Safety, Tolerability, and Efficacy of Saroglitazar Mg 4 mg in Liver Transplant Recipients With Nonalcoholic Fatty Liver Disease (NAFLD)
- Registration Number
- NCT03639623
- Lead Sponsor
- Zydus Therapeutics Inc.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 20
- 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.
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Pregnant or lactating females.
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Patient with abnormal transaminases due to secondary intercurrent illness.
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Patients with bile duct strictures.
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Other causes of chronic liver disease after liver transplantation including autoimmune, viral, and alcoholic liver disease.
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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.
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Body mass index (BMI) <18 kg/m².
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Subjects with change in body weight >5% in the 3 months prior to enrollment.
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Subjects requiring corticosteroid or anticoagulation therapy.
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History of myopathies or evidence of active muscle diseases.
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Unstable cardiovascular disease.
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History of bladder disease and/or hematuria or has current hematuria unless due to a urinary tract infection.
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Active malignancy post-liver transplantation.
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History of malignancy in the past 5 years and/or active neoplasm.
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History of chronic rejection of liver transplant graft.
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Acute cellular rejection of liver transplant graft within the past 6 months.
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Evidence of Acute cellular rejection (ACR) or chronic rejection (CR) or alternative etiologies to NAFLD.
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Poorly controlled diabetes as defined by an HbA1c >8.5% within the past 6 months.
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History of excessive alcohol intake.
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Subject tests positive for a urine drug screen.
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Subject has a history of chronic (uncontrolled) pain.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Saroglitazar Magnesium 4 mg Saroglitazar Saroglitazar Magnesium tablet once daily in the morning 60 minutes before breakfast
- Primary Outcome Measures
Name Time Method Number of Participants With Adverse Events Assessed by CTCAE 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
Name Time Method Very Low-density Lipoprotein (Atherogenic Lipoprotein) Baseline and Week 24 Changes in subtypes of very low-density lipoprotein (VLDL) from baseline to EOT
Very Low-density Lipoprotein Chylomicron Triglyceride (Atherogenic Lipoprotein) Baseline and Week 24 Changes in VLDL chylomicron triglyceride from baseline to EOT
Hepatic Fat Baseline and week 24 Changes in hepatic fat as determined by MRI-PDFF from baseline to end-of-treatment (EOT)
Liver Stiffness Baseline and Week 24 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.
Frequently Sampled Intravenous Glucose Tolerance Test (Insulin Resistance Marker) Baseline and Week 24 Changes in frequently sampled intravenous glucose tolerance test (FSIVGTT) from baseline to EOT
Glycosylated Hemoglobin (Insulin Resistance Marker) Baseline and Week 24 Changes in glycosylated hemoglobin (HbA1c) from baseline to EOT
Fructosamine (Insulin Resistance Marker) Baseline and Week 24 Changes in fructosamine from baseline to EOT
Serum Liver Enzymes Baseline and Week 24 Changes in serum liver enzymes from baseline to EOT
Serum Liver Enzymes; Bilirubin Baseline and Week 24 Changes in bilirubin from baseline to EOT
Serum Lipids Baseline and Week 24 Changes in serum lipids from baseline to EOT
Small Dense Low-density Lipoprotein (Atherogenic Lipoprotein) Baseline and Week 24 Changes in small dense low-density lipoprotein (sdLDL) from baseline to EOT
LDL Size (Atherogenic Lipoprotein) Baseline and Week 24 Changes in LDL size from baseline to EOT
LDL Concentration (Atherogenic Lipoprotein) Baseline and Week 24 Changes in LDL concentration from baseline to EOT
High-density Lipoprotein (Atherogenic Lipoprotein) Baseline and Week 24 Changes in high-density lipoprotein (HDL) from baseline to EOT
Change in Metabolic Flexibility; Time to Peak RQ Baseline and Week 24 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.Quality of Life (SF-36 Health Survey) Baseline and Week 24 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
Peak Plasma Concentration [Cmax] 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 Pharmacokinetics of Saroglitazar following first and last dose.
Time to Reach Peak Plasma Concentration [Tmax] 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 Pharmacokinetics of Saroglitazar following first and last dose
Area Under Plasma Concentration vs. Time Curve Till the Last Time Point [AUC0-t] 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 Pharmacokinetics of Saroglitazar
Area Under Plasma Concentration vs. Time Curve Extrapolated to the Infinity [AUC0-∞] 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 Pharmacokinetics of Saroglitazar
Area Under Plasma Concentration vs. Time Curve in a 24 h Dosing Interval [AUCtau] 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 Pharmacokinetics of Saroglitazar
Elimination Rate Constant [λz] 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 Pharmacokinetics of Saroglitazar
Elimination Half-life [t1/2] 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 Pharmacokinetics of Saroglitazar
Apparent Volume of Distribution [Vd/F] 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 Pharmacokinetics of Saroglitazar
Apparent Clearance [CL/F] 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 Pharmacokinetics of Saroglitazar
Minimal or Trough Plasma Concentration [Cmin] 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 Pharmacokinetics of Saroglitazar
Accumulation Index Calculated as a Ratio of AUCtau (Last Dose)/AUCtau (First 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 Pharmacokinetics of Saroglitazar
Fluctuation Index 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 Fluctuation index is the peak trough fluctuation within complete dosing interval at steady state, calculated as PTF (%) = (\[Cmax - Cmin\]/Cav ) multiplied by 100
Trial Locations
- Locations (1)
Virginia Commonwealth University
🇺🇸Richmond, Virginia, United States