Saroglitazar Magnesium in Patients With Nonalcoholic Fatty Liver Disease and/or Nonalcoholic Steatohepatitis (EVIDENCES IV)

A Phase 2, Prospective, Multicenter, Double-blind, Randomized Study of Saroglitazar Magnesium 1 mg, 2 mg or 4 mg Versus Placebo in Patients With Nonalcoholic Fatty Liver Disease and/or Nonalcoholic Steatohepatitis

This is a randomized, double-blind, placebo-controlled study in up to 104 patients with a diagnosis of Non-alcoholic fatty Liver disease (NAFLD) and/or Non-alcoholic steatohepatitis (NASH). The study will be conducted over a period of up to 22 weeks and will include an optional Prescreening, Screening (Days -35 to -7) Phase, a 16-week Treatment Phase following randomization on Day 1. Patients will be randomly assigned in a ratio of 1:1:1:1 to receive Saroglitazar Magnesium 1mg or 2 mg or 4 mg or matching placebo once daily in the morning before breakfast for 16 Weeks. The primary endpoint of the study is percentage change from baseline in serum Alanine transaminase (ALT) levels at Week 16 in the Saroglitazar Magnesium groups as compared to the placebo group.

Study Overview

• Status: Completed
• Conditions: Nonalcoholic Steatohepatitis; Non-Alcoholic Fatty Liver Disease
• Intervention / Treatment: Drug: Saroglitazar magnesium 1 mg; Drug: Saroglitazar magnesium 2 mg; Drug: Saroglitazar magnesium 4 mg; Drug: Placebos

• Study Type: Interventional
• Enrollment (Actual): 106
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Chula Vista, California, United States, 91910
      • Precision Research
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Montclair, California, United States, 91763
      • Catalina Research Institute
    • Pasadena, California, United States, 91105
      • California Liver Research Institute
    • San Diego, California, United States, 92114
      • Precision Research
  • Florida
    • Gainesville, Florida, United States, 32601
      • University of Florida
    • Miami, Florida, United States, 33136
      • Schiff Center for Liver Diseases/University of Miami
    • Orange City, Florida, United States, 32763
      • Avail Clinical Research
  • Indiana
    • Indianapolis, Indiana, United States, 46290
      • Indiana University
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Mercy Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5362
      • University of Michigan
  • Ohio
    • Marion, Ohio, United States, 43302
      • Awasty Research Network, LLC
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19141
      • Einstein Medical Center
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Gastro One
    • Hermitage, Tennessee, United States, 37076
      • AIG Research
  • Texas
    • Dallas, Texas, United States, 75246
      • Liver Consultants
    • San Antonio, Texas, United States, 78215
      • The Liver Institute
  • Washington
    • Seattle, Washington, United States, 89104
      • Swedish Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Males or females, 18 to 75 years of age, with body mass index (BMI) ≥ 25 kg/m^2.
2. Documented diagnosis of NAFLD established either by imaging (ultrasound, computed tomography [CT] scan or Magnetic resonance imaging [MRI]) or liver biopsy showing NASH or simple steatosis, within the 24 months preceding Visit 1. The diagnosis of NAFLD is made according to the American Association for the Study of Liver Diseases (AASLD) criteria (Chalasani et al. Hepatology 2012; 55:2005-2023).
3. ALT level of ≥50 U/L at Visit 1 and Visit 2 with ≤30% variance between the levels at Visit 1 and Visit 2.
4. Patient's demonstration of understanding of study requirements and treatment procedures, willingness to comply with all protocol-required evaluations; provision of written informed consent before any study specific tests or procedures are performed.

Exclusion Criteria:

1. Consumption of > 3 units of alcohol per day (> 21 units per week) if male and > 2 units of alcohol per day (>14 units per week) if female for at least 3 consecutive months in the 5 years preceding Visit 1 (Note: 1 unit = 12 ounces of beer, 4 ounces of wine or 1 ounce of spirits/hard liquor).

2. Presence of alternative causes of fatty liver, including:

   1. Weight change >5% within the 3 months preceding Visit 1
   2. Total parenteral nutrition, starvation or protein-calorie malnutrition within the 90 days preceding Visit 1.
   3. Use of drugs associated with NAFLD for more than 12 consecutive weeks in the 1 year before Visit 1, including amiodarone, tamoxifen, methotrexate, systemic glucocorticoids, anabolic steroids, tetracycline, estrogens in doses higher than used in oral contraceptives, vitamin A, L asparaginase, valproate, chloroquine or antiretroviral drugs
3. Initiation of vitamin E at doses > 100 IU/day, or multivitamins containing > 100 IU/day of vitamin E in the 3 months preceding Visit 1.
4. Use of drugs with potential effect on NASH such as ursodeoxycholic acid, S-adenosylmethionine (SAM-e), betaine, pentoxifylline, obeticholic acid or milk thistle in the 3 months prior to Visit 1.
5. Changing doses of statins (simvastatin, pitavastatin, pravastatin, atorvastatin, fluvastatin, lovastatin, rosuvastatin) or fibrates (clofibrate, fenofibrate) in the 3 months preceding Visit 1.
6. Use of thiazolidinediones (pioglitazone, rosiglitazone).
7. Use of drugs that are known Cytochrome P4502C8 (CYP2C8) inhibitors/substrate
8. History of bowel surgery (gastrointestinal (bariatric) surgery or undergoing evaluation for bariatric surgery for obesity, extensive small-bowel resection or orthotopic liver transplant (OLT) or listed for OLT.
9. History of other chronic liver disease (chronic hepatitis C, (HCV) infection, irrespective of their mRNA HCV assay status or active hepatitis B infection, (i.e., serum positive for hepatitis B surface antigen) or autoimmune hepatitis, cholestatic and metabolic liver diseases) or hemochromatosis
10. Patient has known cirrhosis, either based on clinical criteria or liver histology.
11. Patient with Internation Normalised Ratio (INR) >1.3.
12. Type 1 diabetes mellitus.
13. Poorly controlled type 2 diabetes mellitus, i.e., glycosylated hemoglobin (HbA1c) > 9%.

14. Unstable cardiovascular disease, including:

    1. unstable angina, (i.e., new or worsening symptoms of coronary heart disease within the 3 months preceding Visit 1), acute coronary syndrome within the 6 months preceding Visit 1, acute myocardial infarction within the 3 months preceding Visit 1 or heart failure of New York Heart Association class (III - IV) or worsening congestive heart failure, or coronary artery intervention, within the 6 months preceding Visit 1
    2. history of (within 3 months preceding Visit 1) or current unstable cardiac dysrhythmias
    3. uncontrolled hypertension (systolic blood pressure [BP] > 160 mmHg and/or diastolic BP > 100 mmHg)
    4. stroke or transient ischemic attack within the 6 months preceding Visit 1.
15. History of myopathies or evidence of active muscle disease.
16. History of malignancy in the 5 years preceding Visit 1 and/or active neoplasm with the exception of resolved superficial nonmelanoma skin cancer.

17. Any of the following laboratory values:

    1. Hemoglobin < 9 g/dL
    2. White blood cell count < 2.5 × 103/μL
    3. Neutrophil count < 1.5 × 103/μL
    4. Platelets < 100 × 103/μL
    5. Total Serum bilirubin > 1.5 mg/dL (except in patient with known Gilbert bilirubin where Total Bilirubin up to 2.5 mg/dL is allowed), if it is <1.5 mg/dL at screening and >30% variance in the levels at Visit 1 and Visit 2
    6. Albumin < 3.2 g/dL
    7. Serum creatinine >1.5 mg/dL
    8. Serum ALT or Aspartate aminotransferase (AST) > 250 IU/L at Visit 1 or Visit 2 .
18. Contraindications to Saroglitazar Magnesium or has any conditions affecting the ability to evaluate the effects of Saroglitazar Magnesium.
19. Known allergy, sensitivity or intolerance to the study drug, placebo or formulation ingredients.
20. Participation in any other therapeutic clinical study within the 3 months preceding Visit 1, including participation in any other NAFLD/NASH clinical trials.
21. History of bladder disease and/or hematuria or has current hematuria except due to a urinary tract infection.
22. Illicit substance abuse within the 12 months preceding Visit 1.

23. Pregnancy-related exclusions, including:

    1. Pregnant/lactating female (including a positive serum pregnancy test at Visit 1)
    2. A male patient has to use a condom with spermicide, and the female partner of the male patient has to use an intrauterine device OR a diaphragm with spermicide OR oral contraceptive pills.
    3. If a male patient has undergone a vasectomy, the female partner does not have to use any contraception.
    4. A female patient has to use either an intrauterine device OR a diaphragm with spermicide OR oral contraceptive pills. The male partner of the female patient has to use a condom with spermicide.
    5. If the female patient is surgically sterilized for at least the 6 months preceding Visit 1 or postmenopausal, defined as at least 12 months with no menses and without an alternative cause, the male partner of the female patient does not have to use any contraception.
24. History or other evidence of severe illness or any other conditions that would make the patient, in the opinion of the investigator, unsuitable for the study (such as poorly controlled psychiatric disease, HIV, coronary artery disease or active gastrointestinal conditions that might interfere with drug absorption).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Saroglitazar magnesium 1 mg; Saroglitazar magnesium 1 mg tablet orally once daily in the morning before breakfast for 16 weeks.	Drug: Saroglitazar magnesium 1 mg; Patients randomly assigned to this group will receive Saroglitazar magnesium 1 mg tablet orally once daily for 16 weeks.
Experimental: Saroglitazar magnesium 2 mg; Saroglitazar magnesium 2 mg tablet orally once daily in the morning before breakfast for 16 weeks.	Drug: Saroglitazar magnesium 2 mg; Patients randomly assigned to this group will receive Saroglitazar magnesium 2 mg tablet orally once daily for 16 weeks.
Experimental: Saroglitazar magnesium 4 mg; Saroglitazar magnesium 4 mg tablet orally once daily in the morning before breakfast for 16 weeks.	Drug: Saroglitazar magnesium 4 mg; Patients randomly assigned to this group will receive Saroglitazar magnesium 4 mg tablet orally once daily for 16 weeks.
Placebo Comparator: Placebos; Placebo tablet orally once daily in the morning before breakfast for 16 weeks.	Drug: Placebos; Patients randomly assigned to this group will receive placebo tablet orally once daily for 16 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change From Baseline in Serum Alanine Aminotransferase (ALT) Levels at Week 16	Percentage change from baseline in serum ALT levels at Week 16 in the Saroglitazar Magnesium groups as compared to the placebo group	Baseline and Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Liver Fat Content as Measured by Magnetic Resonance Imaging-derived Proton Density-fat Fraction (MRI-PDFF)	Change in liver fat content as measured by magnetic resonance imaging-derived proton in Saroglitazar Magnesium groups as compared to the placebo group	Baseline and Week 16
Proportion of Patients With Sustain Decrease in Serum ALT Levels	Proportion of patients with sustain decrease in serum ALT levels in Saroglitazar Magnesium groups as compared to the placebo group	Week 16
Changes in Cytokeratin-18	Changes in cytokeratin-18 in Saroglitazar Magnesium groups as compared to the placebo group	baseline and Week 16
Changes in Enhanced Liver Fibrosis	Changes in enhanced liver fibrosis in Saroglitazar Magnesium groups as compared to the placebo group The ELF Score is a liver fibrosis score that is calculated by use of an algorithm: ELF score score = -7.412 + (ln(HA)*0.681) + (ln(P3NP)*0.775) + (ln(TIMP1)*0.494). HA=hyaluronic acid concentration P3NP=procollagen 3 amino terminal peptide concentration TIMP1=tissue inhibitor matrix metalloproteinase 1 concentration. All are measured in serum. The ELF score has been reported to show good correlations with fibrosis stages in chronic liver disease, with higher ELF scores associated with higher fibrosis stages. The ELF score is hence used as a prognostic marker for disease progression: ELF score < 9.8 : Low risk of progression, ELF score 9.8 to < 11.3 : Moderate risk of progression and ELF score > = 11.3 : High risk of progression	baseline and Week 16
Change in Aspartate Aminotransferase-to-platelet Ratio Index	Change in aspartate aminotransferase-to-platelet ratio index in Saroglitazar Magnesium groups as compared to the placebo group APRI was calculated as ([AST level/AST upper limit of normal]/ [Platelet count 1^09/L]) ×100, where AST is aspartate aminotransferase. The aspartate transaminase to platelet ratio index (APRI) is used to assess the risk of liver fibrosis. Higher APRI score represents a higher risk of liver fibrosis	Baseline and Week 16
Pharmacokinetics of Saroglitazar Magnesium: Maximum Plasma Concentration (Cmax)	Maximum plasma concentration (Cmax) of Saroglitazar	PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16)
Time to Reach Maximum Plasma Concentration (Tmax)	Time to reach maximum plasma concentration (Tmax) of saroglitazar	PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16)
Terminal Half-life (t1/2)	Terminal Half-life (t1/2) of saroglitazar	PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16)
Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUC0-t)	Area under the curve from the time of dosing to the last measurable concentration for saroglitazar	PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 3 (Week 0)
Area Under the Curve From the Time of Dosing to the Infinity (AUC 0-inf)	Area under the curve from the time of dosing to the infinity (AUC 0-inf) for Saroglitazar	PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 3 (Week 0)
Elimination Rate Constant (λz)	Elimination rate constant (λz) for saroglitazar	PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16)
Apparent Volume of Distribution (Vd/F)	Apparent volume of distribution (Vd/F) for Saroglitazar	PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16)
Apparent Clearance (CL/F)	Apparent clearance (CL/F) for Saroglitazar	PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16)
Change in Quality of Life Assessed by the Short-Form 36 Health Survey	Quality of life will be assessed by the Short-Form 36 Health Survey 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 worst health status.	baseline and 16 Week
Safety and Tolerability of Saroglitazar Magnesium	Number of participants with adverse events	Baseline to Week 17

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012 Jun;55(6):2005-23. doi: 10.1002/hep.25762. No abstract available.
• Gawrieh S, Noureddin M, Loo N, Mohseni R, Awasty V, Cusi K, Kowdley KV, Lai M, Schiff E, Parmar D, Patel P, Chalasani N. Saroglitazar, a PPAR-alpha/gamma Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial. Hepatology. 2021 Oct;74(4):1809-1824. doi: 10.1002/hep.31843. Epub 2021 Jul 19.

Helpful Links

• Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of
• Gawrieh S, Noureddin M, Loo N, Mohseni R, Awasty V, Cusi K, Kowdley KV, Lai M, Schiff E, Parmar D, Patel P, Chalasani N. Saroglitazar, a PPAR-alpha/gamma Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial.

Study record dates

Study Major Dates

• Study Start (Actual): April 6, 2017
• Primary Completion (Actual): August 22, 2019
• Study Completion (Actual): August 22, 2019

Study Registration Dates

• First Submitted: February 7, 2017
• First Submitted That Met QC Criteria: February 17, 2017
• First Posted (Actual): February 23, 2017

Study Record Updates

• Last Update Posted (Actual): October 24, 2024
• Last Update Submitted That Met QC Criteria: October 21, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: NAFLD; NASH; Saroglitazar
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: SARO.16.005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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