Study of Saroglitazar Magnesium for PBC Patients With Incomplete Response or Intolerant to UDCA Therapy

A Double-blind, Placebo-controlled, Randomized, Phase 3 Study to Evaluate the Efficacy and Safety of Saroglitazar Magnesium on Normalization of Alkaline Phosphatase Levels in Patients With Primary Biliary Cholangitis and an Incomplete Response or Intolerance to Ursodeoxycholic Acid

Study of Saroglitazar Magnesium for PBC Patients with Incomplete Response or Intolerant to UDCA Therapy

A Double-blind, Placebo-controlled, Randomized, Phase 3 Study to Evaluate the Efficacy of Saroglitazar Magnesium 1 mg on normalization of ALP in patients having ALP > ULN to < 1.67xULN and on Ursodeoxycholic Acid for 12 months or intolerant to Ursodeoxycholic Acid.

Inclusion Criteria:

1. Adults between 18 and 80 years of age (both inclusive at screening)
2. History of confirmed Primary Biliary Cholangitis diagnosis
3. Ursodeoxycholic acid treatment for at least 12 months and a stable dose for at least 6 months prior to first screening visit OR intolerant to Ursodeoxycholic acid (last dose of Ursodeoxycholic acid at least 3 months prior to first screening visit).
4. Average Alkaline Phosphatase at both screening Visits 1 and 2: > 1× Upper Limit of Normal and < 1.67× Upper Limit of Normal, and < 30% variance between both levels
5. Total bilirubin ≤ 2 x Upper Limit of Normal at screening (Visit 1), unless there is a prior diagnosis of Gilbert's syndrome. For participants with Gilbert's syndrome, direct bilirubin is to be ≤ 2 x Upper Limit of Normal at screening (Visit 1).
6. Must have given written informed consent (signed and dated).

Exclusion Criteria:

1. Consumption of 14 or more standard alcohol drinks per week if male and 7 or more standard alcohol drink per week if female for at least 3 consecutive months (i.e., 12 consecutive weeks) within 5 years before screening (Note: 1 unit = 12 ounces of beer, 4 ounces of wine or 1 ounce of spirits/hard liquor).

2. History or presence of other concomitant liver diseases at screening

3. Cirrhosis with complications, including history or presence of the following: spontaneous bacterial peritonitis, hepatocellular carcinoma, ascites requiring treatment, encephalopathy, known large esophageal varices, or history of variceal bleeding within one year prior to screening or history of hepatorenal syndrome.

4. Medical conditions that may cause non-hepatic increases in Alkaline Phosphatase (e.g., Paget's disease) or which may diminish life expectancy to < 2 years, including known cancers.

5. Use of obeticholic acid, thiazolidinediones, fibrates (i.e. fenofibrate, bezafibrate, pemafibrate), other Peroxisome Proliferator-Activated Receptor agonists (i.e., seladelpar, elafibranor, lanifibranor), azathioprine, cyclosporine, methotrexate, mycophenolate, pentoxifylline, systemic corticosteroids (equivalent to prednisone dose more than 10 mg per day); potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazid, or nitrofurantoin) (within 12 weeks prior to screening).

6. History of bowel surgery (gastrointestinal [bariatric] surgery in the preceding 1 year or undergoing evaluation for gastrointestinal surgery (bariatric surgery for obesity, extensive small-bowel resection) or orthotopic liver transplant or listed for orthotopic liver transplant.

7. Type 1 diabetes mellitus.

8. Unstable cardiovascular disease

9. History of intracranial hemorrhage, arteriovenous malformation, bleeding disorder, coagulation disorders, or screening blood tests that, in the opinion of the Investigator, indicate clinically significant altered coagulability (e.g., Prothrombin Time, International Normalized Ratio, Activated partial thromboplastin time) at screening.

10. An uncontrolled thyroid disorder

11. History of myopathies or evidence of active muscle disease demonstrated by Creatine Phosphokinase ≥ 5 x Upper Limit of Normal at screening.

12. For subjects with elevated baseline Alanine Aminotransferase or Aspartate Aminotransferase; Alanine Aminotransferase or Aspartate Aminotransferase exceeding by more than 50% on Visit 2 compared to Visit 1.

13. Any of the following laboratory values at screening:

    1. Platelets < 100 × 10^9/L
    2. Albumin < 3.5 g/dL
    3. Estimated Glomerular Filtration Rate < 45 mL/min/1.73 m^2
    4. Alanine Aminotransferase or Aspartate Aminotransferase > 250 U/L
    5. International Normalized Ratio greater than or equal to 1.7. However, participants with an International Normalized Ratio of 1.7 or above may be included if the elevated International Normalized Ratio is not attributable to liver disease.

14. Participation in another interventional clinical study and receipt of any other investigational medication (within 12 weeks prior to randomization up to the end of the study).

15. History of malignancy in the past 5 years and/or active neoplasm except resolved superficial non-melanoma skin cancer.

16. Contraindications to Saroglitazar Magnesium or has any conditions affecting the ability to evaluate the effects of Saroglitazar Magnesium.

17. Known allergy, sensitivity, or intolerance to the study medication, comparator, or formulation ingredients.

18. Pregnancy-related exclusions, including the following:

    1. Pregnant/lactating female (including positive pregnancy test at screening).
    2. Pregnancy should be avoided by male and female participants either by true abstinence or the use of acceptable effective contraceptive measures for the duration of the study and for at least 1 month after the end of the study treatment.

19. History or other evidence of severe illness or any other conditions that would make the participant, in the opinion of the Investigator, unsuitable for the study (such as poorly controlled psychiatric disease, Human Immunodeficiency Virus, coronary artery disease, or active gastrointestinal conditions that might interfere with drug absorption).

20. Cirrhosis with Child-Pugh-Turcotte Class B or C having a score of 7 or above at screening.

21. Participants with Model for End Stage Liver Disease 3.0 score of 12 or above. For participants on anticoagulation medication, baseline International Normalized Ratio determination for Model for End Stage Liver Disease score calculation should take anticoagulant use into account.

22. Initiation or dose adjustment of anti-pruritic drugs (e.g., cholestyramine, naltrexone, rifampin, sertraline, or any investigational therapeutic) within 1 month prior to screening and till randomization.