Clinical trial NCT03639623: Safety, Tolerability, and Efficacy of Saroglitazar Mg 4 mg in Liver Transplant Recipients With Nonalcoholic Fatty Liver Disease (NAFLD)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Liver Transplant; Complications
NAFLD
Keywords: Peroxisome proliferator-activated receptors
NAFLD
NASH
Post Transplant Metabolic Syndrome
Lead sponsor: Zydus Therapeutics Inc.
Sponsor class: INDUSTRY
First posted: 2018-08-21
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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 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.

Primary outcomes:
measure: Number of Participants With Adverse Events Assessed by CTCAE
timeFrame: 24 weeks
Secondary outcomes:
measure: Hepatic Fat
timeFrame: Baseline and week 24
measure: Liver Stiffness
timeFrame: Baseline and Week 24
measure: Frequently Sampled Intravenous Glucose Tolerance Test (Insulin Resistance Marker)
timeFrame: Baseline and Week 24
measure: Glycosylated Hemoglobin (Insulin Resistance Marker)
timeFrame: Baseline and Week 24
measure: Fructosamine (Insulin Resistance Marker)
timeFrame: Baseline and Week 24
measure: Serum Liver Enzymes
timeFrame: Baseline and Week 24
measure: Serum Liver Enzymes; Bilirubin
timeFrame: Baseline and Week 24
measure: Serum Lipids
timeFrame: Baseline and Week 24
measure: Small Dense Low-density Lipoprotein (Atherogenic Lipoprotein)
timeFrame: Baseline and Week 24
measure: LDL Size (Atherogenic Lipoprotein)
timeFrame: Baseline and Week 24
measure: LDL Concentration (Atherogenic Lipoprotein)
timeFrame: Baseline and Week 24
measure: Very Low-density Lipoprotein (Atherogenic Lipoprotein)
timeFrame: Baseline and Week 24
measure: Very Low-density Lipoprotein Chylomicron Triglyceride (Atherogenic Lipoprotein)
timeFrame: Baseline and Week 24
measure: High-density Lipoprotein (Atherogenic Lipoprotein)
timeFrame: Baseline and Week 24
measure: Change in Metabolic Flexibility; Time to Peak RQ
timeFrame: Baseline and Week 24
measure: Quality of Life (SF-36 Health Survey)
timeFrame: Baseline and Week 24
measure: Peak Plasma Concentration [Cmax]
timeFrame: 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
measure: Time to Reach Peak Plasma Concentration [Tmax]
timeFrame: 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
measure: Area Under Plasma Concentration vs. Time Curve Till the Last Time Point [AUC0-t]
timeFrame: 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
measure: Area Under Plasma Concentration vs. Time Curve Extrapolated to the Infinity [AUC0-∞]
timeFrame: 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
measure: Area Under Plasma Concentration vs. Time Curve in a 24 h Dosing Interval [AUCtau]
timeFrame: 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
measure: Elimination Rate Constant [λz]
timeFrame: 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
measure: Elimination Half-life [t1/2]
timeFrame: 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
measure: Apparent Volume of Distribution [Vd/F]
timeFrame: 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
measure: Apparent Clearance [CL/F]
timeFrame: 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
measure: Minimal or Trough Plasma Concentration [Cmin]
timeFrame: 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
measure: Accumulation Index Calculated as a Ratio of AUCtau (Last Dose)/AUCtau (First Dose)
timeFrame: 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
measure: Fluctuation Index
timeFrame: 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
Other outcomes:
Locations:
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: Zydus Therapeutics Inc.
name: Deven Parmar, MD FCP
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.