or active neoplasm with the exception of superficial, non-melanoma, skin cancer. Participants with child-bearing potential (pregnancy or inability or unwilling to practice contraception for the study duration) or breast-feeding. Unstable cardiovascular disease, including: Unstable angina, (i.e., new or worsening symptoms of coronary heart disease) and/or acute myocardial infarction within the 3 months preceding screening Acute coronary syndrome or coronary artery intervention, within the 6 months preceding screening Heart failure of New York Heart Association (NYHA) class (III-IV) or worsening congestive heart failure within the 6 months preceding screening. History of (within 3 months preceding screening) or current unstable cardiac dysrhythmias. Uncontrolled hypertension (systolic blood pressure [SBP] >155 mm Hg and/or diastolic blood pressure [DBP] >95 mm Hg) at screening. Stroke or transient ischemic attack within the 6 months preceding screening. Unstable pulmonary disease (based upon site investigator's evaluation) at screening. 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 preceding screening. History of severe illness or any other conditions (such as poorly controlled psychiatric disease, active gastrointestinal conditions that might interfere with drug absorption, etc.) that require systemic treatment/or hospitalization, until participant either completes therapy or is clinically stable on therapy as per the opinion of the site investigator, for at least 7 days prior to screening. Use of other PPAR agonists (fibrates, thiazolidinediones, telmisartan) within 6 months prior to screening or historical liver biopsy until time of randomization. Use of unstable doses of sodium-glucose cotransporter-2 (SGLT2) inhibitors (e.g. canagliflozin, empagliflozin, dapagliflozin, etc.) or glucagon-like peptide (GLP)-1 agonists (e.g. exenatide, liraglutide, lixisenatide, etc.) within 6 months prior to screening or historical liver biopsy until time of randomization. Use of pentoxifylline, ursodeoxycholic acid, antioxidants such as vitamin E (>200 IU/day), glutathione, orlistat, betaine, incretin mimetics or non-prescribed complementary alternative medications within 6 months prior to screening or historical liver biopsy until time of randomization. Known allergy, sensitivity or intolerance to the study medication or formulation ingredients. History of any known bleeding disorder or coagulopathy. Any condition that in the opinion of the site investigator, would compromise the participant's ability to participate in the study. Unstable doses of anti-diabetic agents, including sulfonylureas, biguanides or dipeptidyl peptidase-4 (DPP-4) inhibitors in the last 3 months prior to screening or historical liver biopsy until time of randomization. Unstable doses of lipid-lowering agents such as statins (e.g. simvastatin, pravastatin, atorvastatin, fluvastatin, lovastatin, rosuvastatin, etc.) in the last 3 months prior to screening or historical liver biopsy until time of randomization. Participant with weight change >5% within 6 months prior to screening or historical liver biopsy until time of randomization. History of bariatric surgery or currently undergoing evaluation for bariatric surgery. Participation in another interventional clinical study and/or receipt of any other investigational medication within 3 months prior to screening or historical liver biopsy . History of COVID-19 infection in the last 30 days prior to screening. Pregnancy-related exclusions, including: Pregnant/lactating female (including positive pregnancy test at screening) Fertile women participants and their male counterparts or vice versa, not using effective contraceptive methods (such as an intra-uterine contraceptive device, other mechanical contraceptive methods like use of condom and diaphragm along with spermicide, or hormonal contraceptives that inhibit ovulation) throughout the study. (Note: Enrolled females otherwise must be surgically sterilized for at least 24 weeks before screening; postmenopausal, defined as 52 weeks with no menses without an alternative medical cause; or following sexual abstinence).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This phase 2b study is a randomized, placebo-controlled, double-blind, parallel arm trial to evaluate the safety and efficacy of Saroglitazar Magnesium 4 mg compared with placebo in biopsy-proven NASH in PLWH. Eligible participants will be randomized in a 1:1 ratio to receive Saroglitazar Magnesium 4 mg or placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Saroglitazar Magnesium 4 mg<br>Saroglitazar Magnesium 4 mg tablet orally administered once daily in the morning before breakfast without food, for the duration of treatment (72 weeks) | Drug: Saroglitazar Magnesium 4 mg<br>* Subjects randomized to Saroglitazar Magnesium 4 mg arm will receive Saroglitazar Magnesium 4 mg treatment until the duration of study (72 weeks).<br>|
| Placebo Comparator: Placebo Arm<br>Placebo tablet orally administered once daily in the morning before breakfast without food, for the duration of treatment (72 weeks). | Drug: Placebo<br>* Subjects randomized to Placebo arm will receive Placebo treatment until the duration of study (72 weeks).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effect of Saroglitazar Magnesium 4 mg compared with Placebo in improving NASH, defined as an improvement of at least 2 points (without worsening of fibrosis) in the NAFLD activity score (NAS) | Proportion of participants with at least 2-points improvement in NAS with at least 1-point improvement in either ballooning or inflammation and no worsening of liver fibrosis. Lower the scores, better the outcome. | From Baseline to Week 72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effect of Saroglitazar Magnesium 4 mg compared with Placebo on resolution of steatohepatitis and no worsening of liver fibrosis on the NASH Clinical Research Network (CRN) Histologic Scoring System | Proportion of participants achieving resolution of steatohepatitis with no worsening of fibrosis. Lower the scores, better the outcome. | From Baseline to Week 72 | 
| To evaluate the effect of Saroglitazar Magnesium 4 mg compared with Placebo on improvement in fibrosis assessed by NASH CRN Histologic Scoring System with no worsening of steatohepatitis | Proportion of participants achieving improvement in liver fibrosis (reduction of at least one stage) with no increase in NAS for ballooning, inflammation or steatosis. Lower the scores, better the outcome. | From Baseline to Week 72 | 
| To evaluate the effect of Saroglitazar Magnesium 4 mg compared with Placebo on changes in histological scores | Number of participants with change in steatosis, ballooning, lobular inflammation, portal inflammation and fibrosis. Lower the scores, better the outcome. | From Baseline to Week 72 | 
| To evaluate the effect of Saroglitazar Magnesium 4 mg compared with Placebo on changes in Liver Stiffness Measurement (LSM), Continuous Controlled Attenuation Parameter (CAP) and Fibroscan-AST (FAST) score, as measured by FibroScan®/VCTE | Number of participants with change in LSM, CAP, and FAST scores | From Baseline to Week 72 | 
| To evaluate the effects of Saroglitazar Magnesium 4 mg compared with Placebo on changes in non invasive markers of fibrosis and steatosis | Number of participants with change in enhanced liver fibrosis (ELF) score, plasma pro-collagen type 3 (PRO-C3) levels, Fibrosis-4, AST to Platelet Ratio Index (APRI), and NAFLD Fibrosis Score (NFS) | From Baseline to Week 72 | 
| To evaluate the effect of Saroglitazar Magnesium 4 mg compared with Placebo on body weight | Number of participants with change in body weight | From Baseline to Week 72 | 
| To evaluate the effect of Saroglitazar Magnesium 4 mg compared with Placebo on changes in 10-year Atherosclerotic cardiovascular disease (ASCVD) risk score (ACC/AHA Guideline on the Assessment of Cardiovascular Risk, 2013) | Number of participants with change in 10-year ASCVD risk score | From Baseline to Week 72 | 
| To evaluate the effect of Saroglitazar Magnesium 4 mg compared with Placebo on changes in health-related quality of life scores measured by SF-36 Questionnaire | Number of participants with change in SF-36 Questionnaire, mental (MCS) and physical components scores (PCS) | From Baseline to Week 72 | 
| To evaluate the effect of Saroglitazar Magnesium 4 mg compared with Placebo on body mass index (BMI) | Number of participants with change in body mass index (BMI) | From Baseline to Week 72 | 
| To evaluate the effect of Saroglitazar Magnesium 4 mg compared with Placebo on hip circumference | Number of participants with change in hip circumference | From Baseline to Week 72 | 
| To evaluate the effect of Saroglitazar Magnesium 4 mg compared with Placebo on minimum waist circumference | Number of participants with change in minimum waist circumference | From Baseline to Week 72 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Saroglitazar Magnesium, Nonalcoholic Steatohepatitis