Saroglitazar Magnesium in Patients With Nonalcoholic Fatty Liver Disease and/or Nonalcoholic Steatohepatitis

Phase 2

Completed

• Conditions: Nonalcoholic Steatohepatitis; Non-Alcoholic Fatty Liver Disease
• Interventions: Drug: Saroglitazar magnesium 1 mg; Drug: Saroglitazar magnesium 2 mg; Drug: Saroglitazar magnesium 4 mg; Drug: Placebos

• Registration Number: NCT03061721
• Lead Sponsor: Zydus Therapeutics Inc.

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2017-02-07
• Study First Submitted QC: 2017-02-17
• Study First Posted: 2017-02-23
• Study Start: 2017-04-06
• Primary Completion: 2019-08-22
• Study Completion: 2019-08-22
• Results First Submitted: 2024-07-16
• Status Verified: 2024-10
• Results First Submitted QC: 2024-10-21
• Last Update Submitted: 2024-10-21
• Results First Posted: 2024-10-24
• Last Update Posted: 2024-10-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 106

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Saroglitazar magnesium 1 mg	Saroglitazar magnesium 1 mg	Saroglitazar magnesium 1 mg tablet orally once daily in the morning before breakfast for 16 weeks.
Saroglitazar magnesium 2 mg	Saroglitazar magnesium 2 mg	Saroglitazar magnesium 2 mg tablet orally once daily in the morning before breakfast for 16 weeks.
Saroglitazar magnesium 4 mg	Saroglitazar magnesium 4 mg	Saroglitazar magnesium 4 mg tablet orally once daily in the morning before breakfast for 16 weeks.
Placebos	Placebos	Placebo tablet orally once daily in the morning before breakfast for 16 weeks.

Primary Outcome Measures

Name	Time	Method
Percentage Change From Baseline in Serum Alanine Aminotransferase (ALT) Levels at Week 16	Baseline and Week 16	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

Name	Time	Method
Change in Liver Fat Content as Measured by Magnetic Resonance Imaging-derived Proton Density-fat Fraction (MRI-PDFF)	Baseline and Week 16	Change in liver fat content as measured by magnetic resonance imaging-derived proton in Saroglitazar Magnesium groups as compared to the placebo group
Proportion of Patients With Sustain Decrease in Serum ALT Levels	Week 16	Proportion of patients with sustain decrease in serum ALT levels in Saroglitazar Magnesium groups as compared to the placebo group
Changes in Cytokeratin-18	baseline and Week 16	Changes in cytokeratin-18 in Saroglitazar Magnesium groups as compared to the placebo group
Changes in Enhanced Liver Fibrosis	baseline and Week 16	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
Change in Aspartate Aminotransferase-to-platelet Ratio Index	Baseline and Week 16	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
Pharmacokinetics of Saroglitazar Magnesium: Maximum Plasma Concentration (Cmax)	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)	Maximum plasma concentration (Cmax) of Saroglitazar
Time to Reach Maximum Plasma Concentration (Tmax)	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) of saroglitazar
Terminal Half-life (t1/2)	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) of saroglitazar
Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUC0-t)	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 last measurable concentration for saroglitazar
Area Under the Curve From the Time of Dosing to the Infinity (AUC 0-inf)	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) for Saroglitazar
Elimination Rate Constant (λz)	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)	Elimination rate constant (λz) for saroglitazar
Apparent Volume of Distribution (Vd/F)	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) for Saroglitazar
Apparent Clearance (CL/F)	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) for Saroglitazar
Change in Quality of Life Assessed by the Short-Form 36 Health Survey	baseline and 16 Week	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.
Safety and Tolerability of Saroglitazar Magnesium	Baseline to Week 17	Number of participants with adverse events

Trial Locations

Locations (17)

Precision Research; 🇺🇸 San Diego, California, United States

Cedars-Sinai Medical Center; 🇺🇸 Los Angeles, California, United States

Catalina Research Institute; 🇺🇸 Montclair, California, United States

California liver research institute; 🇺🇸 Pasadena, California, United States

University of Florida; 🇺🇸 Gainesville, Florida, United States

Schiff Center for Liver Diseases/University of Miami; 🇺🇸 Miami, Florida, United States

Avail Clinical Research; 🇺🇸 Orange City, Florida, United States

Indiana University; 🇺🇸 Indianapolis, Indiana, United States

Mercy Medical Center; 🇺🇸 Baltimore, Maryland, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

Awasty Research Network, LLC; 🇺🇸 Marion, Ohio, United States

Einstein Medical Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Gastro One; 🇺🇸 Germantown, Tennessee, United States

AIG Research; 🇺🇸 Hermitage, Tennessee, United States

Liver Consultants; 🇺🇸 Dallas, Texas, United States

The Liver Institute; 🇺🇸 San Antonio, Texas, United States

Swedish Medical Center; 🇺🇸 Seattle, Washington, United States