Clinical trial NCT03061721 (phase 2, status: completed)
Conditions: non-alcoholic fatty liver disease, nonalcoholic steatohepatitis
ICD codes: Z52.6, K71.8, K71.7, A06.4, C22.0, C22.3, K70.0, K75.81
Drugs: saroglitazar magnesium 1 mg, saroglitazar magnesium 2 mg, saroglitazar magnesium 4 mg, placebos
SMILES: CCO[C@@H](CC1=CC=C(OCCN2C(C)=CC=C2C2=CC=C(SC)C=C2)C=C1)C(O)=O, CCO[C@@H](CC1=CC=C(OCCN2C(C)=CC=C2C2=CC=C(SC)C=C2)C=C1)C(O)=O, CCO[C@@H](CC1=CC=C(OCCN2C(C)=CC=C2C2=CC=C(SC)C=C2)C=C1)C(O)=O, COCCC1=CC=C(OCC(O)CNC(C)C)C=C1
Eligibility 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).