Safety, Tolerability, and Efficacy of Saroglitazar Mg 4 mg in Liver Transplant Recipients With Nonalcoholic Fatty Liver Disease (NAFLD)

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)

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.

Study Overview

• Status: Completed
• Conditions: NAFLD; Liver Transplant; Complications
• Intervention / Treatment: Drug: Saroglitazar

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) prior to enrollment.
• Patients with ≤20% variance in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (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:

  1. Cirrhosis on historical liver biopsy.
  2. Evidence of cirrhosis on imaging including portal venous collaterals.
  3. Prior history of decompensated liver disease including ascites, hepatic encephalopathy or variceal bleeding.
  4. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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 from baseline to end-of-treatment (EOT)	Baseline and week 24
Liver Stiffness	Changes in Liver stiffness as determined by MRE from baseline to end-of-treatment (EOT) Liver stiffness is a measure of a mechanical property of tissue (stiffness). This can be measured non-invasively by MR elastography, a technique that involves applying an external vibration to the abdomen and measuring the progression of shear waves through the underlying liver using MRI.	Baseline and Week 24
Frequently Sampled Intravenous Glucose Tolerance Test (Insulin Resistance Marker)	Changes in frequently sampled intravenous glucose tolerance test (FSIVGTT) from baseline to EOT	Baseline and Week 24
Glycosylated Hemoglobin (Insulin Resistance Marker)	Changes in glycosylated hemoglobin (HbA1c) from baseline to EOT	Baseline and Week 24
Fructosamine (Insulin Resistance Marker)	Changes in fructosamine from baseline to EOT	Baseline and Week 24
Serum Liver Enzymes	Changes in serum liver enzymes from baseline to EOT	Baseline and Week 24
Serum Liver Enzymes; Bilirubin	Changes in bilirubin from baseline to EOT	Baseline and Week 24
Serum Lipids	Changes in serum lipids from baseline to EOT	Baseline and Week 24
Small Dense Low-density Lipoprotein (Atherogenic Lipoprotein)	Changes in small dense low-density lipoprotein (sdLDL) from baseline to EOT	Baseline and Week 24
LDL Size (Atherogenic Lipoprotein)	Changes in LDL size from baseline to EOT	Baseline and Week 24
LDL Concentration (Atherogenic Lipoprotein)	Changes in LDL concentration from baseline to EOT	Baseline and Week 24
Very Low-density Lipoprotein (Atherogenic Lipoprotein)	Changes in subtypes of very low-density lipoprotein (VLDL) from baseline to EOT	Baseline and Week 24
Very Low-density Lipoprotein Chylomicron Triglyceride (Atherogenic Lipoprotein)	Changes in VLDL chylomicron triglyceride from baseline to EOT	Baseline and Week 24
High-density Lipoprotein (Atherogenic Lipoprotein)	Changes in high-density lipoprotein (HDL) from baseline to EOT	Baseline and Week 24
Change in Metabolic Flexibility; Time to Peak RQ	Metabolic flexibility was measured via a whole room calorimeter (i.e. respiration chamber). The CO2 production and O2 consumption were recorded every minute for a total of 18 hours while study participants were in the respiration chamber on baseline and Week 24. Metabolic flexibility was quantified by measuring whole-body CO2 production relative to O2 consumption or respiratory quotient (RQ). The RQ oscillates between 0.7 and 1.0, which is indicative of either predominantly fatty acid or carbohydrate oxidation, respectively. The time to maximal carbohydrate consumption is measured by the time it takes to reach peak RQ after a standardized meal, whereas maximal carbohydrate consumption is measured at the peak of RQ vs. time curve. Next, the transition from maximal carbohydrate consumption to maximal fatty acid consumption is measured from peak RQ to lowest RQ. Finally, fasting biofuel utilization is measured in the fasting state and represents predominantly fatty acid oxidation.	Baseline and Week 24
Quality of Life (SF-36 Health Survey)	Change in Quality of life score from baseline to EOT 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	Baseline and Week 24
Peak Plasma Concentration [Cmax]	Pharmacokinetics of Saroglitazar following first and last dose.	PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Time to Reach Peak Plasma Concentration [Tmax]	Pharmacokinetics of Saroglitazar following first and last dose	PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Area Under Plasma Concentration vs. Time Curve Till the Last Time Point [AUC0-t]	Pharmacokinetics of Saroglitazar	PK Sampling time points: Day 1 visit at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Area Under Plasma Concentration vs. Time Curve Extrapolated to the Infinity [AUC0-∞]	Pharmacokinetics of Saroglitazar	PK Sampling time points: Day 1 visit at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Area Under Plasma Concentration vs. Time Curve in a 24 h Dosing Interval [AUCtau]	Pharmacokinetics of Saroglitazar	PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Elimination Rate Constant [λz]	Pharmacokinetics of Saroglitazar	PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Elimination Half-life [t1/2]	Pharmacokinetics of Saroglitazar	PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Apparent Volume of Distribution [Vd/F]	Pharmacokinetics of Saroglitazar	PK Sampling time points: Day 1 (Baseline) and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Apparent Clearance [CL/F]	Pharmacokinetics of Saroglitazar	PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Minimal or Trough Plasma Concentration [Cmin]	Pharmacokinetics of Saroglitazar	PK Sampling time points: Week 24 visit at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Accumulation Index Calculated as a Ratio of AUCtau (Last Dose)/AUCtau (First Dose)	Pharmacokinetics of Saroglitazar	PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Fluctuation Index	Fluctuation index is the peak trough fluctuation within complete dosing interval at steady state, calculated as PTF (%) = ([Cmax - Cmin]/Cav ) multiplied by 100	PK Sampling time points: Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Bhati C, Idowu MO, Sanyal AJ, Rivera M, Driscoll C, Stravitz RT, Kohli DR, Matherly S, Puri P, Gilles H, Cotterell A, Levy M, Sterling RK, Luketic VA, Lee H, Sharma A, Siddiqui MS. Long-term Outcomes in Patients Undergoing Liver Transplantation for Nonalcoholic Steatohepatitis-Related Cirrhosis. Transplantation. 2017 Aug;101(8):1867-1874. doi: 10.1097/TP.0000000000001709.
• Siddiqui MS, Parmar D, Shaikh F, Forsgren M, Patel S, Bui AT, Boyett S, Patel V, Sanyal AJ. Saroglitazar improves nonalcoholic fatty liver disease and metabolic health in liver transplant recipients. Liver Transpl. 2023 Sep 1;29(9):979-986. doi: 10.1097/LVT.0000000000000110. Epub 2023 Feb 28.

Helpful Links

• Bhati C, Idowu MO, Sanyal AJ. Long-term Outcomes in Patients Undergoing Liver Transplantation for Nonalc
• Siddiqui MS, Parmar D, Shaikh F, Forsgren M, Patel S, Bui AT, Boyett S, Patel V, Sanyal AJ. Saroglitazar improves nonalcoholic fatty liver disease and metabolic health in liver transplant recipients

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2019
• Primary Completion (Actual): December 13, 2021
• Study Completion (Actual): December 13, 2021

Study Registration Dates

• First Submitted: August 15, 2018
• First Submitted That Met QC Criteria: August 18, 2018
• First Posted (Actual): August 21, 2018

Study Record Updates

• Last Update Posted (Actual): October 24, 2024
• Last Update Submitted That Met QC Criteria: October 1, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: NAFLD; NASH; Peroxisome proliferator-activated receptors; Post Transplant Metabolic Syndrome
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: SARO.17.010

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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