Safety, Tolerability and Efficacy of Saroglitazar Mg 4 mg in Liver Transplant Recipients With NAFLD

Study Overview
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Brief Summary
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This is a phase 2A, single center, open-label, single-arm, 24-week study to evaluate the safety, tolerability and efficacy of Saroglitazar Magnesium 4 mg in liver transplant recipients with NAFLD.

Detailed Description
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This is a phase 2A, single center, open-label, single-arm, 24-week study to evaluate the safety, tolerability and efficacy of Saroglitazar Magnesium 4 mg in liver transplant recipients with NAFLD. The study will be conducted over a period of up to 33 weeks and will include 5 weeks screening, a 24 week treatment period and 4 week follow-up period. The primary end point of the study is to assess the safety of Saroglitazar Magnesium 4 mg in liver transplant recipients with NAFLD over 24 weeks of treatment.

Official Title
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A Phase 2A, Single Center, Open-label, Single-arm, 24-week Study to Evaluate the Safety, Tolerability and Efficacy of Saroglitazar Magnesium 4 mg in Liver Transplant Recipients With Nonalcoholic Fatty Liver Disease (EVIDENCES VIII)

Conditions
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NAFLD, Liver Transplant; Complications

Intervention / Treatment
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* Drug: Saroglitazar


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to give written informed consent. Males or females, 18 to 75 years of age. Patients who are at least 6 months post-transplant for nonalcoholic steatohepatitis (NASH) or cryptogenic cirrhosis thought to be secondary to NASH are eligible for enrolment. The presence of NAFLD determined by MRI-PDFF prior to enrollment. Patients with ≤20% variance in the levels of ALT, AST, ALP and total bilirubin between Visit 1 and Visit 1.1. History of medical compliance with immunosuppression. Female subjects of non-child bearing potential or on highly effective contraception. For male subjects with female partners of childbearing potential, willing to follow highly effective contraception measures during the study, either by the male participant or his female partner or both. Exclusion Criteria: Pregnant or lactating females. Patient with abnormal transaminases due to secondary intercurrent illness. Patients with bile duct strictures. Other causes of chronic liver disease after liver transplantation including autoimmune, viral, and alcoholic liver disease. Graft cirrhosis as defined by: Cirrhosis on historical liver biopsy. Evidence of cirrhosis on imaging including portal venous collaterals. Prior history of decompensated liver disease including ascites, hepatic encephalopathy or variceal bleeding. Evidence of esophageal varices on prior endoscopy. Body mass index (BMI) <18 kg/m². Subjects with change in body weight >5% in the 3 months prior to enrollment. Subjects requiring corticosteroid or anticoagulation therapy. History of myopathies or evidence of active muscle diseases. Unstable cardiovascular disease. History of bladder disease and/or hematuria or has current hematuria unless due to a urinary tract infection. Active malignancy post-liver transplantation. History of malignancy in the past 5 years and/or active neoplasm. History of chronic rejection of liver transplant graft. Acute cellular rejection of liver transplant graft within the past 6 months. Evidence of Acute cellular rejection (ACR) or chronic rejection (CR) or alternative etiologies to NAFLD. Poorly controlled diabetes as defined by an HbA1c >8.5% within the past 6 months. History of excessive alcohol intake. Subject tests positive for a urine drug screen. Subject has a history of chronic (uncontrolled) pain.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Saroglitazar Magnesium 4 mg<br>Saroglitazar Magnesium tablet once daily in the morning 60 minutes before breakfast | Drug: Saroglitazar<br>* Saroglitazar magnesium 4 mg tablet once daily (OD) in the morning 60 minutes before breakfast without food<br>* Other names: Not any;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events assessed by CTCAE | Safety measured by adverse events, vital signs, physical exams, body weight, electrocardiograms (ECGs) and lab results (including hematology, chemistry and urinalysis) | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatic fat | Changes in hepatic fat as determined by MRI-PDFF and MRE from baseline to end-of-treatment (EOT) | 24 weeks | 
| Metabolic flexibility | Changes in metabolic flexibility from baseline to EOT | 24 weeks | 
| Frequently sampled intravenous glucose tolerance test (Insulin resistance marker) | Changes in frequently sampled intravenous glucose tolerance test (FSIVGTT) from baseline to EOT | 24 weeks | 
| Glycosylated hemoglobin (Insulin resistance marker) | Changes in glycosylated hemoglobin (HbA1c) from baseline to EOT | 24 weeks | 
| Fructosamine (Insulin resistance marker) | Changes in fructosamine from baseline to EOT | 24 weeks | 
| Serum liver enzymes | Changes in serum liver enzymes from baseline to EOT | 24 weeks | 
| Serum lipids | Changes in serum lipids from baseline to EOT | 24 weeks | 
| Small dense low-density lipoprotein (Atherogenic lipoprotein) | Changes in small dense low-density lipoprotein (sdLDL) from baseline to EOT | 24 weeks | 
| LDL size and concentration (Atherogenic lipoprotein) | Changes in LDL size and concentration from baseline to EOT | 24 weeks | 
| Very low-density lipoprotein (Atherogenic lipoprotein) | Changes in subtypes of very low-density lipoprotein (VLDL) from baseline to EOT | 24 weeks | 
| High-density lipoprotein (Atherogenic lipoprotein) | Changes in high-density lipoprotein (HDL) from baseline to EOT | 24 weeks | 
| Quality of life (SF-36 Health Survey) | Change in Quality of life score from baseline to EOT | 24 weeks | 
| Peak plasma concentration [Cmax] | Pharmacokinetics of Saroglitazar following first and last dose | 24 weeks | 
| Time to reach peak plasma concentration [Tmax] | Pharmacokinetics of Saroglitazar following first and last dose | 24 weeks | 
| Area under plasma concentration vs. time curve till the last time point [AUC0-t] | Pharmacokinetics of Saroglitazar following first and last dose | 24 weeks | 
| Area under plasma concentration vs. time curve extrapolated to the infinity [AUC0-∞] after first dose | Pharmacokinetics of Saroglitazar following first dose | 24 weeks | 
| Area under plasma concentration vs. time curve in a 24 h dosing interval [AUCtau] | Pharmacokinetics of Saroglitazar following first and last dose | 24 weeks | 
| Elimination rate constant [λz] | Pharmacokinetics of Saroglitazar following first and last dose | 24 weeks | 
| Elimination half-life [t1/2] | Pharmacokinetics of Saroglitazar following first and last dose | 24 weeks | 
| Apparent volume of distribution [Vd/F] | Pharmacokinetics of Saroglitazar following first and last dose | 24 weeks | 
| Apparent clearance [CL/F] | Pharmacokinetics of Saroglitazar following first and last dose | 24 weeks | 
| Minimal or trough plasma concentration [Cmin] -for last dose only | Pharmacokinetics of Saroglitazar following last dose | 24 weeks | 
| Accumulation index calculated as a ratio of AUCtau (last dose)/AUCtau (first dose) | Pharmacokinetics of Saroglitazar following first and last dose | 24 weeks | 
| Fluctuation index | Pharmacokinetics of Saroglitazar following first and last dose | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Peroxisome proliferator-activated receptors, NAFLD, NASH, Post Transplant Metabolic Syndrome