Clinical trial NCT03061721: Saroglitazar Magnesium in Patients With Nonalcoholic Fatty Liver Disease and/or Nonalcoholic Steatohepatitis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-Alcoholic Fatty Liver Disease
Nonalcoholic Steatohepatitis
Keywords: NASH
NAFLD
Saroglitazar
Lead sponsor: Zydus Therapeutics Inc.
Sponsor class: INDUSTRY
First posted: 2017-02-23
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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).

Primary outcomes:
measure: Percentage Change From Baseline in Serum Alanine Aminotransferase (ALT) Levels at Week 16
timeFrame: Baseline and Week 16
Secondary outcomes:
measure: Change in Liver Fat Content as Measured by Magnetic Resonance Imaging-derived Proton Density-fat Fraction (MRI-PDFF)
timeFrame: Baseline and Week 16
measure: Proportion of Patients With Sustain Decrease in Serum ALT Levels
timeFrame: Week 16
measure: Changes in Cytokeratin-18
timeFrame: baseline and Week 16
measure: Changes in Enhanced Liver Fibrosis
timeFrame: baseline and Week 16
measure: Change in Aspartate Aminotransferase-to-platelet Ratio Index
timeFrame: Baseline and Week 16
measure: Pharmacokinetics of Saroglitazar Magnesium: Maximum Plasma Concentration (Cmax)
timeFrame: 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)
measure: Time to Reach Maximum Plasma Concentration (Tmax)
timeFrame: 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)
measure: Terminal Half-life (t1/2)
timeFrame: 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)
measure: Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUC0-t)
timeFrame: 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)
measure: Area Under the Curve From the Time of Dosing to the Infinity (AUC 0-inf)
timeFrame: 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)
measure: Elimination Rate Constant (λz)
timeFrame: 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)
measure: Apparent Volume of Distribution (Vd/F)
timeFrame: 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)
measure: Apparent Clearance (CL/F)
timeFrame: 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)
measure: Change in Quality of Life Assessed by the Short-Form 36 Health Survey
timeFrame: baseline and 16 Week
measure: Safety and Tolerability of Saroglitazar Magnesium
timeFrame: Baseline to Week 17
Other outcomes:
Locations:
city: Chula Vista
country: United States
facility: Precision Research
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Montclair
country: United States
facility: Catalina Research Institute
state: California
city: Pasadena
country: United States
facility: California liver research institute
state: California
city: San Diego
country: United States
facility: Precision Research
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: Schiff Center for Liver Diseases/University of Miami
state: Florida
city: Orange City
country: United States
facility: Avail Clinical Research
state: Florida
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Baltimore
country: United States
facility: Mercy Medical Center
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Marion
country: United States
facility: Awasty Research Network, LLC
state: Ohio
city: Philadelphia
country: United States
facility: Einstein Medical Center
state: Pennsylvania
city: Germantown
country: United States
facility: Gastro One
state: Tennessee
city: Hermitage
country: United States
facility: AIG Research
state: Tennessee
city: Dallas
country: United States
facility: Liver Consultants
state: Texas
city: San Antonio
country: United States
facility: The Liver Institute
state: Texas
city: Seattle
country: United States
facility: Swedish Medical Center
state: Washington
Study officials:
affiliation: Zydus Therapeutics Inc.
name: Deven V Parmar, MD,FACP,FCP
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.