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

• ClinicalTrials.gov Identifier: NCT03639623
• Recruitment Status: Completed
• First Posted: August 21, 2018
• Last Update Posted: October 10, 2023
• Sponsor: Zydus Therapeutics Inc.
• Information provided by (Responsible Party): Zydus Therapeutics Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Liver Transplant; Complications; NAFLD	Drug: Saroglitazar	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: February 25, 2019
• Actual Primary Completion Date: December 13, 2021
• Actual Study Completion Date: December 13, 2021

Arms and Interventions

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 Name: Not any

Outcome Measures

Primary Outcome Measures :

1. Number of participants with adverse events assessed by CTCAE [ Time Frame: 24 weeks ]
   Safety measured by adverse events, vital signs, physical exams, body weight, electrocardiograms (ECGs) and lab results (including hematology, chemistry and urinalysis)

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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:

  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.

Contacts and Locations

Locations

United States, Virginia

Virginia Commonwealth University

Richmond, Virginia, United States, 23298

Sponsors and Collaborators

Zydus Therapeutics Inc.

Investigators

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

More Information

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.

• Responsible Party: Zydus Therapeutics Inc.
• ClinicalTrials.gov Identifier: NCT03639623
• Other Study ID Numbers: SARO.17.010
• First Posted: August 21, 2018
• Last Update Posted: October 10, 2023
• Last Verified: October 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Zydus Therapeutics Inc.:

Peroxisome proliferator-activated receptors; NAFLD; NASH; Post Transplant Metabolic Syndrome

Additional relevant MeSH terms:

Non-alcoholic Fatty Liver Disease; Fatty Liver; Liver Diseases; Digestive System Diseases