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

• ClinicalTrials.gov Identifier: NCT03061721
• Recruitment Status: Completed
• First Posted: February 23, 2017
• Last Update Posted: January 5, 2024
• Sponsor: Zydus Therapeutics Inc.
• Information provided by (Responsible Party): Zydus Therapeutics Inc.

Study Description

Brief Summary:

This is a randomized, double-blind, placebo-controlled study in up to 104 patients with a diagnosis of NAFLD and/or 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 ALT levels at Week 16 in the Saroglitazar Magnesium groups as compared to the placebo group.

Condition or disease	Intervention/treatment	Phase
Non-Alcoholic Fatty Liver Disease; Nonalcoholic Steatohepatitis	Drug: Saroglitazar magnesium 1 mg; Drug: Saroglitazar magnesium 2 mg; Drug: Saroglitazar magnesium 4 mg; Drug: Placebos	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 106 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: April 6, 2017
• Actual Primary Completion Date: October 30, 2020
• Actual Study Completion Date: December 15, 2020

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Percentage change from baseline in serum ALT levels at Week 16 [ Time Frame: 16 Weeks ]
   Percentage change from baseline in serum ALT levels at Week 16 in the Saroglitazar Magnesium groups as compared to the placebo group

Secondary Outcome Measures :

1. Change in liver fat content as measured by magnetic resonance imaging-derived proton density-fat fraction (MRI-PDFF) [ Time Frame: 16 Weeks ]
   Change in liver fat content as measured by magnetic resonance imaging-derived proton in Saroglitazar Magnesium groups as compared to the placebo group
2. Proportion of patients with sustain decrease in serum ALT levels [ Time Frame: 16 Weeks ]
   Proportion of patients with sustain decrease in serum ALT levels in Saroglitazar Magnesium groups as compared to the placebo group
3. Changes in cytokeratin-18 [ Time Frame: 16 Weeks ]
   Changes in cytokeratin-18 in Saroglitazar Magnesium groups as compared to the placebo group
4. Changes in enhanced liver fibrosis [ Time Frame: 16 Weeks ]
   Changes in enhanced liver fibrosis in Saroglitazar Magnesium groups as compared to the placebo group
5. Change in aspartate aminotransferase-to-platelet ratio index [ Time Frame: 16 Weeks ]
   Change in aspartate aminotransferase-to-platelet ratio index in Saroglitazar Magnesium groups as compared to the placebo group
6. Pharmacokinetics of Saroglitazar Magnesium: maximum plasma concentration (Cmax) [ Time Frame: 16 Weeks ]
   Maximum plasma concentration (Cmax) of Saroglitazar
7. Time to reach maximum plasma concentration (Tmax) [ Time Frame: 16 Week ]
   Time to reach maximum plasma concentration (Tmax) of saroglitazar
8. Terminal half life (t1/2) [ Time Frame: 16 Weeks ]
   Terminal half life (t1/2) of saroglitazar
9. Area under the curve from the time of dosing to the last measurable concentration (AUC0-t) [ Time Frame: 16 Week ]
   Area under the curve from the time of dosing to the last measurable concentration for saroglitazar
10. Area under the curve from the time of dosing to the infinity (AUC 0-inf) [ Time Frame: 16 Week ]
    Area under the curve from the time of dosing to the infinity (AUC 0-inf) for Saroglitazar
11. Elimination rate constant (λz) [ Time Frame: 16 Week ]
    Elimination rate constant (λz) for saroglitazar
12. Apparent volume of distribution (Vd/F) [ Time Frame: 16 Week ]
    Apparent volume of distribution (Vd/F) for Saroglitazar
13. Apparent clearance (CL/F) [ Time Frame: 16 Week ]
    Apparent clearance (CL/F) for Saroglitazar
14. Change in quality of life assessed by the Short-Form 36 Health Survey [ Time Frame: 16 Week ]
    Quality of life will be assessed by the Short-Form 36 Health Survey
15. Safety and tolerability of Saroglitazar Magnesium [ Time Frame: 16 Weeks ]
    Assessed by incidence of adverse events

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:

1. Males or females, 18 to 75 years of age, with body mass index (BMI) ≥ 25 kg/m2.
2. Documented diagnosis of NAFLD established either by imaging (ultrasound, CT scan or 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 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 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 TB 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 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).

Contacts and Locations

Locations

United States, California

Precision Research

Chula Vista, California, United States, 91910

Cedars-Sinai Medical Center

Los Angeles, California, United States, 90048

Catalina Research Institute

Montclair, California, United States, 91763

California liver research institute

Pasadena, California, United States, 91105

Precision Research

San Diego, California, United States, 92114

Medical Associates Research Group

San Diego, California, United States, 92123

United States, Florida

University of Florida

Gainesville, Florida, United States, 32601

Schiff Center for Liver Diseases/University of Miami

Miami, Florida, United States, 33136

Avail Clinical Research

Orange City, Florida, United States, 32763

United States, Indiana

Indiana University

Indianapolis, Indiana, United States, 46290

United States, Maryland

Mercy Medical Center

Baltimore, Maryland, United States, 21201

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109-5362

Henry Ford Hospital

Detroit, Michigan, United States, 48202

United States, Ohio

Awasty Research Network, LLC

Marion, Ohio, United States, 43302

United States, Pennsylvania

Einstein Medical Center

Philadelphia, Pennsylvania, United States, 19141

United States, Tennessee

Gastro One

Germantown, Tennessee, United States, 38138

AIG Research

Hermitage, Tennessee, United States, 37076

United States, Texas

Liver Consultants

Dallas, Texas, United States, 75246

The Liver Institute

San Antonio, Texas, United States, 78215

United States, Washington

Swedish Medical Center

Seattle, Washington, United States, 89104

Sponsors and Collaborators

Zydus Therapeutics Inc.

Investigators

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

  Study Documents (Full-Text)

Documents provided by Zydus Therapeutics Inc.:

Study Protocol  [PDF] March 26, 2018

Statistical Analysis Plan  [PDF] October 19, 2018

More Information

Additional Information:

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. 

Publications of Results:

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.

Other 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.

• Responsible Party: Zydus Therapeutics Inc.
• ClinicalTrials.gov Identifier: NCT03061721
• Other Study ID Numbers: SARO.16.005
• First Posted: February 23, 2017
• Last Update Posted: January 5, 2024
• Last Verified: December 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

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

Keywords provided by Zydus Therapeutics Inc.:

NASH; NAFLD; Saroglitazar

Additional relevant MeSH terms:

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